Ling Wang,1– 3,* Fangqing Cai,3,* Yixuan Li,3,* Xiaolan Lin,3 Yuting Wang,3 Weijie Liang,3 Caiyu Liu,4 Cunze Wang,3 Junshan Ruan1– 3 

1School of Pharmacy, Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China; 2Molecular Biology Laboratory of Traditional Chinese Medicine, Fujian Provincial Hospital, Fuzhou, Fujian Province, People’s Republic of China; 3School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 4School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Junshan Ruan, School of Pharmacy, Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, 134 Dongjie, Fuzhou, 350001, People’s Republic of China, Tel +86 591-88216343, Fax +86 591-87532356, Email ruanjunshan@163.com

Purpose: Renal cell carcinoma (RCC) is the most common and lethal type of urogenital cancer, with one-third of new cases presenting as metastatic RCC (mRCC), which, being the seventh most common cancer in men and the ninth in women, poses a significant challenge. For patients with poor prognosis, temsirolimus (TEM) has been approved for first-line therapy, possessing pharmacodynamic activities that block cancer cell growth and inhibit proliferation-associated proteins. However, TEM suffers from poor water solubility, low bioavailability, and systemic side effects. This study aims to develop a novel drug formulation for the treatment of RCC.
Methods: In this study, amphiphilic block copolymer (poly(ethylene glycol) monomethyl ether-poly(beta-amino ester)) (mPEG-PBAE) was utilized as a drug delivery vehicle and TEM-loaded micelles were prepared by thin-film hydration method by loading TEM inside the nanoparticles. Then, the molecular weight of mPEG-PBAE was controlled to make it realize hydrophobic–hydrophilic transition in the corresponding pH range thereby constructing pH-responsive TEM-loaded micelles. Characterization of pH-responsive TEM-loaded nanomicelles particle size, potential and micromorphology while its determination of drug-loading properties, in vitro release properties. Finally, pharmacodynamics and hepatorenal toxicity were further evaluated.
Results: TEM loading in mPEG-PBAE increased the solubility of TEM in water from 2.6 μg/mL to more than 5 mg/mL. The pH-responsive TEM-loaded nanomicelles were in the form of spheres or spheroidal shapes with an average particle size of 43.83 nm and a Zeta potential of 1.79 mV. The entrapment efficiency (EE) of pH-responsive TEM nanomicelles with 12.5% drug loading reached 95.27%. Under the environment of pH 6.7, the TEM was released rapidly within 12 h, and the release rate could reach 73.12% with significant pH-dependent characteristics. In vitro experiments showed that mPEG-PBAE preparation of TEM-loaded micelles had non-hemolytic properties and had significant inhibitory effects on cancer cells. In vivo experiments demonstrated that pH-responsive TEM-loaded micelles had excellent antitumor effects with significantly reduced liver and kidney toxicity.
Conclusion: In conclusion, we successfully prepared pH-responsive TEM-loaded micelles. The results showed that pH-responsive TEM-loaded micelles can achieve passive tumor targeting of TEM, and take advantage of the acidic conditions in tumor tissues to achieve rapid drug release.

Keywords: renal cell carcinoma, drug delivery, pH-responsive, mPEG-PBAE, nanomicelles