ultra-small lipid carriers with adjustable release profiles for synergistic treatment of drug-resistant ovarian cancer.

The combined application of paclitaxel (PTX) and tetrandrine (TET) is a promising avenue in drug-resistant cancer therapy. However, poor drug release and limited intracellular accumulation greatly impede the combinatorial antitumor practices. To address this problem, we successfully developed a tunable controlled release lipid platform for coordinated drug delivery. The ultra-small nanostructured lipid carriers co-loaded with PTX and TET (PT@usNLC) were fabricated through a high-pressure homogenization method. The appropriate size of PT@usNLC is beneficial to efficient localization in tumor sites and cellular internalization. The drug release rate could be tuned by varying the lipid ratio to maximize the therapeutic effect of combined drugs. The TET could be released firstly, which enhanced oxidative stress levels and restored the sensitivity of tumor cells to PTX, and the PTX was released subsequently to exert a synergistic antitumor effect. Both in vitro and in vivo studies revealed that PT@usNLC significantly enhanced the therapeutic effect compared to conventional therapies. This study provides a new strategy for resistant ovarian cancer therapy.