Enhanced Cytotoxicity to Cancer Cells by Codelivery and Controlled Release of Paclitaxel-loaded Sirolimus-conjugated Albumin Nanoparticles

摘要

Recently, it is suggested that mTOR signaling pathway is an important mediator in many cancers especially breast cancer. Therefore, effects of sirolimus as a mTOR inhibitor in breast cancer have been studied in combination with paclitaxel with or without controlled release effect. In this work, we prepared a water-soluble formulation of sirolimus-conjugated albumin nanoparticles loaded with paclitaxel, to study the effects of sirolimus concentration when it releases more later than paclitaxel in comparison with sirolimus-paclitaxel- loaded albumin nanoparticles. Also effects of paclitaxel loading on cytotoxic properties of nanoparticles were studied. Sirolimus was succinylated at 42-OH with enzymatic reaction of Candida antarctica lipase B, and then its carboxylic group was activated with EDC/NHS and conjugated to the lysine residues of albumin. Paclitaxel was loaded on albumin surface by nab technique in concentration range of 0-10 mu g/mL. Sirolimus-conjugated nanoparticles with 0.01 mu g/mL paclitaxel showed lowest cell viability of 44% while it was 53% for non-conjugated nanoparticles in MDA-MB-468 cell lines after 48 h (p-value = 0.003). In MCF-7 cell lines, sirolimus-conjugated nanoparticles with 0.1 mu g/mL paclitaxel showed lowest cell viability of 35.69% while it was 48% for non-conjugated nanoparticles after 48 h (p-value = 0.03). We guess that when cancer cell lines arrest in G2-M by anticancer drugs like paclitaxel, Akt activates mTOR to make cells continue living, then inhibiting mTOR can enhance anticancer effects.