Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel

Abstract

Most drugs are metabolized by hepatic cytochrome P450 3A4 (CYP3A4), resulting in their reduced bioavailability. In this study, we present the design and evaluation of bio-compatible nanocarriers trapping a natural CYP3A4-inhibiting compound. Our aim in using nanocarriers was to target the natural CYP3A4-inhibiting agent to hepatic CYP3A4 and leave drug-metabolizing enzymes in other organs undisturbed. In the design of such nanocarriers, we took advantage of the nonspecific accumulation of small nanoparticles in the liver. Specific targeting functionalization was added to direct nanocarriers toward hepatocytes. Nanocarriers were evaluated in vitro for their CYP3A4 inhibition capacity and in vivo for their biodistribution, and finally injected 24 hours prior to the drug docetaxel, for their ability to improve the efficiency of the drug docetaxel. Nanoparticles of poly(lactic- co -glycolic) acid (PLGA) with a hydrodynamic diameter of 63 nm, functionalized with galactosamine, showed efficient in vitro CYP3A4 inhibition and the highest accumulation in hepatocytes. When compared to docetaxel alone, in nude mice bearing the human breast cancer, MDA-MB-231 model, they significantly improved the delay in tumor growth (treated group versus docetaxel alone, percent treated versus control ratio [%T/C] of 32%) and demonstrated a major improvement in overall survival (survival rate of 67% versus 0% at day 55).

Long-acting parenteral combination antiretroviral loaded nano-drug delivery system to treat chronic HIV-1 infection: A humanized mouse model study

“…The polymeric encapsulation of the ARV drugs demonstrates slow sustained release and limited systemic clearance (Mandal et al, 2017b). As cARV drugs, TAF/FTC/EVG combination were chosen without COBI, as PLGA polymer limits the systemic clearance of EVG and reported to provide hepatic P450 inhibition (Paolini et al, 2017). Based on the present study in the humanized mouse model, we report for the first time three cARV drugs encapsulated single nanoparticle (NP) formulation (i.e.…”

Impacts of Intralipid on Nanodrug Abraxane Therapy and on the Innate Immune System

“…Co-delivery of appropriate materials with nanomedicines is another approach. For example, the nano-sized inhibitors of hepatic cytochrome P450 3A4 (CYP3A4) serve as a priming agent to block hepatic metabolism specifically following treatment with nanomedicine, which increases the drug bioavailability and prolongs the survival of the xenograft mice 36,37 . Here, we have provided a novel strategy by using an FDA-approved nutritional supplement, Intralipid, to enhance the drug bioavailability ( Fig.…”

Saccharide‐based nanocarriers for targeted therapeutic and diagnostic applications

“…Other recent noteworthy works pertaining to galactosamine‐functionalized nanocarriers for targeted drug delivery to liver cancer cells have included poly(lactic‐ co ‐glycolic) acid galactosamine‐functionalized nanoparticles developed by Paolini et al . for the carriage of docetaxel, as well as a prodrug based on poly(malic acid) and DOX‐bearing N ‐acetylgalactosamine that was investigated by Venkatraj and colleagues …”