Ultra-flexible nanocarriers for enhanced topical delivery of a highly lipophilic antioxidative molecule for skin cancer chemoprevention

Abstract

Purpose In this study, we developed cationic ultra-flexible nanocarriers (UltraFLEX-Nano) to surmount the skin barrier structure and to potentiate the topical delivery of a highly lipophilic antioxidative diindolylmethane derivative (DIM-D) for the inhibition of UV-induced DNA damage and skin carcinogenesis. Methods UltraFLEX-Nano was prepared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-3-trimethylammonium-propane, cholesterol and tween-80 by ethanolic injection method; was characterized by Differential Scanning Calorimetric (DSC), Fourier Transform Infrared (FT-IR) and Atomic Force Microscopic (phase-imaging) analyses and permeation studies were performed in dermatomed human skin. The efficacy of DIM-D-UltraFLEX-Nano for skin cancer chemoprevention was evaluated in UVB-induced skin cancer model in vivo. Results DIM-D-UltraFLEX-Nano formed a stable mono-dispersion (110.50±0.71nm) with >90% encapsulation of DIM-D that was supported by HPLC, DSC, FT-IR and AFM phase imaging. The blank formulation was non-toxic to human embryonic kidney cells. UltraFLEX-Nano was vastly deformable and highly permeable across the stratum corneum; there was significant (p<0.01) skin deposition of DIM-D for UltraFLEX-Nano that was superior to PEG solution (13.83-fold). DIM-D-UltraFLEX-Nano pretreatment delayed the onset of UVB-induced tumorigenesis (2 weeks) and reduced (p<0.05) the number of tumors observed in SKH-1 mice (3.33-fold), which was comparable to pretreatment with sunscreen (SPF30). Also, DIM-D-UltraFLEX-Nano caused decrease (p<0.05) in UV-induced DNA damage (8-hydroxydeoxyguanosine), skin inflammation (PCNA), epidermal hyperplasia (c-myc, CyclinD1), immunosuppression (IL10), cell survival (AKT), metastasis (Vimentin, MMP-9, TIMP1) but increase in apoptosis (p53 and p21). Conclusion UltraFLEX-Nano was efficient in enhancing the topical delivery of DIM-D. DIM-D-UltraFLEX-Nano was efficacious in delaying skin tumor incidence and multiplicity in SKH mice comparable to sunscreen (SPF30).

Liposomes co-Loaded with 6-Phosphofructo-2-Kinase/Fructose-2, 6-Biphosphatase 3 (PFKFB3) shRNA Plasmid and Docetaxel for the Treatment of non-small Cell Lung Cancer

“…The cytotoxicity of the blank liposomes was evaluated against HEK293 cells to determine the safety of the formulated delivery systems (23) (Fig. 2).…”

Drug delivery strategies for chemoprevention of UVB‐induced skin cancer: A review

“…UVB radiation also causes immune suppression, oxidative stress, and sunburn. It has also been reported that UVB exposure leads to damage to the skin proteins and lipids which are the main constituents of the cell membrane . Although UVC radiation has ability to induce mutation and immune suppression, it is absorbed by the stratospheric ozone layer and causes minimal damage to the skin.…”

“…Currently, skin cancers are the most diagnosed cancer among all other organ malignancies . Skin cancers mainly are of two types, non‐melanocytic skin cancer (NMSC) and melanoma skin cancer (MSC), depending on the cell from which they derived and their clinical behavior .…”

“…However, in 2012, about 5.4 million people were detected with NMSC (many cases are detected with multiple NMSC). The yearly cost of skin cancers treatment in the United States is estimated at $8.1 billion: $3.3 billion for melanoma and about $4.8 billion for non‐melanoma skin cancers . Ultraviolet (UV) radiation exposure is the main cause for 90 percent cases of NMSC .…”

“…The yearly cost of skin cancers treatment in the United States is estimated at $8.1 billion: $3.3 billion for melanoma and about $4.8 billion for non‐melanoma skin cancers . Ultraviolet (UV) radiation exposure is the main cause for 90 percent cases of NMSC . UV radiation causes ROS production in the skin layers which lead to inflammation and eventually skin cancer.…”