Chemo-Thermo-Immunotherapy with NPrCAP and Magnetite Nanoparticles: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Kazumasa Wakamatsu.
A major advance in drug discovery and targeted therapy directed at cancer cells may be achieved by the exploitation and immunomodulation of their unique biological properties. A novel chemo-thermo-immunotherapy (CTI therapy) is developed by conjugating a melanogenesis substrate, N-propionyl cysteaminylphenol (NPrCAP: amine analog of tyrosine), with magnetite nanoparticles (MNP). In this approach, NPrCAP provides a unique drug delivery system (DDS) because of its selective incorporation into melanoma cells. It also functions as a melanoma-targeted therapeutic drug because of its production of highly reactive free radicals (melanoma-targeted chemotherapy). Moreover, the utilization of MNP is a platform to develop thermo-immunotherapy because of heat shock protein (HSP) expression upon heat generation in MNP by exposure to an alternating magnetic field (AMF). This comprehensive review covers experimental in vivo and in vitro mouse melanoma models and preliminary clinical trials with a limited number of advanced melanoma patients.
  • melanoma
  • chemo-thermo-immunotherapy
  • melanogenesis
  • magnetite nanoparticle
  • drug delivery system
  • heat shock protein
  • in situ vaccine therapy
  • immune checkpoint inhibitor

1. Introduction

The management of advanced metastatic melanoma is an extremely difficult challenge for physicians and scientists because of the limited availability of effective therapies. There is, therefore, a critical need to develop innovative therapies for the control of advanced melanoma. The exploitation of biological properties unique to cancer cells may provide a novel approach to overcome this difficult challenge.
The biological property unique to melanoma cells and their precursor cells, melanocytes, is the biosynthesis of melanin pigments, melanogenesis, within specific cellular compartments called melanosomes. Melanogenesis begins with the conversion of amino acid tyrosine to 3,4-dihydroxyphenylalanine (dopa) and subsequently to dopa quinone in the presence of tyrosinase. This pathway is unique to all melanocytes and melanoma cells, including “amelanotic” melanoma [1]. With the interaction of melanocyte-stimulating hormone (MSH) and the melanocortin 1 receptor (MC1R) [2], the melanogenesis cascade proceeds with activation of microphthalmia transcription factor (MITF) for the induction of either eu- or pheomelanin biosynthesis. Tyrosinase is the major player of this cascade. It is a glycoprotein and its glycosylation process is regulated by a number of molecular chaperones, including calnexin, in the endoplasmic reticulum. Vesicular transport then carries tyrosinase and its related proteins (TRPs) from the trans-Golgi network to melanosomal compartments. A significant number of transporters in this process are involved in early melanosomal maturation, to which early and late endosomes are closely associated [3]. Once melanin biosynthesis is completed, melanosomes move along dendritic processes on melanocytes and are transferred to surrounding keratinocytes in skin. Howresearchersver, melanoma cells do not develop many dendrites and retain melanosomes within their cytoplasm, hence forming a “black mole” [4].
Tyrosine analogs that are the substrates of the melanin-forming enzyme tyrosinase can be some of the best candidates for developing specific melanoma-targeting drugs and therapies. N-acetyl and N-propionyl derivatives of 4-S-cysteaminylphenol (NAc- and NPr-CAP) wresearchersre synthesized and found to be much better substrates of tyrosinase than tyrosine [5].
Hyperthermia provides a promising approach for cancer treatment. In particular, photothermal therapy and magnetic hyperthermia have been extensively studied in scientific research laboratories [6]. In photothermal therapy, a laser is used to irradiate the tumor lesions, and the optical energy can be converted into heat by photothermal conversion agents such as indocyanine green [7], IR820 [8], or gold nanoparticles [9]. Intracellular hyperthermia using magnetite nanoparticles (MNP) (10–100 nm-sized, Fe3O4) has been shown to be effective in treating cancers [10][11]. Incorporated MNP generate heat within the cells after exposure to an alternating magnetic field (AMF), due to hysteresis loss [12][13][14][15]. Compared with other heating systems such as photothermal therapy, magnetic hyperthermia is advantageous because a magnetic field can penetrate deep into the body tissues and has almost no interactions with biological molecules. In this treatment, there is not only heat-mediated cell death but also an immune reaction due to the generation of heat shock proteins (HSPs) [16]. HSP expression induced by hyperthermia has been found to be involved in cancer immunomodulation, providing the basis for developing a novel cancer thermo-immunotherapy.

2. Synthesis of Novel Conjugates of NPrCAP and Magnetite Nanoparticles for Developing Melanoma-Targeted Chemo-Thermo-Immunotherapy (CTI Therapy)

2.1. Preparation of 4-S-CAP-Loaded Magnetite Cationic L Iposomes and Measurement of In Vitro/In Vivo Antimelanoma Effects; Starting Rational Basis for Developing CTI Therapy

CTI therapy is based on the combination of chemotherapy using melanogenesis substrates and hyperthermia using magnetic nanoparticles, and the resulting antitumor immune response induced by in situ vaccination through dying tumor cells. Analogs of the melanogenesis substrate tyrosine are good candidates, such as the sulfur homolog of tyrosine 4-S-cysteaminylphenol (4-S-CAP), which causes cytotoxicity of melanoma [17][18] and can be used for melanoma-targeted chemotherapy. In addition, intracellular hyperthermia can be generated by loading magnetic nanoparticles into tumor cells followresearchersd by inductive heating of the nanoparticles under an alternating magnetic field (AMF). A promising approach of the initial step to improve uptake of nanoparticles into tumor cells was to use cationic liposomes. Weresearchers developed magnetite cationic liposomes (MCLs) that have 10-fold higher affinity for tumor cells than neutrally charged magnetite liposomes [19]. To test the combined effects of chemotherapy using 4-S-CAP and hyperthermia using MNP on melanoma, wresearchers prepared 4-S-CAP-loaded magnetite cationic liposomes (4-S-CAP/MCLs) [20]. An in vitro experiment showresearchersd that 4-S-CAP in 4-S-CAP/MCLs had a dose-dependent antiproliferative effect on B16 melanoma cells, and the combination treatment of 4-S-CAP with hyperthermia was determined to have an additive effect [20]. As a mechanism, the cytotoxicity of 4-S-CAP in melanoma cells depends mostly on its production of reactive oxygen species (ROS) [21]. Hyperthermia also induces ROS in various cells [22], and ROS may play an important role in the additive effect of the combined treatment of 4-S-CAP and hyperthermia on melanoma cells. Moreover, 4-S-CAP/MCLs wresearchersre injected into melanoma nodules in mice and the mice werresearchersre irradiated with an AMF for 30 min. During AMF irradiation, the temperature of the melanoma nodules increased to 45 °C and tumor growth was strongly suppressed for 12 days, including complete regression of 17% (1/6) of the melanoma nodules [20]. These results suggest that melanogenesis substrate-conjugated magnetic nanoparticles are a potent tool in melanoma therapy.

2.2. Synthetic Method of NPrCAP-SH for CTI Therapy

A synthetic route for N-(1-mercaptopropionyl)-4-S-cysteaminyl phenol (NPrCAP-SH) has been reported already [8]. Howresearchersver, there was room for improvement in the synthetic process of NPrCAP-SH, because (1) the reagent N-succinimidyl-3-[2-pyridyldithio] propionate, used in the process described in the previous paper [8], was very expensive, and (2) it was not easy to separate NPrCAP-SH from the by-products yielded in that synthetic process. Thus, it was necessary to develop a new synthetic method that shortens the reaction time, uses less expensive reagents and can generate NPrCAP-SH with larger quantities and higher purity. Obtained by hydrolyzing N-acetyl-4-S-CAP (NAcCAP) with 6 M HCl by the method of Padgette et al. [23], 4-S-CAP was reacted with 3-mercaptopropionic acid, N,N’-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in N,N-dimethylformamide for 1 h at room temperature. The resultant oily compound was purified by silica gel column chromatography to give NPrCAP-SH (90%) as a colorless crystal after recrystallization (ethyl acetate-ether). Thus, wresearchers have established an efficient and reproducible one-pot method for the synthesis of NPrCAP-SH. Wresearchers synthesized four NPrCAP derivatives bound to MNP for CTI therapy, and weresearchers have already reported the synthetic methods for three of these derivatives (NPrCAP/MNP, NPrCAP/PEG/MNP and NPCMD) [8][24][25][26]. In thiRes review, we earchers report a new method for the synthesis of NPrCAP/PEG/APTES/DNM.

2.3. Synthesis of NPrCAP/PEG/APTES/DNM Bound to Dextran Nanomagnetite

Dextran nanomagnetite (DNM) was prepared by adding dextran in water to a magnetite suspension. DNM thus prepared was first reacted with 3-aminopropyltriethoxysilane (APTES) to form APTES/DNM, and then with PEG-NPrCAP obtained by reacting NPrCAP-SH and PEG for 1 h at room temperature. The mixture was kept for 4 to 6 h at room temperature, and then kept in a refrigerator overnight to synthesize NPrCAP/PEG/APTES/DNM.

2.4. Quantification of NPrCAP Bound to DNM

In order to quantify the amount of NPrCAP bound to DNM, 6 M HCl with or without 1% phenol was added to the NPrCAP/PEG/APTES/DNM suspension and reacted for up to 4 h at 110 °C to produce 4-S-CAP. When hydrolyzed with 6 M HCl in the absence of phenol, the amount of 4-S-CAP yielded after 4 h was reduced to 20% of the amount yielded after 1 h. The reduction was considered to be due to the decomposition of 4-S-CAP during HCl hydrolysis. On the other hand, the inclusion of 1% phenol in 6 M HCl suppressed the decomposition of 4-S-CAP, which did not decompose even with 2 h reaction time. Based on the above results, the following experimental conditions to check the amount of NPrCAP bound to NPrCAP/PEG/APTES/DNM wresearchersre established: (1) the NPrCAP/PEG/APTES/DNM suspension is reacted under 6 M HCl containing 1% phenol for 1 h, and (2) the reaction mixture is diluted 10-fold with 0.1M HCl and then 4-S-CAP is quantified by high-performance liquid chromatography (HPLC) analysis.

2.5. The Different Reactivities of NPrCAP/MNP and NPrCAP/PEG/APTES/DNM as Substrates for Tyrosinase

Wresearchers examined whether NPrCAP/MNP and NPrCAP/PEG/APTES/DNM could act as substrates for tyrosinase; 4-S-CAP itself was found to be a good substrate for tyrosinase because tyrosinase oxidation of 4-S-CAP in the presence of cysteine yielded 5-S-cysteaminyl-3-S-cysteinylcatechol (CA-CysC) through ortho-quinone within 10 min [8][27][28]. HPLC analysis showresearchersd that the reaction was almost completed within 10 min, with half of the 4-S-CAP remaining after 4.2 min [8][27]. HPLC analysis showresearchersd that CA-CysC derived from 4-S-CAP was produced at 85 µM (85% yield) at 10 min. The reaction rate constant (k) of 4-S-CAP was 0.17 min−1. As NPrCAP/MNP has the same structural units as 4-S-CAP, it was expected to be a substrate for tyrosinase. If tresearchis weersre the case, CA-CysC would be obtained by HCl hydrolysis, in the presence of 1% phenol, of the cysteinylcatechol derivative of NPrCAP/MNP produced after tyrosinase oxidation of NPrCAP/MNP in the presence of cysteine. NPrCAP/MNP fell to half of the initial concentration after 82 min, and CA-CysC produced after 180 min was 80 µM (80% yield). Thus, the ratio of 4-S-CAP to NPrCAP/MNP in the reaction velocity on tyrosinase oxidation was 19.5, and the reaction rate constant (k) of NPrCAP/MNP was 8.5 × 10−3 min−1. These results indicate that NPrCAP/MNP served as a substrate for tyrosinase. On the other hand, in the case of NPrCAP/PEG/APTES/DNM, the time for reduction to half of the initial concentration was 17 min, and the concentration of CA-CysC produced after 180 min was 98 µM (98% yield). The ratio of 4-S-CAP to NPrCAP/PEG/APTES/DNM in the reaction velocity on tyrosinase oxidation was 4.0, and the reaction rate constant (k) of NPrCAP/PEG/APTES/DNM was 4.1 × 10−2 min−1. Thus, the tyrosinase oxidation of NPrCAP/PEG/APTES/DNM was about five times faster than that of NPrCAP/MNP. This was predicted because (1) the dispersibility of NPrCAP/PEG/APTES/DNM is greater and (2) in NPrCAP/PEG/APTES/DNM, the side chain is longer, and the steric hindrance of the aromatic ring site was alleviated.

3. Specificity and Mechanism of Immunomodulation by CTI Therapy in Melanoma

3.1. NPrCAP as Neo-Antigen Producer

NPrCAP is a good substrate for tyrosinase [29] and is selectively incorporated into melanoma cells, which causes cytotoxicity in vitro and in vivo [29][30]. To clarify the molecular mechanism of NPrCAP-mediated cytotoxicity to melanoma cells, Ishi-Osai reported that mice treated with intratumoral injections of NPrCAP to suppress the growth of primary B16F1 melanoma transplants also rejected secondary re-challenge tumors [10]. The participation of CD8+ T cells was suggested for the NPrCAP-mediated anti-B16F1 melanoma immunity.
Phenolic substrates as prohaptens are oxidized by tyrosinase to produce ortho-quinones, which act as haptens that covalently bind to tyrosinase or other melanosomal proteins to generate potential neo-antigens [31][32][33]. These neo-antigens trigger an immunological response cascade that results in a melanocyte-specific, delayed-type hypersensitivity reaction leading to melanocyte elimination or melanoma rejection.
Based on the haptenation theory, Ito et al. examined the oxidation of NPrCAP and its subsequent binding to sulfhydryl compounds (thiols) [28]. They demonstrated that NPrCAP is oxidized by tyrosinase to form a highly reactive ortho-quinone (N-propionyl-4-S-cysteaminyl-1,2-benzoquinone, NPrCAQ), which binds covalently to biologically relevant thiols, including proteins through cysteine residues. The production and release of NPrCAQ-protein adducts was verified in B16F1 melanoma cells in vitro and in B16F1 melanoma-bearing mice in vivo through the detection of CA-CysC after acid hydrolysis of the protein fraction. These results suggested that the phenol NPrCAP, acting as a prohapten, can be oxidized in melanoma cells by tyrosinase to the active quinone-hapten NPrCAQ, which binds to melanosomal proteins through their cysteine residues to form possible neo-antigens, thus triggering the immunological response.

3.2. T-Cell Receptor Repertoires of Tumor-Infiltrating Lymphocytes

Cytotoxic T lymphocytes (CTLs) play a significant role in antitumor immunity, and the presence of tumor-infiltrating lymphocytes (TILs) has been considered to be a favorable clinical prognostic indicator [34]. To further understand the T-cell response to melanoma in CTI therapy and to develop a more effective strategy based on immunomodulation, wresearchers investigated the diversity of TILs after CTI therapy [16]. The immune response of CTLs is mediated via T-cell receptors (TCRs) consisting of α and β chains. In the variable (V) regions, the gene sequence encoding the third complementarity-determining region (CDR3), which is called the hypervariable region, is considered to play the most important role in antigen recognition [35]. Wresearchers analyzed the diversity of the TCR Vβ family to investigate the qualitative changes of TILs after CTI therapy. Almost all TCR Vβ families (in total, 21 TCR Vβ families werresearchersre analyzed) weresearchersre detected in untreated B16 melanoma in C57BL/6 mice, whereas the TCR repertoire was restricted to a few TCR Vβ families in TILs after CTI therapy. Among them, expression of the Vβ gene was confirmed with good reproducibility, suggesting that T cells expressing the TCR Vβ werresearchersre activated by CTI therapy in B16 melanoma. In addition, weresearchers succeeded in analysis of the CDR3 gene sequence of TCR Vβ in TILs after CTI therapy [28]. Consistent with ourthe result, it was reported that a B16 melanoma-specific CD8+ T cell line, AB1, expressed TCR Vβ11 [36], suggesting that clonal expansion of Vβ11+ TILs can be a useful biomarker for the T-cell response to B16 melanoma in mice. Furthermore, the same group reported that the AB1 cells recognized a melanoma antigen, tyrosinase related protein-2 (TRP-2) peptide, which was consistent with a report by Singh et al. showing that a TRP-2 peptide-specific CD8+ T cell clone expressed Vβ11 [37]. In order to identify the antigen specificity of TILs after CTI therapy of B16 melanoma, wresearchers investigated the interferon (IFN)-γ production ability using melanoma antigen peptides such as TRP-1222–229, TRP-2180–188 and gp10025–33. When stimulated with the TRP-2 peptide, T cells wreserearchersre activated to secrete IFN-γ, indicating that TILs induced by CTI therapy of B16 melanoma responded to the TRP-2 peptide. Taken together, these findings show that tumor-specific TILs werresearchersre produced after CTI therapy and suggest that TCR Vβ11+ T cells are particularly important for immunity against B16 melanoma. Moreover, the melanoma antigen peptides selected by TIL analysis (e.g., TRP-2 peptide for B16 melanoma) may be used to boost antitumor immunity induced by CTI therapy.

3.3. CTI Therapy as In Situ Peptide Vaccine Immunotherapy

By comparing the antitumor effect of NPrCAP/MNP with and without AMF exposure, wresearchers observed that NPrCAP/MNP with AMF exposure had a superior antitumor effect compared with that of NPrCAP/MNP alone. Furthermore, mice bearing primary melanoma tumors treated with NPrCAP/MNP plus AMF showeresearchersd significant suppression of re-challenge second transplant melanoma growth, whereas NPrCAP/MNP without AMF was much less effective, with 30–50% rejection of re-challenge melanoma. These results indicate that NPrCAP/MNP with AMF exposure has a strong immunotherapeutic effect [8][9]. Therefore, wresearchers investigated the underlying mechanisms for the induction of antitumor immunity induced by NPrCAP/MNP with AMF exposure. Incorporated MNP exposed to an AMF generate heat within cells due to hysteresis loss or relaxational loss [19]. It has been demonstrated that intracellular hyperthermia using MNP is effective for the treatment of certain types of cancer, in not only primary but also metastatic lesions [38][39][40][41]. Hyperthermic treatment using cationic magnetite liposomes containing 10 nm MNP induced antitumor immunity by the enhancement of HSP expression [40]. It has been demonstrated that various types of HSPs bind antigenic peptides, and these antigen peptides are cross-presented to specific cytotoxic T cells by professional antigen-presenting cells, including dendritic cells (DCs). This exogenous pathway is called cross-presentation and is important for the development of CD8+ T cell responses against tumors and infectious pathogens that do not have access to the classical MHC class I pathway [42][43]. In ourthe study using B16-OVA melanoma cells, treatment with NPrCAP/MNP with AMF exposure resulted in the increased expression of HSPs, including Hsp72, Hsp90 and ER-resident stress proteins such as gp96, in melanoma cells [11]. Moreover, these HSPs (Hsp72, Hsp90 and gp96) wresearchersre secreted in extracellular milieu and wereresearchersre taken up by DCs. These DCs presented melanoma-associated antigen peptides (OVA peptide and TRP2 peptide) through cross-presentation of HSP-bound peptide(s) to specific CD8+ T cells. Among HSPs, Hsp72 was shown to be largely responsible for the augmented antigen presentation to CD8+ T cells. As Hsp72 is known to be most highly upregulated among several HSPs in response to heat shock, newly synthesized Hsp72 has more chances to bind melanoma-associated antigen peptides.
Thus, ourthe hyperthermia using NPrCAP/MNP with AMF exposure induced an anti-melanoma cytotoxic T lymphocyte (CTL) response through cross-presentation of melanoma-specific antigen peptides bound to hyperthermia-induced HSPs by DCs. More importantly, intracellular hyperthermia using NPrCAP/MNP can be a promising treatment for the prevention of recurrence and/or distant metastasis of melanoma, because systemic antimelanoma immunity is induced by this therapy.
If the treatment with NPrCAP/MNP plus AMF could prevent distant melanoma metastasis such as lung and distant cutaneous metastases, it would be a great boon for patients with advanced melanoma. Therefore, wresearchers examined whether treatment of primary cutaneous B16 melanoma with intracellular hyperthermia using NPrCAP/MNP with AMF can inhibit lung colonization of intravenously injected secondary challenge B16 melanoma cells. Weresearchers observed that NPrCAP/MNP plus AMF clearly inhibited lung metastasis compared with NPrCAP/MNP alone. These results indicated that intracellular hyperthermia using NPrCAP/MNP with AMF elicited systemic antimelanoma immunity and prevented lung metastasis and the recurrence of melanoma.
Thus, CTI therapy using NPrCAP/MNP with AMF against advanced melanoma is a promising strategy not only for the treatment of primary melanoma but also for prevention of the recurrence of melanoma.

4. Approach to Advanced Melanoma Patients

4.1. Scale-Up Production of NPrCAP/PEG/APTES/DNM for Clinical Application

Based on NPrCAP/PEG/APTES/DNM, which is a PEG-mediated conjugate of NPrCAP and APTES with DNM, wresearchers tested further improvements of the synthesis conditions for the development of a good manufacturing practice (GMP)-based production process. Water dispersibility is important for injectable drugs. Weresearchers found that the aggregation of NPrCAP/PEG/APTES/DNM was caused by particle-to-particle interactions due to APTES. By reducing the iron concentration from 10 mg/mL to 1 mg/mL during the APTES reaction, weresearchers found that the particle size of NPrCAP/PEG/APTES/DNM did not increase even after the reaction. Thus, this new formulation of NPrCAP/PEG/APTES/DNM can pass through a 0.2 µm filter, enabling sterilization, which is extremely important in the manufacture of drugs. Furthermore, the equipment for the production of NPrCAP/PEG/APTES/DNM, compliant with GMP, was installed in the laboratory of Meito Sangyo Co., Ltd. (Nagoya, Japan). Meito Sangyo has manufactured ferucarbotran, the drug substance of Resovist [44], which is sold by Bayer Schering Pharma (Berlin, Germany) as a clinically available magnetic resonance imaging contrast agent, in compliance with GMP. As a result of repeated synthesis while complying with the standard operating procedure, a total of 14 lots (800 mL) of NPrCAP/PEG/APTES/DNM wreserearchersre synthesized, and the reproducibility was confirmed. Taken together, a standard for the formulation of NPrCAP/PEG/APTES/DNM was determined.

4.2. Preliminary Human Clinical Trial of CTI Therapy for Advanced Melanoma Patients

Based on ourthe animal experiments and the successful production of GMP grade NPrCAP/PEG/APTES/DNM, a preliminary human clinical trial (Phase I/II) has been carried out with a limited number of stage III and IV melanoma patients, after receiving informed consents from the patients and institutional approval of ourthe human clinical trial protocol (Clinical Trial Research No. 18-67, Sapporo Medical University).
The therapeutic protocol basically followresearchersd an identical experimental schedule as that of the animal experiments. Among four patients treated with NPrCAP/PEG/APTES/DNM plus AMF exposure, two of them showeresearchersd complete and partial responses, respectively, and have been able to carry out normal daily activities after the CTI therapy. In one of those two responding patients, four distant cutaneous metastasis sites werresearchersre evaluated and either significant regression or shrinkage of all four lesions was seen. That patient was able to survive 36 months after several cycles of CTI therapy. The pathological and immunological specimens revealed dense aggregations of lymphocytes and macrophages at the site of CTI therapy. Importantly, there was a trend toward an almost identical distribution of CD8+ T cells and MHC class 1 positive cells. The other responding patient had many lymph node metastases, but has survived more than 32 months so far. In order to evaluate the overall therapeutic value for advanced melanoma, it is important to have larger-scaled clinical trials and to define concisely the molecular interactions betwreesearchersen the chemotherapeutic and thermo-immunotherapeutic effects in ourthe CTI therapy.

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