Development and evaluation of vitamin E D-α-tocopheryl polyethylene glycol 1000 succinate-mixed polymeric phospholipid micelles of berberine as an anticancer nanopharmaceutical

Abstract

Berberine (Brb) is an active alkaloid occurring in various common plant species, with well-recognized potential for cancer therapy. Brb not only augments the efficacy of antineoplastic chemotherapy and radiotherapy but also exhibits direct antimitotic and proapoptotic actions, along with distinct antiangiogenic and antimetastatic activities in a variety of tumors. Despite its low systemic toxicity, several pharmaceutical challenges limit the application of Brb in cancer therapy (ie, extremely low solubility and permeability, very poor pharmacokinetics (PKs), and oral bioavailability). Among lipid-based nanocarriers investigated recently for Brb, stealth amphiphilic micelles of polymeric phospholipid conjugates were studied here as a promising strategy to improve Brb delivery to tumors. Specifically, physicochemically stable micelles made of 1,2-distearoyl- sn -glycero-3-phosphoethanolamine- N -[methoxy(polyethyleneglycol)-2000] (PEG-PE) mixed with d -α-tocopheryl polyethylene glycol 1000 succinate (TPGS) (PEG-succinate ester of vitamin E), in a 3:1 M ratio, increased Brb solubilization by 300%. Our PEG-PE/TPGS-mixed micelles firmly retained the incorporated Brb, displaying extended-release profile in simulated media, with up to 30-fold projected improvement in simulated PKs of Brb. Owing to the markedly better uptake of Brb-containing mixed micelles in vitro, our Brb-mixed micelles nanoformulation significantly amplified apoptosis and overall cytotoxic effectiveness against monolayer and spheroid cultures of human prostate carcinomas (16- to 18-fold lower half-maximal inhibitory concentration values in PC3 and LNPaC, respectively), compared to free Brb. Mixed PEG-PE/TPGS micelles represent a promising delivery platform for the sparingly soluble anticancer agent, Brb, encouraging further pharmaceutical development of this drug for cancer therapy.

Innovative approaches for cancer treatment: current perspectives and new challenges

“…Recently, it has been demonstrated to be effective against different tumours and to act as a chemopreventive agent, modulating many signalling pathways [114, 115]. Like curcumin, it is poorly soluble in water; therefore, different nanotechnological strategies have been developed to facilitate its delivery across cell membranes [116–119]; six clinical trials are open and one has been completed [120].…”

Synthetic phosphoethanolamine: the state of the art of scientific production

“…Based on the notion that phospholipids may be related to the induction of apoptosis (Meneguelo, 2007;Veronez, 2012;Elbayoumi et al, 2016), the ability of PHOS-S to induce apoptosis in cancer cells has been examined.…”

Elucidating Berberine’s Therapeutic and Photosensitizer Potential through Nanomedicine Tools

“…Despite the proven therapeutic efficacy of BBR, some limitations constrain its pharmaceutical development, namely, poor aqueous solubility (~2.0 mg/mL), low oral bioavailability (less than 5% in plasma), and poor gastrointestinal absorption, thus being considered a class IV drug in the Biopharmaceutical Classification System [ 30 , 31 , 32 ]. To overcome the associated drawbacks of BBR, several approaches have been explored, namely, the use of permeation enhancers (e.g., spices, peptides, surfactants, and polymers) [ 33 ].…”