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Magnetic nanoparticles in theranostics of malignant melanoma

Abstract

Malignant melanoma is an aggressive tumor with a tendency to metastasize early and with an increasing incidence worldwide. Although in early stage, melanoma is well treatable by excision, the chances of cure and thus the survival rate decrease dramatically after metastatic spread. Conventional treatment options for advanced disease include surgical resection of metastases, chemotherapy, radiation, targeted therapy and immunotherapy. Today, targeted kinase inhibitors and immune checkpoint blockers have for the most part replaced less effective chemotherapies. Magnetic nanoparticles as novel agents for theranostic purposes have great potential in the treatment of metastatic melanoma. In the present review, we provide a brief overview of treatment options for malignant melanoma with different magnetic nanocarriers for theranostics. We also discuss current efforts of designing magnetic particles for combined, multimodal therapies (e.g., chemotherapy, immunotherapy) for malignant melanoma.

Introduction

Cutaneous melanoma (CM) is a tumor of the skin accounting only for approximately 4% of all skin tumors, but it causes most skin-cancer-related deaths [1]. The incidence of CM is growing and has drastically increased especially in the last 50 years when compared to other malignant tumors [2]. For 2021, 5.8% more newly diagnosed cases and 4.8% more deaths are expected in the USA. CM is a highly aggressive tumor with a propensity to metastasize early. The relative 5-year survival rate based on the time of initial diagnosis is 99% for localized CM, but decreases to 66% and 27% after regional spread and distant metastasis, respectively (American Cancer Society. Cancer Facts & Figs. 2021. Atlanta: American Cancer Society; 2021).

Melanoma develops from melanocytes which are neural crest-derived pigmented cells mainly found in the dermoepidermal junction and hair follicle [3]. Several factors can contribute to the transformation of melanocytes, but exposure to ultraviolet (UV) radiation is thought to be the predominant environmental risk factor [4]. This includes recurrent sunburns and frequent and extensive sunbathing [5] by indoor tanning, in particular in younger age-groups (< 30 years) [6]. Consistent with this, CM compared to other tumor entities is characterized by a high mutational burden with typical UV signatures [7, 8]. Other risk factors include a fair skin phenotype (fair complexion, blond or red hair, blue eyes, tendency to freckle) [9], the number and type of naevi [10, 11], and a personal or family history of melanoma [1214].

For a long period of time, only few therapeutic options, including surgery, chemo- and radiotherapies, the development of immune checkpoint inhibitors and targeted therapies have significantly improved the outcome of CM. Yet, up to 50% of all metastatic patients do not benefit from modern melanoma therapy due to primary or secondary resistance. The current strategy is to overcome these problems with combined therapies that facilitate known and new molecular melanoma vulnerabilities. In addition to new therapeutic approaches, this requires a profound knowledge of the regulation of the immune system such as mechanisms that induce tolerance and suppression or activate effector cells as well as of key signaling pathways in melanoma biology [1522].

In recent decades, nanoparticles (NPs) have emerged as a new theranostic modality for the treatment of melanoma patients [23]. Employment of nanotechnologies has greatly improved the early diagnosis and the therapy of cancer by providing novel strategies for a targeted delivery of anti-tumor agents (e.g., drugs, anti-proliferative proteins, etc.), and genes to the site of tumor [2426]. Nanoscale agents can originate from inorganic (e.g., iron, superparamagnetic iron oxide, gold, mesoporous silica, graphene and carbon, etc.) and organic nanomaterials (e.g., lipids, proteins, silica, carbohydrates, etc.) of various formulations and shapes (e.g., spheres, nanotubes, quantum dots) [2740]. Among the proposed nanocarriers, metal-based NPs, particularly magnetic nanoparticles (MNPs), gained much attention due to their beneficial physicochemical properties.

Among other properties of MNPs, excellent magnetic contrast-enhancing properties, biodegradability and biocompatibility gained specific interest in clinical oncology [41, 42]. Thus, magnetic particles could significantly improve the magnetic resonance contrast enhancement of the tumors when being applied as T2 contrast agents [43, 44]. Additionally, MNPs could be used either for heating of the tumors in an alternating electromagnetic field (AMF) or for a targeted delivery of anti-tumor agents [45, 46]. The clinical relevance of MNPs is further supported by the fact that several iron oxide nanoparticle formulations have been approved by the Food and Drug Administration (FDA) as MR contrast agents, including Feridex IV® for detection of liver lesions and Combidex® for visualization of lymph nodes metastasis [47, 48]. Recent advances in the physicochemical formulations of NPs including surface modifications such as binding of various tumor-homing ligands (e.g., antibodies, Fab-fragments, peptides, etc.) have significantly broadened the potential of MNPs application in translational and clinical dermato-oncology.

In the current review, the application of NPs for diagnosis and therapy of malignant melanoma is discussed with a special focus on translational studies. Additionally, we describe currently applied combined therapeutic approaches of MNPs together with other treatment modalities.

Current treatment strategies of malignant melanoma

Depending on a histopathological combination of tumor thickness with or without ulceration, and the presence of local, lymph node or distant metastasis (TNM system), the American Joint Committee on Cancer (AJCC) classified melanoma in five different stages [49], which are important for treatment decisions. The prognosis worsens with increasing stage, it starts with stage 0, the melanoma in situ, which is restricted to the epidermis without any indication of invasion, and ends with stage 4, advanced malignant melanoma, which has already spread to distant parts of the body [49, 50]. While early disease is limited to the epidermis (melanoma in situ, “Tis”) and most melanomas with a tumor thickness of less than 1 mm can be cured surgically, metastatic disease requires multidisciplinary treatment approaches.

For a long time, surgery, chemotherapy and radiation were the only available therapeutic options, but in most cases response rates were low and patients with advanced tumor stages had a short life expectancy [51]. The cytostatic drug dacarbazine, approved in 1974 by the FDA (Table 1), has long been used for systemic treatment of metastatic melanoma, but with low response rates and without improvements in overall survival [52, 53]. Immunotherapies with interferon (IFN)α-2b and interleukin (IL)-2 also failed to result in high response rates [54, 55]. However, anti-tumor effects have been reported for both cytokines [56, 57], and both cytokines are presently still used in combination with other treatment modalities in clinical trials (Clinical trials.gov). An improved pathomechanistic understanding has led to a paradigm shift in the last 10 years, and treatment options for malignant melanoma dramatically changed due to the development of new innovative systemic and local therapies. The use of immune checkpoint inhibitors on the one hand and the targeted treatment of tumor-specific genetic alterations with kinase inhibitors on the other hand significantly contributed to this success.

Table 1 FDA-approved drugs for the treatment of metastatic melanoma

Immune checkpoint inhibitor therapies

Immune checkpoints are important regulatory elements of the immune system. As gatekeepers, they prevent overshooting and autoreactive immune responses by a mechanism dependent on a ligand-induced signaling. In 2011, the FDA approved the first checkpoint inhibitor (ICI) ipilimumab for the treatment of metastatic melanoma (Table 1). Ipilimumab is a human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a surface molecule expressed on T cells after T cell receptor (TCR) engagement [58]. Checkpoint inhibitor binding to CTLA-4 prevents a negative feedback loop and maintains T cells in an activated, proliferating state. Although the response rate to anti-CTLA-4 monotherapy was generally low, in case of a response it was long-lasting and significantly increased overall survival [59, 60]. The disadvantage of this non-specific treatment with anti-CTLA-4 is several immune-related adverse events (irAEs) [59, 61]. Approvals for other ICIs such as programmed cell death protein 1 (PD-1) blocking antibodies nivolumab and pembrolizumab followed in 2014 (Table 1). Compared to CTLA-4, PD-1 is also expressed on activated T cells and NK cells, at a lower density in primary lymphoid tissues, but in the periphery [62]. Compared to ipilimumab, the PD-1 inhibitors reached even higher overall response rates of 30–40% [63], with less irAEs and longer relapse-free and overall survival rates [64, 65]. Currently, for patients with unresectable metastatic melanoma anti-PD-1 blockage alone or in combination with CTLA-4 blockage is recommended and approved as a first-line treatment [50]. Unfortunately, a large proportion of patients still does not benefit from ICIs because they either initially do not respond or develop resistances during the course of treatment [64, 66, 67]. The reasons for this are complex and include immunosuppressive factors of the tumor microenvironment, immune editing, lack of neoantigens, loss of antigen presentation, heterogeneity of the melanoma tumor cells and an impaired function of tumor-infiltrating T and NK cells [64, 6875]. A summary of FDA-approved therapy options for metastatic melanoma is shown in Table 1.

Targeted therapies

With a high mutational burden [7], CM provides a wide-ranging landscape of genomic alterations. Mutations in the mitogen-activated protein kinase (MAPK) signaling pathway are among the most common genetic alterations in CM. MAPK signaling cascades are evolutionarily conserved, complex pathways that transfer extracellular signals to intracellular responses, thereby controlling many cellular processes, including proliferation, differentiation, migration and apoptosis [76]. Three MAPK cascades—the extracellular signal-regulated kinases (ERK), p38 MAPK and c-Jun-N-terminal kinase (JNK)—have been intensively studied in mammalian cells, in which the binding of an extracellular signal to a membrane-bound receptor activates a multistep phosphorylation pathway. In the ERK1/2 pathway, this is the RAS-RAF-MEK-ERK cascade, initially activated by the binding of a mitogenic factor to its receptor. Dysregulation of the ERK1/2 pathway mainly due to an activation of genetic alterations is most often involved in oncogenesis [77] and is associated with an increase in the growth and proliferation of tumor cells [78, 79]. In melanoma, this is of particular interest, as about 50% of the melanomas show mutations in BRAF (a member of the RAF family), about 25% show mutations in NRAS (a member of the Ras family) [80, 81] and around 15% have mutations in NF1 (neurofibromin), a tumor suppressor that negatively regulates Ras. Based on these most commonly mutated genes, The Cancer Genome Atlas (TCGA) Network established a genomic classification of melanoma into four subtypes: mutant BRAF, mutant NRAS, mutant NF1 and triple wildtype [82]. About 90% of BRAF mutations in CM involve amino acid 600 with an exchange of valine to glutamic acid (BRAfV600E), resulting in an enhanced, Ras-independent activation of MEK [83] and an increased proliferation of the affected cells. With Vemurafenib, a sulfonamide that selectively inhibits the BRAFV600E kinase, the first BRAF inhibitor for unresectable or metastatic melanoma was approved in 2011 [8486]. Dabrafenib, a second-line BRAFV600E-specific kinase inhibitor followed shortly afterward [87, 88] (Table 1). Although the treatment initially showed promising therapeutic effects (even complete remissions), relapses occurred within 8–12 months due to (mainly secondary) resistance mechanisms with alterations leading to reactivation of the MAPK pathway [84, 87, 89]. Furthermore, about 10% of patients did not respond to the drug at all due to an intrinsic, primary resistance [90]. To counteract this effect, a combination of inhibitors targeting BRAF and MEK, the downstream kinase of BRAF, was tested. Trametinib, a MEK inhibitor licensed in 2013 for monotherapy, was approved in 2014 for the combined treatment with dabrafenib [91], others followed in 2015 (vemurafenib and cobimetinib) [92] and in 2018 (encorafenib and binimetinib) [93] (Table 1).

Combination of checkpoint inhibitor and targeted therapy

Interestingly, BRAF inhibitors also seem to have immunomodulatory properties by impacting melanoma antigen presentation [94], tumor-infiltrating T cells [95] and cytokines indicative for immune response [96], suggesting that the tumor microenvironment is less immunosuppressive under this treatment regimen. Based on this, ICIs have been combined with targeted therapies. The combination with atezolimab (anti-PD-1 antibody) plus cobimetinib and vemurafenib showed a significant improvement compared to targeted therapy alone and was approved for the treatment of BRAFV600E-positive patients with metastatic melanoma by the FDA in 2020 (Table 1). Today, it still remains unclear which patients benefit most from a triple therapy consisting of BRAF plus MEK plus PD-1 inhibition and whether this treatment is superior to a combined PD-1 and CTLA-4 checkpoint blockade. Significant treatment-related side effects also limit the use of combined targeted and immunotherapy.

Oncolytic virus therapy

In 2015, the FDA approved a therapy with modified herpes simplex virus type I, talimogene laherparepvec (T-VEC), for melanoma patients with locally advanced disease. T-VEC lacks a virulence gene, an immunogenicity gene but contains a gene to express the human granulocyte macrophage colony-stimulating factor (GM-CSF) [97] (Table 1). T-VEC is injected directly into metastatic lesions, where the virus selectively replicates in tumor cells, causing them to lyse, while healthy tissue remains unaffected. A systemic immune response is also induced by tumor cell lysis [97]. The treatment resulted in improved durable responses, objective response rates and progression-free survival in a randomized phase III clinical trial for patients with locally advanced melanoma [98, 99], although overall survival was not improved. In most cases, only injected lesions responded to therapy. Thus, T-VEC has to be considered as a local treatment.

Considering the increasing incidence and aggressiveness of melanoma, prevention and early diagnosis are key for combating melanoma. Nevertheless, approximately 10% of patients already have advanced, metastatic melanoma at first diagnosis. Furthermore, a large proportion of affected patients currently do not benefit from the available therapies and it remains challenging to develop more effective approaches. Figure 1 provides a schematic overview of presently FDA-approved treatment options including targeted therapy, chemotherapy, virotherapy and immunotherapy for patients with malignant melanoma. Significant progress in nanotechnology has already been made with the emerging of new biomedical nanoplatforms, particularly in the development of MNPs that can be applied for theranostic purposes in melanoma. Currently, the NIH database of the U.S. National library of Medicine (ClinicalTrials.gov) lists only 10 clinical trials worldwide using NPs for the treatment and/or diagnostics of malignant melanoma (Table 2) [100104]. Due to their unique intrinsic physicochemical properties, MNPs can be used for imaging and therapy after coating with dyes, radionuclides, antibodies, drugs, etc.; drug release and positioning of the MNPs can be controlled in a localized magnetic field; different modes of cell death (e.g., ferroptosis) and thermotherapy can be induced in an alternating electromagnetic field (Fig. 2). Tailoring of extrinsic properties of NPs by introducing biocompatible and biodegradable coatings, surface modifications with various bioligands, incorporation of various molecules with diagnostic and therapeutic properties can increase their tumor-targeting (and thus decrease off-target side effects) and theranostic potential.

Fig. 1
figure 1

Schematic overview of currently applied therapies for the treatment of malignant melanoma. Abbreviations: T: T cells; APC: antigen-presenting cell; CTLA-4: cytotoxic T-lymphocyte-associated protein-4; PD-1: programmed cell death protein 1; PD-L1: PD ligand 1; i: inhibitor

Table 2 Clinical trials using nanoparticles with melanoma patients
Fig. 2
figure 2

Schematic representation of magnetic nanoparticle and its application in melanoma theranostics

Nanoparticles in melanoma theranostics

Basic principles of nanomaterials

Organic and inorganic nanomaterials can improve diagnosis and therapy of melanomas. Liposomes with a high biocompatibility can be utilized as drug vehicles for a targeted delivery of anti-tumor agents, while sparing normal tissues [105]. Changing the composition, size, shape and load of NPs can alter tissue specificity, pharmacokinetics and tumor-homing capacity of NPs [23]. Inorganic (e.g., metal- or non-metal-based) nanomaterials harbor theranostic potential: On the one hand, they can be used as vehicles for drug delivery; on the other hand, they improve the monitoring of response of a tumor toward a drug by utilizing its imaging properties in MR [43, 44, 47]. Coating of NPs with biological materials is able to improve biocompatibility of metal-based nanomaterials in vivo. Functionalization of NPs with tumor-specific antibodies, proteins, peptides, enzymes [34], dyes, radionuclides, etc., enhances their efficacy and tumor-specific targeting. Due to their conductivity properties, metal-based nanomaterials are able to induce local hyperthermia at the site of the tumor [46] (Table 3).

Table 3 Magnetic nanoparticles in melanoma theranostics

Magnetic hyperthermia (MH)

Magnetic NPs typically consist of an iron oxide core (including magnetite (Fe3O4), hematite (α-Fe2O3) and maghemite (γ-Fe2O3 and β-Fe2O3)) coated with biocompatible and biodegradable polymers (e.g., dextran, polyethylene glycol (PEG), polylactic-co-glycolic acid (PLGA), etc.). Due to their magnetic properties, NPs can be employed for thermotherapy via an increase in the temperature inside the tumor (ranging from 41 to 46 °C) and an induction of apoptotic signaling cascades [106]. Additionally, the rise in temperature alters the enzymatic activity and structure of numerous proteins and affects the synthesis of the nucleic acids that in turn impairs cell differentiation and proliferation [107110]. A further increase in the temperature (above 50 °C), that is employed for thermal ablation, results in irreversible cellular damage due to coagulation and necrosis [68, 69].

When exposed to an external alternating magnetic field, magnetic particles generate the heat via the mechanisms of hysteresis loss and Brownian and Néel relaxation [111, 112]. Indeed, several preclinical studies reported the efficacy of the MH in melanoma treatment [113115]. Thus, highly focalized thermotherapy in the B16F10 melanoma model in C57/Bl6 mice inhibited the tumor growth by 70% as compared to a sham-treated control group [115]. Intriguingly, in another study MH resulted in a decrease in transforming growth factor (TGF)-β(1) protein expression that also might have an impact on the tumor progression [114].

One of the future efforts in the application of MH in melanoma treatment could be based on the immunostimulatory effects of hyperthermia. As shown by Duval et al., modest magnetic hyperthermia of B16 melanoma cells induced the expression of various immunogenic genes including heat shock protein (Hsp)70, CXCR3, and innate immune activators Toll-like receptor (TLR)3, TLR4 [116]. Further in vivo studies demonstrated that localized MH strongly correlated with the expression of Hsp70 in the tumor and the influx of activated cytotoxic CD8+ T lymphocytes [45, 117]. Presumably, combination of MH with other immunotherapeutic approaches might have a synergistic therapeutic effect [118, 119]. Hoopes et al. reported application of MH (43 °C/60 min) of intratumorally delivered immunoadjuvant plant-based virus-like nanoparticle VLP (4 × 200 µg) and magnetic NPs (2 × 7.5 mg/g tumor) combined with hypofractionated radiotherapy in the canine oral melanoma patients. The authors demonstrated an increased immune cell infiltration into the tumor and extended tumor control intervals [120].

Further modifications of magnetic NP formulations can increase their theranostic properties. Thus, hybrid gold ferric oxide NPs enable the magnetic targeting of NPs to the tumor site for subsequent photothermal therapy [121123]. Subsequent application of magnetically targeted nano-photothermal therapy based on Fe3O4@Au NPs decreased tumor progression in a preclinical melanoma model [124]. Furthermore, in the recent report by Zhang et al. it was demonstrated that NPs could be used as a platform for the multimodal theranostics in melanoma [125]. Thus, MSN(Mn)-ICG/DTIC NPs (that incorporated dacarbazine (DTIC), indocyanine green (ICG), mesoporous silica NPs (MSN(Mn))) achieved a significant anti-tumor chemo-photothermal effect [125].

Magneto-mechanical manipulation

Therapeutic approaches based on magneto-mechanical effect of particles are a growing field in the treatment of tumors [126, 127]. Upon application of the external magnetic field, internalized NPs align themselves to the plane of the rotating magnetic field, creating a strong mechanical force which damages tumor cells and induces apoptosis [128]. Oscillation of the NPs under a low-frequency magnetic field can result in the mechanical stretching of the cytoskeleton and an impairment of the ion channel activity [129]. Furthermore, after lysosomal targeting (via antibodies targeting the lysosomal protein marker LAMP1), rotating NPs damage lysosomal membranes and thus induce apoptotic cell death [130].

One of the promising approaches for the treatment of melanoma could be based on nanosecond pulsed electric fields (nsPEF) that have thus far been evaluated in vitro and in superficial malignancies, in vivo. Previously, Bardet et al. demonstrated for the first time that a single 10 ns, high-voltage electric pulse (35–45 kV/cm), collapses the perfusion of the neovasculature and alters the diameter of capillaries and larger vessels in normal tissue [131]. Furthermore, weak magnetic fields (40–75 mT) applied on tumor cells containing polymer-coated multi-walled carbon nanotubes induce magnetoporation of tumor cell membranes and tumor cell death by magnetolysis [132, 133] (Fig. 3).

Fig. 3
figure 3

Schematic overview of the potential use of nanoparticles alone or in combination with approved treatment options in malignant melanoma, exemplified for nanoparticles with Fe3O4 core. Abbreviations: CA: contrast agent; Ab: antibody

Although magneto-mechanical approaches demonstrated a therapeutic potency in vitro, only a few in vivo studies were reported with highly heterogenous magnetic nanocarriers. Further preclinical studies in clinically relevant melanoma models are mandatory to decipher the mechanisms underlying the observed therapeutic effect (particularly taking into consideration the recent advances in mechano-transduction pathways).

Localized magnetic field for drug release

Application of drug-eluting beads triggered by the external alternating magnetic field demonstrated promising results in various preclinical models [134138]. Indeed, encapsulation of anti-melanoma drugs in triggerable magnetic NPs can beneficially modify biodistribution and pharmacokinetics of therapeutic agents (thus increasing on-site drug concentration and reducing off-target side effects) and trigger the release of the chemotherapeutic compound by electromagnetic field in the required time period [139, 140] (Fig. 3). Additionally, magnetic NPs as shown by numerous studies can induce vasodilatation that increases blood circulation and thereby enhances chemotherapeutic drug delivery. Furthermore, employment of the magnetoresponsive particles facilitated the doxorubicin release and its efficient distribution inside the tumor tissue upon application of low-frequency (Lf) electromagnetic-induced magnetophoresis [135] (Fig. 3). In another study, a radical initiator (AIPH) loaded into porous hollow iron oxide nanoparticles (PHIONs) under AMF resulted in production of oxygen-independent alkyl radicals with significant therapeutic potency [141]. Colloidally stable core–shell cobalt ferrite@barium titanate (CFO@BTO) ME NPs were shown to release doxorubicin and methotrexate upon application of the magnetic field (5 mT) inhibiting the growth of human malignant melanoma cells HT144 [142]. In another study, cell-penetrating peptides (CPP) and tumor necrosis factor (TNF)-α (CTNF-α)-anchored exosomes coupled to superparamagnetic iron oxide NPs (CTNF-α-exosome-SPIONs) showed a membrane-targeting anticancer activity in a melanoma model when external magnetic fields were applied [143]. In the recently published work of García-Hevia et al., the authors developed a nanoplatform based on magnetic lipid nanocomposite vehicles (mLNVs) loaded with doxorubicin that demonstrated a therapeutic potency in B16 mouse melanoma models [144]. Presumably, a combination of a triggered release of anti-melanoma drugs with other therapies (e.g., radiotherapy, immunotherapy, targeted therapy, etc.) could further increase the therapeutic potential of the magnetic particles (Fig. 3).

Enzyme mimetic for melanoma therapy

In 2007, it was demonstrated for the first time that metal NPs, particularly magnetite (Fe3O4) particles, possess an intrinsic enzyme mimetic activity similar to that of peroxidase [145]. This discovery triggered the development of a new class of catalytic agents that were termed “nanozyme,” thus distinguishing nanomaterials with intrinsic enzyme properties from other particles with externally immobilized enzymes [146] (Fig. 3). Up to date, more than 300 nanomaterials are described with enzyme-mimicking activity [147]. Currently, nanozyme has demonstrated to mimic activities of enzymes belonging to the oxidoreductase family (i.e., catalase and peroxidase) and therefore can also be applied for cancer theranostics [145, 148]. The developed nanoparticle-based sensor platform successfully identified circulating tumor cells in melanoma by catalyzing the oxidation of TMB (3,3',5,5'-tetramethylbenzidine) into a blue-colored product [25]. Subsequent studies reported that magnetite NPs catalyzing decomposition of hydrogen peroxide with production of reactive oxygen species (ROS) can significantly inhibit the growth of subcutaneously implanted HeLa tumors in BALB/c mice. Tumor inhibition rates of 99% could be achieved when NPs were combined with H2O2 [149]. Furthermore, as shown by Kim et al., ultrasmall NPs could induce ferroptosis via the enhanced generation of ROS in cancer cells (Fig. 3) that was abrogated by the application of liproxstatin-1, an inhibitor of ferroptosis [150]. In another study, ferumoxytol, an FDA-approved iron supplement, induced polarization of tumor-associated macrophages into pro-inflammatory type 1 macrophages that corresponded with an inhibition of growth of subcutaneous adenocarcinomas in mice [151]. Taking into consideration the immunomodulatory and anti-tumor effects of MNPs, further combinations with other immunotherapeutic approaches, particularly with ICIs, might further improve melanoma theranostics (Fig. 3).

Theranostic approaches based on extrinsic properties of nanoparticles

Apart from applications of MNPs as tools for direct tumor eradication due to their unique intrinsic characteristics, also other types of NPs are employed for a targeted melanoma theranostics in combination with other treatment modalities (Fig. 3). Their properties can be improved by introducing biocompatible and biodegradable coatings and by attaching various targeting and diagnostic therapeutic agents to their surface. It was demonstrated that decoration of particle surfaces with anti-melanoma agents could result in an enhanced potential in the delivery of chemotherapeutic drugs into tumor cells, thereby avoiding side effects. The most studied nanoparticle system, PEG-PLGA, mediates effective anti-melanoma effects [152154]. In a recent work of Zhou et al., it was demonstrated that celastrol-containing PEG-PLGA NPs coated with membranes of neutrophils displayed significantly enhanced cytotoxicity and apoptosis rate in a B16F10 melanoma mouse model [155]. In another study, fabricated PLGA containing ursolic acid (UA) (pentacyclic triterpenoid extracted from plants) also demonstrated a therapeutic efficacy in the management of melanoma [156]. To further potentiate the therapeutic properties, these particles could be loaded with magnetic active substances such as iron. Liposomes loaded with dichloro(1,10-phenanthroline) copper (II) (CuPhen), a cytotoxic metallodrug, enabled iron oxide nanoparticles (IONPs) to retain their magnetic properties and to exert anti-melanoma effects [157]. Indeed, inclusion of iron oxide provides the possibility for an MR-guided assessment of tumor volume and allows the monitoring of therapy responses. MR imaging-guided chemotherapy by LDH-stabilized ultrasmall iron oxide Fe3O4 NPs coated with hyaluronic acid (HA) and loaded with the anticancer drug doxorubicin (DOX) demonstrated efficiency in melanoma treatment [158]. In addition to the loading with chemotherapeutic agents, magnetic NPs can also be conjugated to other molecules (e.g., fluorescent dyes, radionuclides, contrast-enhancing agents for MRI, siRNA, shRNA, etc.) to improve their theranostic capacity. A promising approach is the delivery of immunoadjuvants such as agonists for pattern recognition receptors by NPs [159]. Activation of TLR has been shown to modulate immune responses by stimulating recruitment and effector functions of T cells [21, 160164]. In fact, several TLR ligands have already been coupled to NPs and used in preclinical models for cancer immunotherapy [165].

Accumulation of non-targeted magnetic particles in the tumor tissue occurs due to the enhanced permeability and retention effect (EPR). However, undesirable off-target uptake of NPs by the reticuloendothelial system (particularly in liver, spleen, and lungs) cannot be ruled out that can lead to toxic side effects. Inclusion of iron into NPs can enable magnetic targeting of NPs to the region of interest inside the body. Thus, cell-penetrating peptides (CPP) and TNF-α (CTNF-α)-anchored exosomes coupled to superparamagnetic iron oxide NPs (CTNF-α-exosome-SPIONs) showed an enhanced membrane targeting in a melanoma model when an external magnetic field was applied [143].

Among tumor-associated antigens for the development of targeted NPs, the 70 kDa heat shock protein Hsp70 is of particular interest as the presentation of this protein on the cell surface of tumor cells was shown in a large variety of solid tumors, hematological malignancies and melanoma but not on corresponding normal cells [166168]. The tumor-specific cell surface localization of Hsp70 could be explained by an association of the chaperone with globotriaosylceramide Gb3, a tumor cell-specific sphingolipid residing in cholesterol-rich microdomains [169]. Subsequent in vitro studies clearly demonstrated that Hsp70 predominantly attaches to artificial liposomes that contain Gb3 (PC/SM/Chol/Gb3 at a ratio of 17/45/33/5), indicating that Gb3 is indeed an interacting partner of Hsp70 [169]. Apart from Gb3, phosphatidylserine (PS), a non-lipid raft component, also was shown to interact with Hsp70 in stressed tumor cells [170, 171]. Indeed, decoration of the nanoparticle surface with anti-Hsp70 bioligands (i.e., monoclonal antibodies, Fab-fragments of antibodies, peptides) significantly increased the targeting potential of the applied nanomaterials, thus enhancing their diagnostic properties in guided detection of the tumor employing magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) and fluorescent imaging [34, 172175]. Furthermore, the attachment of therapeutic molecules to NPs targeting membrane-bound Hsp70 on tumor cells has the potential to further enhance anti-melanoma properties of MNPs. Granzyme B, a serine protease, has been shown to interact with membrane-bound Hsp70 on tumor cells [169]. Upon binding and uptake, granzyme B induces apoptosis selectively in tumor cells. Therefore, a decoration of MNPs with granzyme B resulted not only in an efficient homing of NPs to tumor cells, but also provides therapeutic effects via the stimulation of a granzyme B-mediated apoptosis 34.

Conclusions

NPs and MNPs have been widely applied in the therapy of cancer. Due to their biophysical properties, they improve the accuracy of diagnosis and increase the efficacy of therapy. Over the last decade, the composition as well as the targeting properties (e.g., fluorescent dyes, radionuclides, chemotherapeutic molecules, antibodies, etc.) of MNPs has been optimized.

Another promising approach involves the combination of nanoparticle-based theranostics with other treatment modalities (i.e., radio- and/or chemotherapy, immunotherapy, targeted therapy, etc.) that can help to achieve a synergistic anti-melanoma effect. In conclusion, these further developments of nanoparticle composition through molecular tuning supported by comprehensive analysis could lead to the establishment of novel nanoplatforms for melanoma therapy (Fig. 3).

Availability of data and materials

Not applicable.

Abbreviations

AJCC:

American Joint Committee on Cancer

AMF:

Alternating electromagnetic field

ICI:

Immune checkpoint inhibitor

PD-1:

Death protein 1

CPP:

Cell-penetrating peptide

CT:

Computed tomography

CM:

Cutaneous melanoma

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

DOX:

Doxorubicin

EPR:

Enhanced permeability and retention effect

ERK:

Extracellular signal-regulated kinase

Fab:

Fragment antigen binding

FDA:

Food and Drug Administration

Gb3:

Globotriaosylceramide 3

Hsp:

Heat shock protein

Lf:

Low frequency

irAEs:

Immune-related adverse events

IONP:

Iron oxide nanoparticle

JNK:

C-Jun-N-terminal kinase

MH:

Magnetic hyperthermia

mLNV:

Magnetic lipid nanocomposite vehicle

MNP:

Magnetic nanoparticle

MRI:

Magnetic resonance imaging

Tis:

Tumor in situ

MAPK:

Mitogen-activated protein kinase

nsPEF:

Nanosecond pulsed electric field

PS:

Phosphatidylserine

PHION:

Porous hollow iron oxide nanoparticles

PET:

Positron emission tomography

ROS:

Reactive oxygen species

SPION:

Superparamagnetic iron oxide nanoparticle

T-VEC:

Talimogene laherparepvec

TCR:

T cell receptor

TMB:

3,3',5,5'-Tetramethylbenzidine

TCGA:

The Cancer Genome Atlas

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNM system:

Tumor, node, metastasis system

UV:

Ultraviolet

UA:

Ursolic acid

VLP:

Virus-like nanoparticle

References

  1. Arnold M, et al. Trends in incidence and predictions of cutaneous melanoma across Europe up to 2015. J Eur Acad Dermatol Venereol. 2014;28:1170–8. https://doi.org/10.1111/jdv.12236.

    CAS  Article  PubMed  Google Scholar 

  2. Burns D, et al. The pathogenesis and clinical management of cutaneous melanoma: an evidence-based review. J Med Imaging Radiat Sci. 2019;50:460–9. https://doi.org/10.1016/j.jmir.2019.05.001.

    Article  PubMed  Google Scholar 

  3. Cichorek M, Wachulska M, Stasiewicz A, Tyminska A. Skin melanocytes: biology and development. Postepy Dermatol Alergol. 2013;30:30–41. https://doi.org/10.5114/pdia.2013.33376.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Gandini S, Autier P, Boniol M. Reviews on sun exposure and artificial light and melanoma. Prog Biophys Mol Biol. 2011;107:362–6. https://doi.org/10.1016/j.pbiomolbio.2011.09.011.

    Article  PubMed  Google Scholar 

  5. Dennis LK, et al. Sunburns and risk of cutaneous melanoma: does age matter? A comprehensive meta-analysis. Ann Epidemiol. 2008;18:614–27. https://doi.org/10.1016/j.annepidem.2008.04.006.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ghiasvand R, et al. Indoor tanning and melanoma risk: long-term evidence from a prospective population-based cohort study. Am J Epidemiol. 2017;185:147–56. https://doi.org/10.1093/aje/kww148.

    Article  PubMed  Google Scholar 

  7. Alexandrov LB, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21. https://doi.org/10.1038/nature12477.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Hodis E, et al. A landscape of driver mutations in melanoma. Cell. 2012;150:251–63. https://doi.org/10.1016/j.cell.2012.06.024.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Gandini S, et al. Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer. 2005;41:2040–59. https://doi.org/10.1016/j.ejca.2005.03.034.

    Article  PubMed  Google Scholar 

  10. Olsen CM, et al. Nevus density and melanoma risk in women: a pooled analysis to test the divergent pathway hypothesis. Int J Cancer. 2009;124:937–44. https://doi.org/10.1002/ijc.24011.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Whiteman DC, et al. Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma. J Natl Cancer Inst. 2003;95:806–12. https://doi.org/10.1093/jnci/95.11.806.

    Article  PubMed  Google Scholar 

  12. Beroukhim K, Pourang A, Eisen DB. Risk of second primary cutaneous and noncutaneous melanoma after cutaneous melanoma diagnosis: a population-based study. J Am Acad Dermatol. 2020;82:683–9. https://doi.org/10.1016/j.jaad.2019.10.024.

    CAS  Article  PubMed  Google Scholar 

  13. Levi F, Randimbison L, Te VC, La Vecchia C. High constant incidence rates of second cutaneous melanomas. Int J Cancer. 2005;117:877–9. https://doi.org/10.1002/ijc.21262.

    CAS  Article  PubMed  Google Scholar 

  14. van der Leest RJ, Flohil SC, Arends LR, de Vries E, Nijsten T. Risk of subsequent cutaneous malignancy in patients with prior melanoma: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2015;29:1053–62. https://doi.org/10.1111/jdv.12887.

    Article  PubMed  Google Scholar 

  15. Dhayade S, et al. Sildenafil potentiates a cGMP-dependent pathway to promote melanoma growth. Cell Rep. 2016;14:2599–610. https://doi.org/10.1016/j.celrep.2016.02.028.

    CAS  Article  PubMed  Google Scholar 

  16. Kaesler S, Skabytska Y, Volz T, Biedermann T. The biodiversity hypothesis and immunotolerance in allergy. Allergo Journal International. 2018;27:140–6. https://doi.org/10.1007/s40629-018-0072-0.

    Article  Google Scholar 

  17. Sinnberg T, et al. Suppression of casein kinase 1alpha in melanoma cells induces a switch in beta-catenin signaling to promote metastasis. Cancer Res. 2010;70:6999–7009. https://doi.org/10.1158/0008-5472.CAN-10-0645.

    CAS  Article  PubMed  Google Scholar 

  18. Volz T, Kaesler S, Biedermann T. Innate immune sensing 2.0—From linear activation pathways to fine tuned and regulated innate immune networks. Exp Dermatol. 2012;21:61–9. https://doi.org/10.1111/j.1600-0625.2011.01393.x.

    CAS  Article  PubMed  Google Scholar 

  19. Leonardi GC, et al. Cutaneous melanoma: From pathogenesis to therapy (review). Int J Oncol. 2018;52:1071–80. https://doi.org/10.3892/ijo.2018.4287.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Banstola A, Jeong JH, Yook S. Immunoadjuvants for cancer immunotherapy: a review of recent developments. Acta Biomater. 2020;114:16–30. https://doi.org/10.1016/j.actbio.2020.07.063.

    CAS  Article  PubMed  Google Scholar 

  21. Kaesler S, et al. Targeting tumor-resident mast cells for effective anti-melanoma immune responses. JCI Insight. 2019. https://doi.org/10.1172/jci.insight.125057.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Koberle M, Amar Y, Holge IM, Kaesler S, Biedermann T. Cutaneous barriers and Skin immunity. Handb Exp Pharmacol. 2021. https://doi.org/10.1007/164_2021_477.

    Article  Google Scholar 

  23. Song MM, Liu C, Chen SY, Zhang WX. Nanocarrier-based drug delivery for melanoma therapeutics. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms22041873.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hare JI, et al. Challenges and strategies in anti-cancer nanomedicine development: an industry perspective. Adv Drug Deliver Rev. 2017;108:25–38. https://doi.org/10.1016/j.addr.2016.04.025.

    CAS  Article  Google Scholar 

  25. Li J, Wang J, Wang Y, Trau M. Simple and rapid colorimetric detection of melanoma circulating tumor cells using bifunctional magnetic nanoparticles. Analyst. 2017;142:4788–93. https://doi.org/10.1039/c7an01102d.

    CAS  Article  PubMed  Google Scholar 

  26. Ren ZG, et al. A metal-polyphenol-coordinated nanomedicine for synergistic cascade cancer chemotherapy and chemodynamic therapy. Adv Mater. 2020. https://doi.org/10.1002/adma.201906024.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Akakuru OU, et al. Metal-free organo-theranostic nanosystem with high nitroxide stability and loading for image-guided targeted tumor therapy. ACS Nano. 2021;15:3079–97. https://doi.org/10.1021/acsnano.0c09590.

    CAS  Article  PubMed  Google Scholar 

  28. Chen L, et al. Merging metal organic framework with hollow organosilica nanoparticles as a versatile nanoplatform for cancer theranostics. Acta Biomater. 2019;86:406–15. https://doi.org/10.1016/j.actbio.2019.01.005.

    CAS  Article  PubMed  Google Scholar 

  29. Kimm MA, et al. Gold nanoparticle mediated multi-modal CT imaging of Hsp70 membrane-Positive tumors. Cancers. 2020. https://doi.org/10.3390/cancers12051331.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Mu LM, et al. Dual-functional drug liposomes in treatment of resistant cancers. Adv Drug Deliver Rev. 2017;115:46–56. https://doi.org/10.1016/j.addr.2017.04.006.

    CAS  Article  Google Scholar 

  31. Nayak D, et al. Synergistic combination of antioxidants, silver nanoparticles and chitosan in a nanoparticle based formulation: Characterization and cytotoxic effect on MCF-7 breast cancer cell lines. J Colloid Interface Sci. 2016;470:142–52. https://doi.org/10.1016/j.jcis.2016.02.043.

    CAS  Article  PubMed  Google Scholar 

  32. Pang YC, et al. Metal-organic framework nanoparticles for ameliorating breast cancer-associated osteolysis. Nano Lett. 2020;20:829–40. https://doi.org/10.1021/acs.nanolett.9b02916.

    CAS  Article  PubMed  Google Scholar 

  33. Park SJ. Protein-nanoparticle interaction: corona formation and conformational changes in proteins on nanoparticles. Int J Nanomed. 2020;15:5783–802. https://doi.org/10.2147/Ijn.S254808.

    CAS  Article  Google Scholar 

  34. Shevtsov M, et al. Granzyme B functionalized nanoparticles targeting membrane Hsp70-Positive tumors for multimodal cancer theranostics. Small. 2019;15: e1900205. https://doi.org/10.1002/smll.201900205.

    CAS  Article  PubMed  Google Scholar 

  35. Shevtsov MA, et al. Zero-valent Fe confined mesoporous silica nanocarriers (Fe(0) @ MCM-41) for targeting experimental orthotopic glioma in rats. Sci Rep. 2016;6:29247. https://doi.org/10.1038/srep29247.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Yu B, et al. Reassembly of (89) Zr-labeled cancer cell membranes into multicompartment membrane-derived liposomes for PET-trackable tumor-targeted theranostics. Adv Mater. 2018;30: e1704934. https://doi.org/10.1002/adma.201704934.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Zhang Y, Fang F, Li L, Zhang J. Self-assembled organic nanomaterials for drug delivery, bioimaging, and cancer therapy. ACS Biomater Sci Eng. 2020;6:4816–33. https://doi.org/10.1021/acsbiomaterials.0c00883.

    CAS  Article  PubMed  Google Scholar 

  38. Alvarez-Rodriguez B, Latorre A, Posch C, Somoza A. Recent advances in uveal melanoma treatment. Med Res Rev. 2017;37:1350–72. https://doi.org/10.1002/med.21460.

    Article  PubMed  Google Scholar 

  39. Latorre A, et al. DNA and aptamer stabilized gold nanoparticles for targeted delivery of anticancer therapeutics. Nanoscale. 2014;6:7436–42. https://doi.org/10.1039/c4nr00019f.

    CAS  Article  PubMed  Google Scholar 

  40. Posch C, et al. Detection of GNAQ mutations and reduction of cell viability in uveal melanoma cells with functionalized gold nanoparticles. Biomed Microdevices. 2015;17:15. https://doi.org/10.1007/s10544-014-9908-7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Sun CR, et al. PEG-mediated synthesis of highly dispersive multifunctional superparamagnetic nanoparticles: their physicochemical properties and function in vivo. ACS Nano. 2010;4:2402–10. https://doi.org/10.1021/nn100190v.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Weissleder R, et al. Superparamagnetic iron-oxide - pharmacokinetics and toxicity. Am J Roentgenol. 1989;152:167–73. https://doi.org/10.2214/ajr.152.1.167.

    CAS  Article  Google Scholar 

  43. Estelrich J, Sanchez-Martin MJ, Busquets MA. Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents. Int J Nanomed. 2015;10:1727–41. https://doi.org/10.2147/Ijn.S76501.

    CAS  Article  Google Scholar 

  44. Hobson NJ, et al. Clustering superparamagnetic iron oxide nanoparticles produces organ-targeted high-contrast magnetic resonance images. Nanomedicine-Uk. 2019;14:1135–52. https://doi.org/10.2217/nnm-2018-0370.

    Article  Google Scholar 

  45. Carter TJ, et al. Potential of magnetic hyperthermia to stimulate localized immune activation. Small. 2021;17: e2005241. https://doi.org/10.1002/smll.202005241.

    CAS  Article  PubMed  Google Scholar 

  46. Huang PC, et al. Biomechanical sensing of in vivo magnetic nanoparticle hyperthermia-treated melanoma using magnetomotive optical coherence elastography. Theranostics. 2021;11:5620–33. https://doi.org/10.7150/thno.55333.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Bonnemain B. Superparamagnetic agents in magnetic resonance imaging: Physicochemical characteristics and clinical applications - a review. J Drug Target. 1998;6:167–74. https://doi.org/10.3109/10611869808997890.

    CAS  Article  PubMed  Google Scholar 

  48. Harisinghani MG, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. New Engl J Med. 2003;348:2491-U2495. https://doi.org/10.1056/NEJMoa022749.

    Article  PubMed  Google Scholar 

  49. Keung EZ, Gershenwald J. The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care. Expert Rev Anticancer Ther. 2018; 18: 775–784. https://doi.org/10.1080/14737140.2018.1489246

  50. Garbe C, et al. European consensus-based interdisciplinary guideline for melanoma. Part 2: Treatment - update 2019. Eur J Cancer. 2020;126:159–77. https://doi.org/10.1016/j.ejca.2019.11.015.

    CAS  Article  PubMed  Google Scholar 

  51. Bhatia S, Tykodi SS, Thompson JA. Treatment of metastatic melanoma: an overview. Oncology (Williston Park). 2009;23:488–96.

    Google Scholar 

  52. Flaherty LE. Rationale for intergroup trial E-3695 comparing concurrent biochemotherapy with cisplatin, vinblastine, and DTIC alone in patients with metastatic melanoma. Cancer J Sci Am. 2000;6(Suppl 1):S15-20.

    PubMed  Google Scholar 

  53. Kim C, et al. Long-term survival in patients with metastatic melanoma treated with DTIC or temozolomide. Oncologist. 2010;15:765–71. https://doi.org/10.1634/theoncologist.2009-0237.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Bright R, Coventry BJ, Eardley-Harris N, Briggs N. Clinical response rates from interleukin-2 therapy for metastatic melanoma over 30 years’ experience: a meta-analysis of 3312 patients. j Immunother. 2017;40:21–30. https://doi.org/10.1097/CJI.0000000000000149.

    CAS  Article  PubMed  Google Scholar 

  55. Tarhini AA, Gogas H, Kirkwood JM. IFN-alpha in the treatment of melanoma. J Immunol. 2012;189:3789–93. https://doi.org/10.4049/jimmunol.1290060.

    CAS  Article  PubMed  Google Scholar 

  56. Kirkwood JM, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18:2444–58. https://doi.org/10.1200/JCO.2000.18.12.2444.

    CAS  Article  PubMed  Google Scholar 

  57. Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985;161:1169–88. https://doi.org/10.1084/jem.161.5.1169.

    CAS  Article  PubMed  Google Scholar 

  58. Walunas TL, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1:405–13. https://doi.org/10.1016/1074-7613(94)90071-x.

    CAS  Article  PubMed  Google Scholar 

  59. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23. https://doi.org/10.1056/NEJMoa1003466.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Schadendorf D, et al. Pooled analysis of long-term survival data from Phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33:1889–94. https://doi.org/10.1200/JCO.2014.56.2736.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. McDermott D, et al. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol. 2013;24:2694–8. https://doi.org/10.1093/annonc/mdt291.

    CAS  Article  PubMed  Google Scholar 

  62. Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8:1069–86. https://doi.org/10.1158/2159-8290.CD-18-0367.

    Article  PubMed  Google Scholar 

  63. Ribas A, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315:1600–9. https://doi.org/10.1001/jama.2016.4059.

    CAS  Article  PubMed  Google Scholar 

  64. Robert C, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32. https://doi.org/10.1056/NEJMoa1503093.

    CAS  Article  PubMed  Google Scholar 

  65. Weber J, et al. Adjuvant nivolumab versus ipilimumab in resected Stage III or IV melanoma. N Engl J Med. 2017;377:1824–35. https://doi.org/10.1056/NEJMoa1709030.

    CAS  Article  PubMed  Google Scholar 

  66. Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:1270–1. https://doi.org/10.1056/NEJMc1509660.

    Article  PubMed  Google Scholar 

  67. Robert C, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30. https://doi.org/10.1056/NEJMoa1412082.

    CAS  Article  PubMed  Google Scholar 

  68. Falcone I, et al. Tumor microenvironment: implications in melanoma resistance to targeted therapy and immunotherapy. Cancers. 2020. https://doi.org/10.3390/cancers12102870.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Fares CM, Van Allen EM, Drake CG, Allison JP, Hu-Lieskovan S. Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am Soc Clin Oncol Educ Book. 2019;39:147–64. https://doi.org/10.1200/EDBK_240837.

    Article  PubMed  Google Scholar 

  70. Lee JH, et al. Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition. Nat Commun. 2020;11:1897. https://doi.org/10.1038/s41467-020-15726-7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. Lin Z, et al. Intratumor heterogeneity correlates with reduced immune activity and worse survival in melanoma patients. Front Oncol. 2020;10: 596493. https://doi.org/10.3389/fonc.2020.596493.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Reuben A, et al. Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma. NPJ Genom Med. 2017. https://doi.org/10.1038/s41525-017-0013-8.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science (New York, NY). 2011;331:1565–70. https://doi.org/10.1126/science.1203486.

    CAS  Article  Google Scholar 

  74. Tirosh I, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science (New York, NY). 2016;352:189–96. https://doi.org/10.1126/science.aad0501.

    CAS  Article  Google Scholar 

  75. Tucci M, et al. immune system evasion as hallmark of melanoma progression: the role of dendritic cells. Front Oncol. 2019;9:1148. https://doi.org/10.3389/fonc.2019.01148.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Guo YJ, et al. ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 2020;19:1997–2007. https://doi.org/10.3892/etm.2020.8454.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov. 2014;13:928–42. https://doi.org/10.1038/nrd4281.

    CAS  Article  PubMed  Google Scholar 

  78. Ascierto PA, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85. https://doi.org/10.1186/1479-5876-10-85.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. Brose MS, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62:6997–7000.

    CAS  PubMed  Google Scholar 

  80. Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol. 2011;164:776–84. https://doi.org/10.1111/j.1365-2133.2010.10185.x.

    CAS  Article  PubMed  Google Scholar 

  81. Posch C, et al. Searching for the chokehold of NRAS mutant melanoma. J Invest Dermatol. 2016;136:1330–6. https://doi.org/10.1016/j.jid.2016.03.006.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. Cancer Genome Atlas N. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681–96. https://doi.org/10.1016/j.cell.2015.05.044.

    CAS  Article  Google Scholar 

  83. Cantwell-Dorris ER, O’Leary JJ, Sheils OM. BRAFV600E: implications for carcinogenesis and molecular therapy. Mol Cancer Ther. 2011;10:385–94. https://doi.org/10.1158/1535-7163.MCT-10-0799.

    CAS  Article  PubMed  Google Scholar 

  84. Chapman PB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16. https://doi.org/10.1056/NEJMoa1103782.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. Sosman JA, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–14. https://doi.org/10.1056/NEJMoa1112302.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. Beck D, et al. Vemurafenib potently induces endoplasmic reticulum stress-mediated apoptosis in BRAFV600E melanoma cells. Sci Signal. 2013;6:7. https://doi.org/10.1126/scisignal.2003057.

    CAS  Article  Google Scholar 

  87. Hauschild A, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65. https://doi.org/10.1016/S0140-6736(12)60868-X.

    CAS  Article  PubMed  Google Scholar 

  88. Menzies AM, Long GV, Murali R. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Devel Ther. 2012;6:391–405. https://doi.org/10.2147/DDDT.S38998.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Johannessen CM, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72. https://doi.org/10.1038/nature09627.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Long GV, et al. Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma who received dabrafenib combined with trametinib. J Clin Oncol. 2018;36:667–73. https://doi.org/10.1200/JCO.2017.74.1025.

    CAS  Article  PubMed  Google Scholar 

  91. Eroglu Z, Ribas A. Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy. Ther Adv Med Oncol. 2016;8:48–56. https://doi.org/10.1177/1758834015616934.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Ascierto PA, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17:1248–60. https://doi.org/10.1016/S1470-2045(16)30122-X.

    CAS  Article  PubMed  Google Scholar 

  93. Shirley M. Encorafenib and binimetinib: first global approvals. Drugs. 2018;78:1277–84. https://doi.org/10.1007/s40265-018-0963-x.

    CAS  Article  PubMed  Google Scholar 

  94. Frederick DT, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19:1225–31. https://doi.org/10.1158/1078-0432.CCR-12-1630.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. Wilmott JS, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18:1386–94. https://doi.org/10.1158/1078-0432.CCR-11-2479.

    CAS  Article  PubMed  Google Scholar 

  96. Wilmott JS, et al. Dynamics of chemokine, cytokine, and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment. J Immunol. 2014;192:2505–13. https://doi.org/10.4049/jimmunol.1302616.

    CAS  Article  PubMed  Google Scholar 

  97. Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: a new era of cancer treatment at dawn. Cancer Sci. 2016;107:1373–9. https://doi.org/10.1111/cas.13027.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Bommareddy PK, Patel A, Hossain S, Kaufman HL. Talimogene Laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma. Am J Clin Dermatol. 2017;18:1–15. https://doi.org/10.1007/s40257-016-0238-9.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Ressler JM, et al. Real-life use of talimogene laherparepvec (T-VEC) in melanoma patients in centers in Austria, Switzerland and Germany. J Immunother Cancer. 2021. https://doi.org/10.1136/jitc-2020-001701.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Kottschade LA, et al. A randomized phase 2 study of temozolomide and bevacizumab or nab-paclitaxel, carboplatin, and bevacizumab in patients with unresectable stage IV melanoma : a North Central Cancer Treatment Group study, N0775. Cancer. 2013;119:586–92. https://doi.org/10.1002/cncr.27760.

    CAS  Article  PubMed  Google Scholar 

  101. Hersh EM, et al. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer. 2010;116:155–63. https://doi.org/10.1002/cncr.24720.

    CAS  Article  PubMed  Google Scholar 

  102. Quaresmini D, Guida M. Neoangiogenesis in melanoma: an issue in biology and systemic treatment. Front Immunol. 2020;11: 584903. https://doi.org/10.3389/fimmu.2020.584903.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Hrkach J, et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med. 2012;4:128–39. https://doi.org/10.1126/scitranslmed.3003651.

    Article  Google Scholar 

  104. Deng Y, et al. A sunblock based on bioadhesive nanoparticles. Nat Mater. 2015;14:1278–85. https://doi.org/10.1038/nmat4422.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. Zou L, et al. Peptide-modified vemurafenib-loaded liposomes for targeted inhibition of melanoma via the skin. Biomaterials. 2018;182:1–12. https://doi.org/10.1016/j.biomaterials.2018.08.013.

    CAS  Article  PubMed  Google Scholar 

  106. Harmon BV, Takano YS, Winterford CM, Gobe GC. The role of apoptosis in the response of cells and tumours to mild hyperthermia. Int J Radiat Biol. 1991;59:489–501. https://doi.org/10.1080/09553009114550441.

    CAS  Article  PubMed  Google Scholar 

  107. Christophi C, Winkworth A, Muralihdaran V, Evans P. The treatment of malignancy by hyperthermia. Surg Oncol. 1998;7:83–90. https://doi.org/10.1016/S0960-7404(99)00007-9.

    CAS  Article  PubMed  Google Scholar 

  108. Wong RS, Kapp LN, Krishnaswamy G, Dewey WC. Critical steps for induction of chromosomal aberrations in CHO cells heated in S phase. Radiat Res. 1993;133:52–9.

    CAS  Article  PubMed  Google Scholar 

  109. Ahmed M, Goldberg SN. Basic science research in thermal ablation. Surg Oncol Clin N Am. 2011;20:237. https://doi.org/10.1016/j.soc.2010.11.011.

    Article  PubMed  Google Scholar 

  110. Haemmerich D, Laeseke PF. Thermal tumour ablation: devices, clinical applications and future directions. Int J Hyperthermia. 2005;21:755–60. https://doi.org/10.1080/02656730500226423.

    CAS  Article  PubMed  Google Scholar 

  111. Deatsch AE, Evans BA. Heating efficiency in magnetic nanoparticle hyperthermia. J Magn Magn Mater. 2014;354:163–72. https://doi.org/10.1016/j.jmmm.2013.11.006.

    CAS  Article  Google Scholar 

  112. Hervault A, Thanh NT. Magnetic nanoparticle-based therapeutic agents for thermo-chemotherapy treatment of cancer. Nanoscale. 2014;6:11553–73. https://doi.org/10.1039/c4nr03482a.

    CAS  Article  PubMed  Google Scholar 

  113. Heidari M, et al. Effect of magnetic fluid hyperthermia on implanted melanoma in mouse models. Iran J Med Sci. 2016;41:314–21.

    PubMed  Google Scholar 

  114. Jin H, et al. Hyperthermia inhibits the proliferation and invasive ability of mouse malignant melanoma through TGF-beta(1). Oncol Rep. 2013;29:725–34. https://doi.org/10.3892/or.2012.2128.

    CAS  Article  PubMed  Google Scholar 

  115. Portela A, et al. Highly focalised thermotherapy using a ferrimagnetic cement in the treatment of a melanoma mouse model by low temperature hyperthermia. Int J Hyperthermia. 2013;29:121–32. https://doi.org/10.3109/02656736.2013.767478.

    CAS  Article  PubMed  Google Scholar 

  116. Duval KEA, et al. Immunogenetic effects of low dose (CEM43 30) magnetic nanoparticle hyperthermia and radiation in melanoma cells. Int J Hyperthermia. 2019;36:37–46. https://doi.org/10.1080/02656736.2019.1627433.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. Ito A, et al. Heat shock protein 70 expression induces antitumor immunity during intracellular hyperthermia using magnetite nanoparticles. Cancer Immunol Immun. 2003;52:80–8. https://doi.org/10.1007/s00262-002-0335-x.

    CAS  Article  Google Scholar 

  118. Moy AJ, Tunnell JW. Combinatorial immunotherapy and nanoparticle mediated hyperthermia. Adv Drug Deliv Rev. 2017;114:175–83. https://doi.org/10.1016/j.addr.2017.06.008.

    CAS  Article  PubMed  Google Scholar 

  119. Stephen ZR, Zhang M. Recent progress in the synergistic combination of nanoparticle-mediated hyperthermia and immunotherapy for treatment of cancer. Adv Healthc Mater. 2021;10: e2001415. https://doi.org/10.1002/adhm.202001415.

    CAS  Article  PubMed  Google Scholar 

  120. Hoopes PJ, et al. Treatment of canine oral melanoma with nanotechnology-based immunotherapy and radiation. Mol Pharm. 2018;15:3717–22. https://doi.org/10.1021/acs.molpharmaceut.8b00126.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. Rajkumar S, Prabaharan M. Theranostics based on iron oxide and gold nanoparticles for imaging- guided photothermal and photodynamic therapy of cancer. Curr Top Med Chem. 2017;17:1858–71. https://doi.org/10.2174/1568026617666161122120537.

    CAS  Article  PubMed  Google Scholar 

  122. Wang H, et al. Magnetic/NIR-responsive drug carrier, multicolor cell imaging, and enhanced photothermal therapy of gold capped magnetite-fluorescent carbon hybrid nanoparticles. Nanoscale. 2015;7:7885–95. https://doi.org/10.1039/c4nr07335e.

    CAS  Article  PubMed  Google Scholar 

  123. Abedin MR, et al. Polymer coated gold-ferric oxide superparamagnetic nanoparticles for theranostic applications. J Nanobiotechnology. 2018;16:80. https://doi.org/10.1186/s12951-018-0405-7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. Pandesh S, Haghjooy Javanmard S, Shakeri-Zadeh A, Shokrani P. Targeted photothermal therapy of melanoma in C57BL/6 mice using Fe3O4@Au core-shell nanoparticles and near-infrared laser. J Biomed Phys Eng. 2021;11:29–38. https://doi.org/10.31661/jbpe.v0i0.736.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. Zhang D, et al. Dual modal imaging-guided drug delivery system for combined chemo-photothermal melanoma therapy. Int J Nanomed. 2021;16:3457–72. https://doi.org/10.2147/IJN.S306269.

    Article  Google Scholar 

  126. Mansell R, et al. Magnetic particles with perpendicular anisotropy for mechanical cancer cell destruction. Sci Rep. 2017;7:4257. https://doi.org/10.1038/s41598-017-04154-1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. Naud C, et al. Cancer treatment by magneto-mechanical effect of particles, a review. Nanoscale Adv. 2020;2:3632–55. https://doi.org/10.1039/d0na00187b.

    CAS  Article  Google Scholar 

  128. Cheng Y, et al. Rotating magnetic field induced oscillation of magnetic particles for in vivo mechanical destruction of malignant glioma. J Control Release. 2016;223:75–84. https://doi.org/10.1016/j.jconrel.2015.12.028.

    CAS  Article  PubMed  Google Scholar 

  129. Kim DH, et al. Biofunctionalized magnetic-vortex microdiscs for targeted cancer-cell destruction. Nat Mater. 2010;9:165–71. https://doi.org/10.1038/nmat2591.

    CAS  Article  PubMed  Google Scholar 

  130. Zhang E, et al. Dynamic magnetic fields remote-control apoptosis via nanoparticle rotation. ACS Nano. 2014;8:3192–201. https://doi.org/10.1021/nn406302j.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. Bardet, S. M. et al. Multiphoton imaging reveals that nanosecond pulsed electric fields collapse tumor and normal vascular perfusion in human glioblastoma xenografts. Sci Rep-Uk. https://doi.org/10.1038/srep34443 (2016)

  132. Liu D, Wang LJ, Wang ZG, Cuschieri A. Magnetoporation and magnetolysis of cancer cells via carbon nanotubes induced by rotating magnetic fields. Nano Lett. 2012;12:5117–21. https://doi.org/10.1021/nl301928z.

    CAS  Article  PubMed  Google Scholar 

  133. Wang LJ, Liu D, Zhou R, Wang ZG, Cuschieri A. Tumour cell membrane poration and ablation by pulsed low-intensity electric field with carbon nanotubes. Int J Mol Sci. 2015;16:6890–901. https://doi.org/10.3390/ijms16046890.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. Gogineni VR, et al. Localized and triggered release of oxaliplatin for the treatment of colorectal liver metastasis. J Cancer. 2020;11:6982–91. https://doi.org/10.7150/jca.48528.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. Liu X, et al. Electromagnetic field-programmed magnetic vortex nanodelivery system for efficacious cancer therapy. Adv Sci (Weinh). 2021. https://doi.org/10.1002/advs.202100950.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Penate Medina T, et al. Lipid-iron nanoparticle with a cell stress release mechanism combined with a local alternating magnetic field enables site-activated drug release. Cancers. 2020. https://doi.org/10.3390/cancers12123767.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Ray S, et al. Magnetic heating stimulated cargo release with dose control using multifunctional MR and thermosensitive liposome. Nanotheranostics. 2019;3:166–78. https://doi.org/10.7150/ntno.31164.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Xiang Z, et al. MOF-derived novel porous Fe3O4@C nanocomposites as smart nanomedical platforms for combined cancer therapy: magnetic-triggered synergistic hyperthermia and chemotherapy. J Mater Chem B. 2020;8:8671–83. https://doi.org/10.1039/d0tb01021a.

    CAS  Article  PubMed  Google Scholar 

  139. Qasim M, Asghar K, Dharmapuri G, Das D. Investigation of novel superparamagnetic Ni0.5Zn0.5Fe2O4@albumen nanoparticles for controlled delivery of anticancer drug. Nanotechnology. 2017;28:365101. https://doi.org/10.1088/1361-6528/aa7d81.

    CAS  Article  PubMed  Google Scholar 

  140. Stewart TS, et al. Magnetoelectric nanoparticles for delivery of antitumor peptides into glioblastoma cells by magnetic fields. Nanomedicine (Lond). 2018;13:423–38. https://doi.org/10.2217/nnm-2017-0300.

    CAS  Article  Google Scholar 

  141. Huang G, et al. Magnetothermally triggered free-radical generation for deep-seated tumor treatment. Nano Lett. 2021;21:2926–31. https://doi.org/10.1021/acs.nanolett.1c00009.

    CAS  Article  PubMed  Google Scholar 

  142. Shahzad K, et al. Field-controlled magnetoelectric core-shell CoFe2O4@BaTiO3 nanoparticles as effective drug carriers and drug release in vitro. Mater Sci Eng C Mater Biol Appl. 2021;119: 111444. https://doi.org/10.1016/j.msec.2020.111444.

    CAS  Article  PubMed  Google Scholar 

  143. Zhuang M, et al. SPION decorated exosome delivery of TNF-alpha to cancer cell membranes through magnetism. Nanoscale. 2020;12:173–88. https://doi.org/10.1039/c9nr05865f.

    CAS  Article  PubMed  Google Scholar 

  144. García-Fernández C, Saz A, Fornaguera C, Borrós S. Cancer immunotherapies revisited: state of the art of conventional treatments and next-generation nanomedicines. Cancer Gene Ther. 2021. https://doi.org/10.1038/s41417-021-00333-5.

    Article  PubMed  Google Scholar 

  145. Gao L, Fan K, Yan X. Iron oxide nanozyme: a multifunctional enzyme mimetic for biomedical applications. Theranostics. 2017;7:3207–27. https://doi.org/10.7150/thno.19738.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. Wei H, Wang E. Nanomaterials with enzyme-like characteristics (nanozymes): next-generation artificial enzymes. Chem Soc Rev. 2013;42:6060–93. https://doi.org/10.1039/c3cs35486e.

    CAS  Article  PubMed  Google Scholar 

  147. Wang P, Wang T, Hong J, Yan X, Liang M. Nanozymes: a new disease imaging strategy. Front Bioeng Biotechnol. 2020;8:15. https://doi.org/10.3389/fbioe.2020.00015.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. Wei M, et al. Chemical design of nanozymes for biomedical applications. Acta Biomater. 2021;126:15–30. https://doi.org/10.1016/j.actbio.2021.02.036.

    CAS  Article  PubMed  Google Scholar 

  149. Zhang D, et al. Anti-bacterial and in vivo tumor treatment by reactive oxygen species generated by magnetic nanoparticles. J Mater Chem B. 2013;1:5100–7. https://doi.org/10.1039/c3tb20907e.

    CAS  Article  PubMed  Google Scholar 

  150. Kim SE, et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nat Nanotechnol. 2016;11:977–85. https://doi.org/10.1038/nnano.2016.164.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. Zanganeh S, et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat Nanotechnol. 2016;11:986–94. https://doi.org/10.1038/nnano.2016.168.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. Avgoustakis K. Pegylated poly(lactide) and poly(lactide-co-glycolide) nanoparticles: preparation, properties and possible applications in drug delivery. Curr Drug Deliv. 2004;1:321–33. https://doi.org/10.2174/1567201043334605.

    CAS  Article  PubMed  Google Scholar 

  153. Parveen S, Sahoo SK. Long circulating chitosan/PEG blended PLGA nanoparticle for tumor drug delivery. Eur J Pharmacol. 2011;670:372–83. https://doi.org/10.1016/j.ejphar.2011.09.023.

    CAS  Article  PubMed  Google Scholar 

  154. Rafiei P, Haddadi A. Docetaxel-loaded PLGA and PLGA-PEG nanoparticles for intravenous application: pharmacokinetics and biodistribution profile. Int J Nanomedicine. 2017;12:935–47. https://doi.org/10.2147/IJN.S121881.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. Zhou X, Yu R, Cao X, Zhang ZR, Deng L. Bio-mimicking nanoparticles for targeted therapy of malignant melanoma. J Biomed Nanotechnol. 2019;15:993–1004. https://doi.org/10.1166/jbn.2019.2739.

    CAS  Article  PubMed  Google Scholar 

  156. Baishya R, et al. Ursolic acid loaded PLGA nanoparticles: in vitro and in vivo evaluation to explore tumor targeting ability on B16F10 melanoma cell lines. Pharm Res. 2016;33:2691–703. https://doi.org/10.1007/s11095-016-1994-1.

    CAS  Article  PubMed  Google Scholar 

  157. Cruz N, et al. A novel hybrid nanosystem integrating cytotoxic and magnetic properties as a tool to potentiate melanoma therapy. Nanomaterials (Basel). 2020. https://doi.org/10.3390/nano10040693.

    Article  PubMed Central  Google Scholar 

  158. Zhang N, et al. LDH-stabilized ultrasmall iron oxide nanoparticles as a platform for hyaluronidase-promoted MR imaging and chemotherapy of tumors. Theranostics. 2020;10:2791–802. https://doi.org/10.7150/thno.42906.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  159. Yang M, Li J, Gu P, Fan X. The application of nanoparticles in cancer immunotherapy: targeting tumor microenvironment. Bioact Mater. 2021;6:1973–87. https://doi.org/10.1016/j.bioactmat.2020.12.010.

    CAS  Article  PubMed  Google Scholar 

  160. Kaesler S, et al. Staphylococcus aureus-derived lipoteichoic acid induces temporary T-cell paralysis independent of Toll-like receptor 2. J Allergy Clin Immunol. 2016;138:780 e786-790. https://doi.org/10.1016/j.jaci.2015.11.043.

    CAS  Article  Google Scholar 

  161. Kaesler S, et al. Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4-mediated suppression of IL-10. J Allergy Clin Immunol. 2014;134:92–9. https://doi.org/10.1016/j.jaci.2014.02.017.

    CAS  Article  PubMed  Google Scholar 

  162. Skabytska Y, et al. Cutaneous innate immune sensing of Toll-like receptor 2–6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells. Immunity. 2014;41:762–75. https://doi.org/10.1016/j.immuni.2014.10.009.

    CAS  Article  PubMed  Google Scholar 

  163. Volz T, et al. Induction of IL-10-balanced immune profiles following exposure to LTA from Staphylococcus epidermidis. Exp Dermatol. 2018;27:318–26. https://doi.org/10.1111/exd.13540.

    CAS  Article  PubMed  Google Scholar 

  164. Volz T, et al. Natural Staphylococcus aureus-derived peptidoglycan fragments activate NOD2 and act as potent costimulators of the innate immune system exclusively in the presence of TLR signals. FASEB J. 2010;24:4089–102. https://doi.org/10.1096/fj.09-151001.

    CAS  Article  PubMed  Google Scholar 

  165. Tran TH, et al. Toll-like receptor-targeted particles: A paradigm to manipulate the tumor microenvironment for cancer immunotherapy. Acta Biomater. 2019;94:82–96. https://doi.org/10.1016/j.actbio.2019.05.043.

    CAS  Article  PubMed  Google Scholar 

  166. Multhoff G. Heat shock protein 72 (HSP72), a hyperthermia-inducible immunogenic determinant on leukemic K562 and Ewing’s Sarcoma cells. Int J Hyperther. 1997;13:39–48. https://doi.org/10.3109/02656739709056428.

    CAS  Article  Google Scholar 

  167. Multhoff G, et al. A stress-inducible 72-Kda heat-shock protein (Hsp72) is expressed on the surface of human tumor-cells, but not on normal-cells. Int J Cancer. 1995;61:272–9. https://doi.org/10.1002/ijc.2910610222.

    CAS  Article  PubMed  Google Scholar 

  168. Shevtsov MA, et al. Exogenously delivered heat shock protein 70 displaces its endogenous analogue and sensitizes cancer cells to lymphocytes-mediated cytotoxicity. Oncotarget. 2014;5:3101–14. https://doi.org/10.18632/oncotarget.1820.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Gehrmann M, et al. Tumor-specific hsp70 plasma membrane localization is enabled by the glycosphingolipid Gb3. PLoS ONE. 2008. https://doi.org/10.1371/journal.pone.0001925.

    Article  PubMed  PubMed Central  Google Scholar 

  170. Bilog AD, et al. Membrane localization of HspA1A, a stress inducible 70-kDa heat-shock protein, depends on its interaction with intracellular phosphatidylserine. Biomolecules. 2019. https://doi.org/10.3390/biom9040152.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Schilling D, et al. Binding of heat shock protein 70 to extracellular phosphatidylserine promotes killing of normoxic and hypoxic tumor cells. FASEB J. 2009;23:2467–77. https://doi.org/10.1096/fj.08-125229.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. Shevtsov MA, et al. Ionizing radiation improves glioma-specific targeting of superparamagnetic iron oxide nanoparticles conjugated with cmHsp70.1 monoclonal antibodies (SPION-cmHsp70.1). Nanoscale. 2015;7:20652–64. https://doi.org/10.1039/c5nr06521f.

    CAS  Article  PubMed  Google Scholar 

  173. Stangl S, et al. Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody. Proc Natl Acad Sci USA. 2011;108:733–8. https://doi.org/10.1073/pnas.1016065108.

    CAS  Article  PubMed  Google Scholar 

  174. Stangl S, et al. Preclinical evaluation of the Hsp70 peptide tracer TPP-PEG24-DFO[(89)Zr] for tumor-specific PET/CT imaging. Cancer Res. 2018;78:6268–81. https://doi.org/10.1158/0008-5472.CAN-18-0707.

    CAS  Article  PubMed  Google Scholar 

  175. Stangl S, et al. Selective in vivo imaging of syngeneic, spontaneous, and xenograft tumors using a novel tumor cell-specific Hsp70 peptide-based probe. Can Res. 2014;74:6903–12. https://doi.org/10.1158/0008-5472.Can-14-0413.

    CAS  Article  Google Scholar 

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Acknowledgements

Authors are grateful to Nan-Jong Lee for figure preparation.

Funding

Open Access funding enabled and organized by Projekt DEAL. The study was supported by the DFG Grant SFB824 project B4 and project B10, Technische Universität München (TUM), within the DFG funding program Open Access Publishing. MS was funded by the Ministry of Science and Higher Education of the Russian Federation (Agreement No. 075-15-2020-901).

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MS and SK contributed to writing of the original draft; CP, GM and TB performed review and editing. All authors read and approved the final manuscript.

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Shevtsov, M., Kaesler, S., Posch, C. et al. Magnetic nanoparticles in theranostics of malignant melanoma. EJNMMI Res 11, 127 (2021). https://doi.org/10.1186/s13550-021-00868-6

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Keywords

  • Melanoma
  • Magnetic nanoparticles
  • SPIONs
  • Theranostics