Melanoma (MEL) is a less common type of skin cancer, but it is more aggressive with a high mortality rate. The World Cancer Research Fund International (GLOBOCAN 2012) estimates that there were 230,000 new cases of MEL in the world in 2012. Conventional MEL treatment includes surgery and chemotherapy, but many of the chemotherapeutic agents used present undesirable properties. Drug delivery systems are an alternative strategy by which to carry antineoplastic agents. Encapsulated drugs are advantageous due to such properties as high stability, better bioavailability, controlled drug release, a long blood circulation time, selective organ or tissue distribution, a lower total required dose, and minimal toxic side effects. This review of scientific research supports applying a nanotechnology-based drug delivery system for MEL therapy.
Malignant melanoma (MEL) are tumors that mainly affect adult and elderly patients; the highest incidence is at approximately 60 years of age [
The World Cancer Research Fund International (GLOBOCAN 2012) estimates that there were 230,000 new cases of MEL in the world in 2012; MEL incidence rates are much higher in the White population than in the Black population, and it is uncommon in the Asian population, likely due to better protection from their skin pigment and different sun exposure habits; African and Asian societies consider fair skin beautiful [
Melanoma describes melanocyte malignance; a melanocyte is a melanin-producing cell located in the basal layer of the epidermis [
In summary, the most significant causes of MEL development are at personal history of MEL in the family, advanced age, the presence an atypical nevus, intense exposure to sunlight, sunburn during childhood [
Genetic predisposition plays an important role in MEL development due to the relative risk of people with a family history of MEL developing this cancer, which is 2-3 times greater than in people without such a family history; several genes (CDKN2A; BRAFV600E; N-Ras codon 61; CKIT; GNAQ/GNA11; BRCA2; OCA1 and MC1R) related to this predisposition have been identified [
UV radiation also has a profound influence on MEL development. Sunscreens use, which protect the skin against this radiation, does not prevent MEL development, because the UV radiation spectrum that causes erythema (UVB) and that traditional sunscreens protect against differ from the spectrum that promotes MEL (UVA). Thus, users of sunscreens are relatively unprotected from UVA radiation [
The cutaneous MEL is manifested in different regions of the body through lesions on the head and neck and is associated with chronic sun exposure and lesions on the trunk related to the presence of numerous melanocytic nevi [
Almost all MEL lesions are pigmented and flat; malignant melanocytes growth is restricted to the epidermis (“MEL
For melanocyte transformation in MEL, resistance to apoptosis is necessary [
For MEL diagnosis, five main characteristics of the lesion are analyzed: asymmetry, border-color, diameter, and elevation; MEL diagnoses are more accurate where dermatoscopy is used [
The MEL stage can be determined through a complete clinical examination [
Moreover, an immunohistochemical technique can also be used to diagnose metastasis because antigens are expressed on malignant cells’ membrane and cytoplasm surface, which can be immunohistochemically detected using antibodies that are specific to these antigens [
The conventional treatment for primary MEL is surgical; the lesion is removed, and the tissue is analyzed to determine the MEL stage, which depend on the lesion thickness and location (epidermis or dermis). The lesion is removed with a certain safety margin; however, where lesion excision is inappropriate, such as for MELs in the nasopharyngeal, sinonasal, and oral regions, radiotherapy is a way to eliminate the lesion. For patients who present risk of metastasis, the above indicated laboratory tests are also used, such as radiography of the thorax [
The conventional MEL chemotherapy treatment is performed using dacarbazine, temozolomide (dacarbazine analogue), nitrosoureas (carmustine, lomustine), vinca alkaloids (vincristine, vinblastine), platinum compounds (cisplatin, carboplatin), and taxanes (Taxol, docetaxel), but these single agents are not an improvement over dacarbazine [
The benefits of therapy with interferon alfa-2b are directly related to the MEL stage [
Vemurafenib and dabrafenib are BRAF inhibitors approved for use in MEL metastases that express BRAFV600E and lead to dramatic shrinkage of tumors. However, they are short-lived and resistance to treatment eventually emerges in most melanomas. In addition, treatment with BRAF inhibitors can lead to the induction of second primary cancers, including squamous cell carcinomas of the skin and new primary BRAF wild-type melanomas; other side effects are nausea, diarrhea, arthralgias, nonspecific skin rashes, fatigue, alopecia, and photosensitivity [
Tremelimumab is an antibody against the cytotoxic T lymphocyte-associated antigen 4 and is well-tolerated, but it does not offer many benefits over conventional chemotherapy [
Ipilimumab is a humanized antibody against CTLA-4, a negative regulatory checkpoint protein that is expressed on T cells surface after activation; the ipilimumab specifically blocks the CTLA-4 inhibitory signal, resulting in activation of T cells and tumour infiltrating lymphocytes; this is an indirect mechanism that enhances the immune response mediated by T cells. The adverse effects are colitis, dermatitis, hepatitis, endocrinopathy, and neuritis [
Nivolumab and pembrolizumab are anti-PD-1 antibodies; PD-1, like CTLA-4, is expressed on the surface of activated T cells and has a function to turn off the T-cell response to prevent an excessive immune reaction. Anti-PD-1 antibodies may have higher response and lower toxicity rates than ipilimumab, as well as improved overall survival compared to chemotherapy [
Studies demonstrated that a combination therapy with ipilimumab and nivolumad was responsible for more adverse effects than monotherapy; on the other hand the patient’s median survival was higher when patients were treated with combination therapy [
Many active ingredients used in MEL therapy present undesirable properties and, thus, have been discarded [
Drug delivery systems represent an alternative strategy to carrier antineoplastic agents. Encapsulated drug could result in advantages such as high stability, better bioavailability, controlled drug release, long circulation time in blood, selective organs or tissue distribution, a reduction of the total dose required, and minimizing the toxic side effects [
Polymeric systems can be classified by their physical forms such as (i) linear polymer chain in solution, (ii) physically or covalently cross-linked reversible gels, and (iii) polymer chains grafting or adsorption on the surface of micro- and nanoparticles [
An increased interest in hydrogels as a drug delivery system has been demonstrated as a result of their easy handling and similar physical properties to animal tissue, which depend on the polymer employed [
A wide variety of polymeric materials with different properties have been used to form hydrogels. The required polymer is selected based on the tissue of interest and the specific application [
Hydrogels have been employed as a drug delivery system in MEL therapy because they may act as an intratumoral chemotherapy depot by promoting accumulation or maintenance of high intracellular levels of the chemotherapeutic agent. In recent years, a hydrogel composed of a cyclodextrin-containing linear polymer and decorated with PEG as well as transferrin was approved for commercial use in MEL therapy [
Hydrogels are classified as stimuli-sensitive swelling-controlled release systems because they can respond to various environmental conditions, such as pH, the surrounding fluid ionic strength, temperature, an applied electrical or magnetic field, or glucose level changes. These changes promote altered network structure, swelling, mechanical strength and permeability [
Certain studies suggest using topical hydrogels; topical ibuprofen-releasing hydrogels promote lower metastatic spread of primary MEL through significantly lower tumor necrosis factor (TNF)-
Injectable hydrogels have been widely explored for cancer therapy [
Subcutaneous injection of a doxorubicin-loaded hydrogel composed of sugar beet pectin (SBP) associated with biodegradable gelatin (SBP/gelatin) successfully suppressed mouse MEL B16F1 cell tumor growth in nude mice [
The human MEL cell line Me665/2/21 derived from a cutaneous metastasis was treated for 48 h with a cisplatin-loaded hydrogel and it showed similar and, in certain cases, higher cytotoxic activity towards the MEL cell line compared with free cisplatin at the same concentration [
A novel system for incorporating paclitaxel has been investigated to lower toxicity and improve efficacy [
Recently, research has described the importance of lipids in drug carrier systems such as liposomes [
The liposomes are microscopic spherical nanostructured with a well-defined shape and size, which varies from 10 nm to several micrometers, depending on the technique used to create them [
Micelle with hydrophobic compounds.
Micelle with hydrophilic compounds.
Liposome encapsulated hydrophobic and hydrophilic compounds.
Liposomes have high versatility because they can be modified based on pharmacological and pharmaceutical needs. Thus, the size, surface, lamellarity, lipid composition, volume, and inner aqueous medium composition can be modified in these vesicles [
Liposomes can be formed with natural lipids, such as sphingomyelins, as well as lecithins and synthetic lipids, such as dimyristoyl, distearoyl, dipalmitoyl, and dioleoyl [
The extrusion technique forces a lipid suspension to pass through a polycarbonate membrane with a well-defined pore size [
For the sonication technique, liposomes are prepared using a sonicator to mix the lipid suspension. The pressure exerted by the sonicator stirring causes a decrease in the larger vesicles sizes. Thus, the stirring time is decisive for liposome size formed. The main advantage of this technique is less time in liposome preparation [
Liposomes have attracted the attention of the scientific community due to their high versatility. Liposomes have greater therapeutic efficacy than conventional pharmaceutical system because they promote slow drug release at the target site [
Wolf et al. (2000) [
Another study using T4 endonuclease V in liposomes was conducted by Yarosh et al. (2001) [
Pierre et al. (2001) [
Chen et al. (2012) [
Nobayashi et al. (2002) [
Liu and colleagues (2013) [
Cyclodextrins (CDs) are a family of natural cyclic oligosaccharides with
Recent studies have demonstrated that CDs are efficient drug delivery systems for targeting cancer cells [
In general, the pH surrounding tumor tissues tends to be more acidic (i.e., ~ 5.5 to 6.5) than normal tissue (i.e., 7.4) [
Polypseudorotaxanes are inclusion complexes formed between cyclodextrins and linear macromolecules such as polymers [
4-Hydroxynonenal (4-HNE) is the end product of lipid peroxidation, which has been broadly used to inducer oxidative stress, and it produces a cytotoxic effect in cancer cells [
Disrupting the lipid rafts’ integrity, which are plasma membrane microdomains rich in cholesterol, may modify tumorigenic processes by altering the functionality of CD44, which is a cell surface receptor involved in cell migration and tumor metastasis [
Mazzaglia and coworkers (2013) [
Mistletoe extract is often used in complementary cancer therapy [
Betulin (BET) is found in
Interleukin-2 (IL-2) promotes immune recognition of MEL, while sparing normal cells [
Cancer photodynamic therapy (PDT) combines a photosensitizer or photosensitizing drug with a specific type of light source to treat cancers [
Pharmaceutical companies have shown an interest in developing nanostructured systems, such as liquid crystals, which have advantages that are mainly related to controlled drug release, and protect the active ingredients from thermal degradation or photobleaching [
Liquid crystalline systems can compartmentalize drugs in the inner phase droplets, which have different physicochemical properties than the dispersing medium, and induce changes in the biological properties of the incorporated substances [
Lehmann described an intermediate state in the thermal transformation from solid to liquid, which became known as liquid crystals (CLs) [
Liquid crystals are classified as lyotropic and thermotropic. When these systems are formed through adding solvents, they are lyotropic; thermotropic formation is temperature-dependent. As the surfactant concentration changes occur, different liquid-crystalline forms can be generated, such as lamellar, hexagonal (hexasomes), and cubic (cubosomes) forms. The lamellar phase is formed by parallel, planar layers of surfactant bilayers separated by a solvent layer, which form a one-dimensional network. Beginning in the hexagonal phase, aggregates are formed through an arrangement of long cylinders that form two-dimensional structures. In the cubic phase systems, the molecules are arranged in a three-dimensional system that consists of two corresponding water channel networks surrounded by lipid bilayers or surfactant [
Polarized light microscopy is an important tool to identify and classify liquid crystalline materials. Photomicrographs are used to demonstrate the observed textures, typically using polarized light [
Figures
Polarized light microscopy of the lamellar phase (anisotropic system).
Polarized light microscopy of the hexagonal phase (anisotropic system).
Liquid crystals have increasingly been used as delivery systems; Bitan-Cherbakovsky and colleagues (2013) [
Cubosomes present potential utility as a drug delivery system in skin cancer therapy, such as for MEL, due to their bioadhesion properties and enhancer penetration [
5-FC phytanyl (5-FCPhy) is an amphiphile prodrug, carried in a lyotropic liquid crystalline system, and its
von Eckardstein et al. (2005) developed an intracavitary carrier system composed of cubosomes that encapsuled carboplatin and paclitaxel; the release kinetics, the antitumor activity against glioma, and the prolonged survival were analyzed. The results show a significantly smaller tumor in animals treated with paclitaxel/carboplastin compared with the control group although survival did not differ among the groups studied. Both the drugs carried in the crystalline cubic phases presented cytotoxic activity in tumor cells, which indicates that they play an important role in cancer therapy [
Many studies show the advantages of liquid crystals as a drug delivery system. However, most studies conducted using liquid crystals as a chemotherapy drug delivery systems remain at an early development stage. Several studies have been executed to characterize certain systems without efficacy trials [
The Food and Drug Administration (FDA) defines a nanoparticle as any material with a dimensional range of approximately 1 to 100 nm or end products with a dimension up to 1
In 1996, Müller and Lucks introduced the term solid lipid nanoparticle (SLN) to patent a manufacturing process using high pressure homogenization [
Subsequent modifications to SLNs have been described, which are nanostructured lipid carriers (NLC) and are the second generation of LN [
The image shows an SLN-organized lipid matrix composed of only solid lipids (a) and imperfections in the crystal lattice (b) on NLC or SLN that are composed of multiple solid lipid components with distinct structural features that are distorted upon forming a perfect crystal.
In addition to LN, polymeric nanoparticles (PN) may be constructed from organic polymers or inorganic materials, such as silica [
PN can be referred to as nanocapsules or nanospheres depending on their composition [
Polymeric nanoparticles schematics: nanospheres (a) and nanocapsules (b).
Drugs are entrapped in PN throughmixing the drug and polymer solution. Drug compounds are physically entrapped in the nanoparticle through polymer self-assembly [
Both types of nanoparticles (lipid and polymeric nanoparticles) can be used as a drug delivery system with antitumor properties in MEL therapy.
Identifying tumor microenvironment properties is critically important for accumulating the most nanoparticles at the site of action, which decreased drug toxicity and adverse effects. Pathological systems’ metabolism, cell morphology, and microenvironment have peculiar characteristics [
Nonspecific interactions may appear in addition to specific biomarkers such as van der Waals bonds and electrostatic and steric affinities that can be used to predict the propensity for nanoparticle adhesion and uptake [
Particular nanocarrier structural components for improving drug targeting to the tumor tissue.
Components for successful targeted drug delivery in antitumor | Benefits in anticancer therapy | References |
---|---|---|
Active targeting | ||
Cholesterol | Cancer cells take up 100-fold more low density lipoprotein (LDL) than normal tissue due to upregulated LDL receptors in cancer cells for membrane synthesis during cell division associated with malignant transformation processes. Thus, LDL has been proposed as a drug carrier for anticancer agents. | [ |
Polyunsaturated fatty acids ( |
They can be attached to the tumor cell membrane more easily, which results in disruption and fluidity of the cell membranes. Tumor progression is reduced by modulating p53, p16, and p27 expression and cell cycle regulation, as well as by inducing cell death by apoptosis and necrosis. | [ |
Hyaluronic acid | Hyaluronic acid is an extracellular matrix compound that specifically binds CD44, which is an extracellular membrane protein that regulates various cellular responses. CD44 is overexpressed in cancer cells, while normal cells underexpress this protein. Thus, CD44 is a good candidate biomarker for cancer cells. | [ |
Folic acid | Folate is important for producing and maintaining new cells because it can participate in nucleotide synthesis. Folates receptors are highly overexpressed in cancer cells. In addition, only the malignant cells, not normal cells, transport folate-conjugates; thus, the folate-drug conjugation can improve tumor-targeted drug delivery. | [ |
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Passive targeting | ||
Polysaccharides; polyacrylamide; polyvinyl alcohol; polyvinylpyrrolidone; PEG; PEG-containing copolymers (poloxamers; poloxamines; polysorbates; and PEG copolymer). | They prevent the opsonin binding to the nanoparticle surfaces and, consequently, recognition as well as phagocytosis of the nanoparticles by the mononuclear phagocytic system, which enhances the blood circulation time. |
[ |
Cationic surfactants | The positive charge of a cationic surfactant interacts through electrostatics with the negatively charged phospholipids that are preferentially expressed on the cancer cell surface. |
[ |
Recent studies have shown improved SLN uptake and accumulation in tumor tissue [
Xu and coworkers (2009) development a docetaxel-loaded SLN composed by egg phosphatidylcholine, dioleoylphosphatidylethanolamine, trimyristin, and lactobionic acid that showed 2.4-fold greater accumulation in tumors compared with the nonencapsulated drug 6 hours after intravenous administration. Galactosylation of the nanoparticle surfaces enhanced the cellular uptake of docetaxel and promoted passive targeting of the drug into the tumor cell, which reduced systemic toxicity [
Guo et al. (2010) investigated the antitumor effects of resveratrol (RES) bovine serum albumin nanoparticles. The results showed that the concentration of RES was greatly increased in the target tissue when the RES-loaded nanoparticle was injected. High levels of RES were observed in bloodstream for long periods of time after the RES suspension was administered (nonencapsulated RES), which illustrated incomplete RES distribution. Moreover, the results show that RES-loaded nanoparticles promoted greater tumor growth inhibition [
The drug release profile was modulated using drug-loaded LN. A recent study demonstrates that the camptothecin release rate can be modified by changing lipid nanoparticle inner phases. The SLN composed of precirol as the solid lipid showed the most sustained release (45% of the total drug was released after 30 hours) while the NLC composed of precirol as the solid lipid and squalene as the liquid lipid showed more rapid release (65% of the total drug was released after 30 hours). Drug mobility decreased when solid or crystalline substances were incorporated into the nanoparticles, which decreased the drug levels released as a function of time. Greater inhibition of MEL cell proliferation was observed when the cells were treated with nanoparticles, which may be because MEL cells exhibit excellent uptake endocytosis [
Docetaxel-loaded NLC (DTX-NLC) composed of stearic acid, glyceryl monostearate, soya lecithin, and oleic acid showed as sustained-release drug profile (77% of the total drug after 24 hours), while Duopafei (docetaxel injection provided by Qilu Pharmaceutical Co., Ltd. in China) showed 100% release after 24 hours. In addition, DTX-NLC showed greater cytotoxicity against MEL cells compared with Duopafei through enhanced apoptosis. Moreover, DTX-NLC showed low cytotoxicity for healthy cells because the drug is only released after endocytosis by a target cell [
Camptothecin was encapsulated into NLC, which was composed of cetyl palmitate, coconut oil, and Myverol associated with a quantum dot (metallic compounds at the core of the semiconductor NLC) as oil phase and Pluronic 68 solution as water phase. Camptothecin-loaded NLC presented superior cytotoxicity against MEL cells and the greater cell uptake compared with other carriers. Cellular endocytosis was essential for cell viability and the quantum dots showed a minimal capacity to influence proliferation. In addition, camptothecin accumulation in the MEL increased by approximately 6.4-fold following administration of the camptothecin-loaded nanoparticle.
Multiple synthetic and natural biodegradable polymers may be used in antitumor drug delivery systems, such as polyesters (e.g., polylactic acid, PLA), polyamino acids (e.g
Interleukin-2 was delivered by a polymeric nanoparticle composed of a low molecular weight polyethylenimine linked by
Polymeric nanoparticle using polylactic-co-glycolic acid (PLGA) as a polymer to incorporate coumarin increased the cellular uptake rate 2-fold versus nonencapsulated coumarin. In addition, molecular signals for mRNA expression were used to demonstrate that the coumarin-loaded nanoparticle downregulated cyclin-D1, proliferating cell nuclear antigen (PCNA), survivin, and Stat-3, and it upregulated p53 and caspase-3, promoting enhanced apoptosis of MEL tumor cells compared with nonencapsulated coumarin [
As a drug delivery system for apigenin, PLGA-PN promotes faster mobility and site-specific activity in MEL in addition to efficiently preserving apigenin photodegradation. The results also showed increased free radical accumulation and antioxidant enzymes depletion inside tumor cells, which exacerbated DNA damage and results in apoptosis through mitochondrial dysfunction [
A polymer-based delivery vehicle for cisplatin composed of chitosan and carboxymethylcellulose showed enhanced cytotoxicity (approximately 10-fold greater) in MEL tumor cells compared with nonencapsulated cisplatin. Further, rapid intracellular drug release was observed upon endocytosis of this system by a tumor cell, and only high-density NPs and positively charged-surfaces were capable of releasing cisplatin into MEL. Moreover, it decreased drug loss during blood circulation [
Superparamagnetic iron oxide nanoparticles consist of a carboxydextran shell and show increased uptake in human mesenchymal stem cells; the nanoparticle uptake efficiency was related to a higher density of carboxyl groups on the nanoparticle surface [
This paper describes umpteen benefits to use nanocarriers system to vehiculate drugs used in melanoma therapy. But, to choose the better system type, it is also necessary to analyze the disadvantage of each system. Table
Main advantages and disadvantages of each system.
Nanocarrier | Advantages | Disadvantages | References |
---|---|---|---|
Hydrogels | Cells and fragile drugs, like peptides, proteins, DNA, and oligonucleotides, could be protected by aqueous environment |
Can be difficult to manufacture |
[ |
|
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Liposomes | They can be formed by natural or synthetic lipids |
High-energy sonication frequently causes oxidation and degradation of phospholipid |
[ |
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Micelles | Ease to prepare |
Risk of disintegration after administration | [ |
|
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Cyclodextrins | Potential solubilizing and stabilizing agents |
Some cyclodextrins have been shown to be irritants |
[ |
|
|||
Liquid crystals | They are easy to prepare |
Difficult to prepare and administer due to high viscosity |
[ |
|
|||
Nanoparticles | They can be prepared by different methods |
Toxicological assessment is uncompleted |
[ |
Particular nanocarrier structural components were previously described for improving drug targeting to the tumor tissue (Table
A study realized by Shi and coworkers (2014) demonstrated that microRNA-34a and paclitaxel-loaded functional cationic solid lipid nanoparticles presented a synergistic anticancer efficacy.
C57BL/6 mice were inoculated subcutaneously with B16-F10 melanoma cells (1 × 106 in 100
Interleukin-2-loaded polymeric nanoparticle inhibited the tumor growth and can lengthen survival in mice B16F1-bearing melanoma. The antitumor effect was dose-dependent and the system demonstrated low toxicity, representing a new strategy in drug delivery system for melanoma gene therapy [
Cai et al., 2012, carried out a study to verify the influence of tumor-targeting nanocarrier in long-circulation effects promoted by PEGylated liposome. Results demonstrated that paclitaxel-loaded targeted PEGylated liposomes (TL-PTX) lengthen the half-life of paclitaxel 2.01-fold of conventional liposome and 3.40-fold of free paclitaxel in plasma. Higher accumulation of TL-PTX in tumor tissue, liver, and spleen was observed compared to conventional liposome and free paclitaxel [
Doxil, the first FDA-approved nanodrug [
In a clinical phase II study, Ugurel et al. (2004) verified that patients treated with liposomal doxorubicin as monotherapy present survival benefit. Outpatients setting (30 patients) were included on this study. Liposomal doxorubicin is used at 50 mg/m2 i.v. on days 1, 22, 43 and 64, subsequently at 40 mg/m2 at day 85 before first staging and in 4-week intervals thereafter. The results demonstrated that 7 patients stay alive more than 300 days and 5 patients more than 400 days [
Patients with cancer stage IV melanoma participated in an open-label, phase II study conducted by Hwu and coworkers (2006). Patients received a combination of 75 mg/m2 per day of temozolomide, during 6 weeks, there was a 2-week break between cycles, and they were continuously subcutaneously administrated PEGylated IFN-2b at 0.5 g/kg/week. Results showed that patient’s median survival was 12 months and they were followed for 16 months and brain metastases were developed in any patients. Researchers concluded that a combination therapy promotes antitumor activity in metastatic melanoma [
The wide range of compositions, morphologies, and particle sizes exhibited by drug delivery systems makes it difficult to understand their cellular uptake mechanisms. Thus, elucidating fundamental cellular processes that cells used to import and export select extracellular molecules may contribute to understanding the cellular internalization mechanisms of the systems and aid in selecting the appropriate system to transport active compounds [
Advances in nanotechnology based drug delivery systems have improved our understanding of the biological effects of nanotechnology-based systems, which will undoubtedly lead to important, clinically relevant improvements in drug delivery. New challenges in developing nanotechnology-based drug delivery systems for MEL antitumoral therapy include the feasibility of upscaling processes to quickly bring the innovative therapeutic techniques to the market and the potential for multifunctional systems that will fulfill several biological and therapeutic requirements, such as the system needing to be able to target tumor cells or tumor environment after systemic delivery. Further challenges include researches on efficiency of targeted anticancer therapies and imaging agents as well as international standards regarding their toxicology and biocompatibility.
So, the possibility of nanocarriers can promote the targeted cancer therapy and potentially early detection of cancer lesions; noninvasive imaging that permits determination of molecular signatures induces the concept of personalized medicine [
Drug delivery systems represent an alternative strategy to carrier antineoplastic agents. Many advantages of drug delivery system have been described in recent studies such as better drug stability, better bioavailability, controlled drug release, long circulation time in blood, selective organs or tissue distribution, a reduction of the total dose required, and minimizing the toxic side effects.
Certain drug delivery characteristic can distinguish their application such as hydrogel that are stimuli-sensitive swelling-controlled release system. Liposome can encapsulate both hydrophobic and hydrophilic compounds. CD can form drug complexes and are biocompatible. LC protects the active ingredients from thermal degradation or photobleaching. SLN and NLC are maintained in the tumor for long period of the time due to low venous return and lymphatic drainage. PN forms reservoir-based drug delivery systems in nanocapsules and matrix organized polymeric chains in nanospheres. The wide range of compositions, morphologies, and particle sizes exhibited by drug delivery systems makes it variable mechanism for successful targeted delivery, while making it difficult to understand their cellular uptake mechanisms.
Another important aspect is identifying pathological systems’ metabolism, tumor cell morphology, and microenvironment properties for accumulating the most drug delivery system at the site of action, at which decreased drug toxicity and adverse effects and biomarkers (antibodies, aptamers, peptides, and small molecules) can be identified, and molecules can be attached to the systems surface for successful targeted drug delivery to the site of action.
Thus, elucidating fundamental cellular processes that cells used to import and export select extracellular molecules may contribute to understanding the cellular internalization mechanisms of the systems and aid in selecting the appropriate system to transport active compounds. Endocytosis of particles into cells depends not only on particle size, but also on surface coating and cell type.
Several studies on cancer have been conducted worldwide, but peculiarities of tumor cells that distinguish them from normal cells are not completely elucidated, which made the delineation of targeted drug delivery for cancer therapy difficult.
Another problem is that chemotherapy drug delivery systems remain at an early development stage. Several studies have been executed to physicochemically characterize certain systems. However, the influence of systems to improve drug biological properties is understudied.
Tumor microenvironment plays an important role in tumorigenesis and may also influence the success rate of melanoma therapy. The drug delivery systems need to cross anatomical and physiological barriers of tumor microenvironment. However, many mysteries emphasize the complexity of the task.
In the recent decade, one of the most studied fields is nanotechnology-based drug delivery and various targeting mechanisms were discovered such as cancer-specific ligand for receptor-mediated active targeting (i.e., folate and hyaluronic acid); microenvironment-responsive molecules that respond to changes in pH, temperature, light, chemicals, and electromagnetic fields; PEGylation-induced passive targeting; electrostatics interaction and molecules that prevent the opsonization.
Drug delivery system for melanoma therapy may target the several pathways involved in melanoma development such as three-tiered Ras/Raf/MEK mitogen-activated protein kinase (MAPK); PI(3)K; NF-kappaB; p16INK4a/RB and ARF signalling pathways.
Although breakthrough in melanoma antitumor therapy research has been observed, more studies are necessary to better understand the role of drug delivery system in MEL therapy.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Programa de Apoio ao Desenvolvimento Científico da Faculdade de Ciências Farmacêuticas (PADC-FCF-UNESP).