Nanoformulations-based advancement in the delivery of phytopharmaceuticals for skin cancer management
Graphical abstract
Introduction
Anatomically skin is the major outermost defensive system of the human body, and it has four different layers, namely, the stratum corneum (uppermost layer of the skin), epidermis, dermis, and subcutaneous tissue, respectively [1]. As a protective barrier, skin shields the body mechanism from external environmental toxins, pollutants, and UV (ultra-violet) radiations, generating free radicals/reactive oxygen species (ROS), etc. (Fig. 1) [2]. The overproduction of ROS imbalances the antioxidant defense system of the body leading to oxidative stress. This oxidative stress, along with environmental toxins or chemicals, and exposure of stratum corneum to ultraviolet radiation are potential hazards for the manifestation of skin cancer as it can cause oxidative damage to DNA bases such as making 8-oxo-G [3]. Generally, when mutations occur in the DNA of skin cells, they will respond to the development of skin cancer. Disorder in a signaling pathway is presented by alteration of the gene that codes for a protein in the pathway. The impairment of the DNA leads to mutation or absolute loss of the gene. The altered radiation protein or its complete absence can manipulate the signal transduction pathway of the cells. There are two types of genes, which are directly involved in the development of skin cancer, such as oncogenes, whose proteins lead to cancer formation through a dominant gain of function, and tumor suppressor genes, whose proteins conquer the progression of carcinogen or cancer-causing agents [4].
Skin cancer is the most common malignancy in the Caucasian population, having a high impact on global health. It is divided into two main classes that are melanoma and non-melanoma skin cancer (NMSC), which is similarly subdivided into squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) [5]. NMSCs are the most frequently developed skin malignancies, with a wide range of clinical behaviors [6], whereas melanoma is the most destructive form of skin cancer and records for almost 5% of every effective malignant growth/topical cancer. In 2015 WHO (World Health Organization) released worldwide data on skin cancer, and according to that, skin cancer is contributing significantly towards mortality. Statistically, the occurrence rate of melanoma and NMSCs are expanding worldwide consistently. Melanoma is the nineteenth most frequently happening cancer among people, to such an extent that around 300,000 new cases were found in 2018. On average, 2490 females and 4740 males lost their lives due to melanoma at some stages of skin cancer during 2019 [7,8].
The UV sunrays, especially UV-B (280–320 nm range), damage human skin DNA under extensive sun exposure [9]. The UV-induced tumor lesions in DNA, including cyclobutane pyrimidine dimers (CPD), have a tendency to produce mutations that are engaged with skin tumorigenesis (Fig. 2) [10].
Phytopharmaceuticals have the potential to play a safe and unique role in the management of skin cancer. More than 70% of all the available drugs for cancer in the market have originated from herbal sources. Phytopharmaceuticals show anticancer activities through various mechanisms, including encouraging apoptosis, cell cycle arrest, inflection of cell signaling pathways, and anticipation of epigenetic changes and DNA damage [11]. In addition, phytopharmaceuticals may target one or more signaling pathways to control cancer cell growth [12]. The market is flooded with various conventional topical formulations of herbal drugs or phytopharmaceuticals. However, the delivery of conventional topical formulations suffers from various limitations such as insufficient drug penetration to the diseased tissues of the skin due to its hydrophilic nature, multidrug resistance, high dose, instability, non-selectivity leading to damage of healthy tissues, and severe unintended and undesirable side effects [13]. Hence, there is a need for a drug delivery system, which can lead to an increase in the efficacy of phytopharmaceuticals.
Amongst the scientific developments of treatments for skin cancer, nanoformulations have been an attractive and novel strategy for delivering therapeutic agents in a controlled and targeted manner. For skin cancer therapy, the nano-drug delivery system overcomes the problems of conventional formulation of phytopharmaceuticals in terms of poor bioavailability at the desired targeted site due to lesser concentration after restricted permeation. Thus, nanoformulations take benefits by lowering the treatment dose with enhanced efficacy. It also decreases the severity of the side effects by modulating the size, surface charge, and specific targeting efficiencies, which can improve patient compliance [14]. Besides, nanoformulations can improve the drug targeting and retention time inside the cancer cells by incorporating some intelligent polymers which are pH and thermosensitive and releases the drug at a zero-order rate, such as the cancer cells have slightly acidic pH and high temperature where the polymers release the drug according to the pH & temperature which results in targeted and effective drug delivery [15]. Thus, the purposes of using nanoformulations for skin cancer therapies are evident, though most of the nanoformulations are at the development and research stage, and some of them are under the process of clinical trial phase Ⅲ for stage Ⅲ and Ⅳ melanoma skin cancer [16].
This review aims to gather and discuss various phytopharmaceutical-based conventional and topical nanoformulations with the outlines of the clinical management of skin cancer. Further, this review article gives a comprehensive outlook of various types of nano-based drug delivery reported to treat skin cancer as a topical drug delivery approach, which treats skin cancer with reduced side effects and improved drug targeting.
Section snippets
Clinical management of skin cancer
Skin cancer is a serious illness that is hardest to treat, and most cancer patients bite the dust in any event when treated with extremely advanced current methods. There are many treatments available for the removal and destruction of both types of skin cancer (NMSCs and melanoma) and also prevent a recurrence of skin tumors (Table 1). Skin cancer is treated by curettage, Mohs surgery, cryotherapy (high cure rate and low risk, generally safe), or laser therapy, immunotherapy, chemotherapy,
Role of phytopharmaceuticals in skin cancer treatment
Phytopharmaceuticals have the potential to play a safe and unique role in skin cancer and many other diseases. Phytopharmaceuticals used in skin cancer treatments strengthen the body's own functions and immune system, which support healing the body itself. Over 50% of all drugs available in the market have originated from natural sources, of which over 70% of anticancer agents have their origin from natural sources [33]. Some of the natural plant extracts that have been used in phytomedicine to
Nano-based drug delivery system for the treatment of skin cancer
Nanotechnology is also known as the magic bullet in pharmaceutical drug delivery science as it is capable of delivering the drug precisely to the target tissues so that the maximum benefits with reduced side effects can be achieved [84]. The use of nanoformulation has been an attractive strategy for delivering therapeutic agents at the tumor site [85]. The promising quality of nanoformulation systems is their ability to increase the permeability of the drug formulation through the porous tumor
Ligand modified nanoparticles as a novel drug delivery tool in the treatment of skin cancer
Nanoparticles are functionalized with explicit ligands that can target malignancy cells in an anticipated and synergistic way and transport typified payloads effectively [152,153]. The significant aspect of selecting ligands for tumor targeting is their distinctive capability to initiate receptor-intervened endocytosis. The characteristics of ligand choice are influenced by the cooperation/association between the targeting ligand and targeted surface epitope. This method upgrades the movement
Future of nano-based topical drug delivery against skin cancer
For effective treatment of skin cancer, nano-based topical drug delivery is gaining momentum in order to achieve improved permeation and retention of the drug molecules into the desired layers of skin. Polymeric-based nanoparticles and lipid-based systems such as liposomes, nanoemulsion, NLC are extensively being researched to find better treatment outcomes. In addition, the use of ligands is also being explored for specificity. Further, to improve the treatment regimen, combination therapy is
Conclusion
Nanoformulations offer new ideas for the treatment of skin cancer. Nano-based topical drug delivery has become an attractive therapeutic system due to its unique features like being non-toxic, effective, non-irritant, and non-invasive for the management of skin cancer. The nanoformulations carry active molecules or their combination and are attractive for reducing the tumor mass. The system is specifically beneficial for those patients that are not applicable for surgery or highly intensive
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors would like to thank the Indian Council of Medical Research (ICMR), Government of India, New Delhi, India, for providing financial assistance (ICMR-Senior Research Fellowship Ref. No. 45/31/2020-Nan/BMS).
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