Tumor-targeting, pH-sensitive nanoparticles for docetaxel delivery to drug-resistant cancer cells

Tuan Hiep Tran,¹ Thiruganesh Ramasamy,¹ Ju Yeon Choi,¹ Hanh Thuy Nguyen,¹ Thanh Tung Pham,¹ Jee-Heon Jeong,¹ Sae Kwang Ku,² Han-Gon Choi,³ Chul Soon Yong,¹ Jong Oh Kim<sup>1

1</sup>College of Pharmacy, Yeungnam University, Dae-Dong, ²College of Korean Medicine, Daegu Haany University, Gyeongsan, ³College of Pharmacy, Hanyang University, Hanyangdaehak-ro, Sangnok-gu, Ansan, South Korea

Abstract: The attachment of polyethylene glycol (PEG) increases the circulation time of drug-containing nanoparticles; however, this also negatively affects cellular uptake. To overcome this problem, unique lipid polymer hybrid (LPH) nanoparticles were developed with a pH-responsive PEG layer that detached prior to cell uptake. Docetaxel (DTX) was incorporated into the lipid core of the nanoparticles, which was then shielded with the pH-responsive block co-polymer polyethylene glycol-b-polyaspartic acid (PEG-b-PAsp) using a modified emulsion method. The optimized LPH nanoparticles were ~200 nm and had a narrow size distribution. Drug release from DTX-loaded LPH (DTX-LPH) nanoparticles was pH-sensitive, which is beneficial for tumor targeting. More importantly, DTX-LPH nanoparticles were able to effectively induce apoptosis in cancer cells. The negative surface charge and PEG shell of vehicle remarkably enhanced the blood circulation and physiological activity of DTX-LPH nanoparticles compared with that of free DTX. The nanoparticles were also found to reduce the size of tumors in tumor-bearing xenograft mice. The in vivo anticancer effect of DTX-LPH nanoparticles was further confirmed by the elevated levels of caspase-3 and poly ADP ribose polymerase found in the tumors after treatment. Thus, the results suggest that this novel LPH system could be an effective new treatment for cancer.

Keywords: docetaxel, polyaspartic acid, drug delivery systems, antitumor, pH-sensitive