Quality by Design Galvanized development of resveratrol loaded PLGA nanoparticles: In vitro and Ex vivo evaluation for the non-invasive treatment of metastatic melanoma

Cutaneous malignant skin cancer (melanoma) is a lethal form of skin cancer that arises from melanocytes, the melanin-producing cells present in the epidermis of the skin. Malignant melanoma is a deadly disease that rapidly invades layers of the skin and intravasates into the blood vessels, ultimately leading to the development of metastatic tumors in distant organs [1]. Global statistics reveal that melanoma is the 17th most common cancer that affected ∼324,635 individuals and caused 57,043 deaths in the year 2020 [2]. The available therapeutic interventions for melanoma include radiotherapy, surgery, chemotherapy and/or immunotherapy [3]. Radiotherapy and surgeries are preferred when the disease is confined to the site of origin i.e., skin. Further, systemic chemo- and immuno-therapies are used as a stand-alone therapy or after radiation or surgery to eradicate residual tumor cells. However, systemic chemo- or immuno-treatments are associated with severe adverse effects that can lead to poor patient compliance and compromised quality of life [[4], [5], [6]]. Findings from the cohort studies suggest that approx. 13.4 % of primary melanoma patients experience disease recurrence within 2 years [7].

Metastasis is a complex process that involves invasion, migration, and tumorigenesis in a new distant organ spreading cancer cells from the primary location (skin). This process consists of a sequence of events wherein primary tumor cells transform to mesenchymal lineage and invade distant organs [1]. Reports reveal that melanoma metastasizes to organs such as lung, liver, intestine, brain and bone and causes serious complications, eventually leading to death [[8], [9], [10]]. Therefore, development of novel therapeutic interventions that eliminate tumor cells and reduce metastasis while circumventing adverse effects of conventional chemotherapeutic agents are needed. Literature reveals that RES, a natural polyphenolic phytoalexin, causes inhibition of melanoma cell proliferation and as a consequence, suppresses melanoma growth and progression [[11], [12], [13]].

It has been demonstrated to arrest cancer cell proliferation via various pathways mainly PI3K. Moreover, this compound inhibits epithelial to mesenchymal transition (EMT) of melanoma cells [14] thereby showing anti-metastatic effect. In addition, RES possesses anti-inflammatory [15], immunomodulatory [16], neuroprotective [17], antioxidant [18], antiproliferative [19], and anti-metastatic [20] properties. Therefore, RES can be explored as a therapeutic agent in the treatment of metastatic melanoma. Bruna carletto et al. prepared RES-loaded nanocapsules for the inhibition of murine melanoma cell growth. Results from histopathology and tumor volumes measurment studies demonstrated that encapsulated RES showed increased necrotic area and decreased tumor volume [21]. Marinheiro et al. reported that loading of RES in mesoporus silica NPs improved aqueous dissolution, ultimately improving aticancer activity in melanoma cancer cells [22]. Despite numerous attempts, an effective therapeutic strategy that shows dual therapeutic benefits (anticancer and anti-metastatic effects) while offering loco-regional drug delivery at the site of melanoma (deep epidermal layer) is still an unmet need. Literature reveals that topical application of therapeutic agents in ointment- or gel-based conventional formulations resulted in rapid drug clearance and compromised therapeutic efficacy [23].

The disadvantages associated with traditional formulations have been addressed using particulate drug delivery systems such as micro- and nano-particles. Nanoparticulate drug delivery systems showed encouraging results in transdermal drug delivery applications by offering improved skin permeation and retention in the stratum corneum or viable skin [24]. NPs are colloidal drug delivery systems that provide several advantages over microparticles and conventional drug delivery methods. NPs, attributed to the nanometric dimensions and high aspect ratio, can easily interact with dermal cells and get permeated across various layers of the skin. These properties potentially improve the bioavailability of entrapped therapeutic agents at the melanoma site [25]. Further, NPs offer protection to entrapped therapeutic agents from external factors, enhancing drug stability. Reports reveal that NPs of ∼200 nm can easily permeate across the epidermal layer and accumulate at the site of melanoma [26]. In turn, the extent of permeation and subsequent deposition of NPs in melanomas can be improved by using a suitable gel-based matrix system [27,28]. Furthermore, polymeric NPs composed of slow biodegradable polymer such as PLGA 50:50 can prolong drug release, reducing the frequency of topical applications.

Therefore, we hypothesized that non-invasive topical delivery of a therapeutic agent with dual pharmacological action (i.e., inhibition of cell proliferation and metastasis) via a nanoparticulate delivery system could improve the overall tumor-free survival among melanoma patients. To test our hypothesis, we initially performed formulation optimization studies in silico using QbD tool and developed an optimal formulation. After the development, we performed in vitro studies to demonstrate anti-proliferative and anti-metastatic ability of RES loaded NPs, followed by ex vivo studies to demonstrate skin permeation of developed formulation.

Read more

Ganesh Vambhurkar, Paras Famta, Saurabh Shah, Naitik Jain, Dadi A. Srinivasarao, Anamika Sharma, Syed Shahrukh, Dharmendra Kumar Khatri, Shashi Bala Singh, Saurabh Srivastava, Quality by Design Galvanized development of resveratrol loaded PLGA nanoparticles: In vitro and Ex vivo evaluation for the non-invasive treatment of metastatic melanoma, Journal of Drug Delivery Science and Technology, Volume 91, 2024, 105252, ISSN 1773-2247,