Enhanced effectiveness of tocotrienol-based nano-emulsified system for topical delivery against skin carcinomas

Abstract

The potent anti-proliferative and pro-apoptotic actions of tocotrienols (T3) against cancer, but not normal tissues, have been hampered by their limited systemic bioavailabilty. Recent expansive development of diverse nanoemulsion (NE) vehicles emphasized their vast potential to improve the effective dosing of different clinical and experimental drugs of lipophilic nature, such as T3. The emphasis of the present work is to develop a pharmaceutically scalable, low-energy nano-emulsification approach for optimized incorporation of T3-rich palm oil (Tocomin®), possessing anticancer activity as a potential cutaneous delivery platform for adjunctive therapy of skin carcinomas, either alone or in combination with other chemotherapeutic agents. Different Tocomin®-NEs, obtained with different homogenization strategies, were screened based on physicochemical uniformity (droplet size, charge and polydispersity) and subjected to stress physical stability testing, along with chemical content analysis (≥90% Tocomin® - incorporation efficiency). Adopted hybrid nano-emulsification of Tocomin®, correlated with highest preservation of DPPH-radical scavenging capacity of active T3 in prototype formulation, Tocomin®-NE, which effectively permeated diffusion cell membranes 4-folds higher than propyleneglycol (PG)-admixed Tocomin® control. Against two different cell models of human cutaneous carcinoma, Tocomin®-hybrid NE demonstrated significantly stronger cytotoxic profiles (p ≤ 0.01), visible in both concentration- and time- dependent manners, with at least 5-folds lower IC50 values, compared to those estimated for the closest Tocomin®-control. The proposed hybrid nano-emulsified formulation of Tocomin® provides simple and stable delivery platform, for effective topical application against keratinocyte tumors.

Tocotrienol Nanoemulsion Platform of Curcumin Elicit Elevated Apoptosis and Augmentation of Anticancer Efficacy against Breast and Ovarian Carcinomas

“…The present communication builds upon our previous reports of hybrid homogenization protocols [12], for optimal hybrid emulsification of T3-based VE oil cores, to yield model NE pharmaceutical platforms [12,26]. We have employed various emulsifying mixtures based on Vitamin E-TPGS (VE-TPGS), or Poloxamer/Lutrol F68 (LF68), as main co-surfactants [19,20], yielding different prototype NE formulations, demonstrating extended shelf-life stability, controlled release profiles of bioactives, and exhibited superior biological activities, in biological test systems [10,12,27].…”

“…We have employed various emulsifying mixtures based on Vitamin E-TPGS (VE-TPGS), or Poloxamer/Lutrol F68 (LF68), as main co-surfactants [19,20], yielding different prototype NE formulations, demonstrating extended shelf-life stability, controlled release profiles of bioactives, and exhibited superior biological activities, in biological test systems [10,12,27]. …”

“…Owing to its temperature dependent self-assembly behavior (exhibited at low phase inversion temperature, PIT < 50 °C) and thermo-gelling behavior, LF-127 facilitated successful low-energy emulsification of our VE-rich oil phase, when combined with co-surfactant, VE-TPGS, analogous to earlier nano-self emulsifying drug delivery systems for VE in general, and T3 in particular [10,12]. In fact, the employed polyethylene glycol(PEG)-based surfactant mixture, composed of both VE-TPGS and LF-127, would further increase the stability of produced NE in external aqueous phase, owing to extended steric PEG chains on the NE droplet surface.…”

“…Vitamin E (VE), including T3 analogues, has been shown to be a highly useful compound to encapsulate and enhance the delivery of poorly water-soluble drugs, such as genistein (Gen), quercetin, and other active polyphenols in green tea [10,11]. Effectively, T3-analogues (in particular γ- and δ-T3) have also shown strong potential for cancer chemoprevention and therapy, owing to their potent anti-proliferative and direct mitochondrial pro-apoptotic effects (i.e., specific inhibition of NF-κB, and BCl-2, plus stimulation of JNK/BAX pathways, resulting in mitochondrial uncoupling and cytosolic release of cytochrome c ) in different solid and hematological tumors [8,12,13,14]. While the notion about the much higher accumulation of T3s in cells, in comparison to Tphs, might contribute to their prominent effects, the diverse mechanisms implicated in T3s action on cancer cell death and other inhibitory pathways are still not fully elucidated [13].…”

“…Owing to their superior pharmaceutical properties (such as good biocompatibility, biodegradability, physical stability, and ease of large-scale production), optimized nanoemulsion (NE) formulations can incorporate hydrophobic CUR as a payload within its VE-based core matrix [10]. In fact, nano-emulsification of VE compounds has been reported with great success in multiple reports, via the utilization of non-ionic surfactant blends [12,18,19]. Stable NEs enriched with VE compounds (such as γ- and δ-T3s in particular) have been developed for parenteral and oral administration, as nano-delivery vehicles to enhance the systemic bioavailability of many slightly water-soluble chemotherapeutic agents, such as paclitaxel, simvastatin, and Gen [10,20,21,22,23].…”