Challenges and Opportunities of Nanotechnology as Delivery Platform for Tocotrienols in Cancer Therapy

Abstract

Plant-derived phytonutrients have emerged as health enhancers. Tocotrienols from the vitamin E family gained high attention in recent years due to their multi-targeted biological properties, including lipid-lowering, neuroprotection, anti-inflammatory, antioxidant, and anticancer effects. Despite well-defined mechanism of action as an anti-cancer agent, their clinical use is hampered by poor pharmacokinetic profile and low oral bioavailability. Delivery systems based on nanotechnology were proven to be advantageous in elevating the delivery of tocotrienols to tumor sites for enhanced efficacy. To date, preclinical development of nanocarriers for tocotrienols include niosomes, lipid nanoemulsions, nanostructured lipid carriers (NLCs) and polymeric nanoparticles. Active targeting was explored via the use of transferrin as targeting ligand in niosomes. In vitro, nanocarriers were shown to enhance the anti-proliferative efficacy and cellular uptake of tocotrienols in cancer cells. In vivo, improved bioavailability of tocotrienols were reported with NLCs while marked tumor regression was observed with transferrin-targeted niosomes. In this review, the advantages and limitations of each nanocarriers were critically analyzed. Furthermore, a number of key challenges were identified including scale-up production, biological barriers, and toxicity profiles. To overcome these challenges, three research opportunities were highlighted based on rapid advancements in the field of nanomedicine. This review aims to provide a wholesome perspective for tocotrienol nanoformulations in cancer therapy directed toward effective clinical translation.

Beta-Tocotrienol Exhibits More Cytotoxic Effects than Gamma-Tocotrienol on Breast Cancer Cells by Promoting Apoptosis via a P53-Independent PI3-Kinase Dependent Pathway

“…It is noteworthy that subsequent in vivo and clinical studies using beta-T3 will require specific delivery systems as previously suggested for tocotrienols. As reported by Maniam et al, the use of tocotrienols is hampered by their lower bioavailability, solubility, and poor pharmacokinetic profile when compared to tocopherols [87,88]. Despite the fact that oral T3s have better bioavailability in rats than intramuscular and intra-peritoneal routes of administration, this bioavailability couldn't exceed more than 28% in the case of alpha-T3, and not more than 9% for γand δ-tocotrienols [59,89].…”

“…In order to overcome these challenges, nanotechnology delivery tools were developed to improve tocotrienols efficacy in vivo. Using nano-formulations (tumor-targeted nano-carriers) in animal models, tocotrienols exhibited a 10-fold higher anti-proliferative effect and resulted in up to 60% of tumor regression [87]. Thus, improving tocotrienols, especially beta-T3 s, bio-absorption and access to tumor cells through nanotechnology bio-systems, will provide an enhanced therapeutic effect than usual delivery routes.…”

The synergism of Clinacanthus nutans Lindau extracts with gemcitabine: downregulation of anti-apoptotic markers in squamous pancreatic ductal adenocarcinoma

“…By reducing the dose of gemcitabine, we can potentially reduce the toxicities associated by gemcitabine [53][54][55]. Nanotechnology in formulation, such as niosomes or liposomes, may be able to co-deliver SN extract and gemcitabine together [56]. These studies supported that SN extracts could be used to potentiate a chemotherapy, and are worth further investigation.…”

Nanomedicines: Challenges and perspectives for future nanotechnology in the healthcare system

“…The production of various nanoformulations such as niosomes, liposomes, and polymeric nanoparticles, require high energy for its processing so that they can overcome stability related challenges such as coalescence and creaming (Maniam et al, 2018). Generally, nanoformulations are produced by either of the two processes that are top to bottom (pulverization, micronization) or bottom to top approach (nucleation).…”