Chimeric Peptide Engineered Nanomedicine for Synergistic Suppression of Tumor Growth and Therapy-Induced Hyperlipidemia by mTOR and PCSK9 Inhibition
Hua Cai,
Rongrong Zheng,
Ningxia Wu,
Jiaman Hu,
Ruixin Wang,
Jianing Chi,
Wei Zhang,
Linping Zhao,
Hong Cheng,
Ali Chen,
Shiying Li,
Lin Xu
Affiliations
Hua Cai
Department of Geriatric Cardiology, General Hospital of Southern Theater Command, People’s Liberation Army, Guangzhou 510010, China
Rongrong Zheng
Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
Ningxia Wu
Department of Geriatric Cardiology, General Hospital of Southern Theater Command, People’s Liberation Army, Guangzhou 510010, China
Jiaman Hu
Department of Geriatric Cardiology, General Hospital of Southern Theater Command, People’s Liberation Army, Guangzhou 510010, China
Ruixin Wang
Department of Geriatric Cardiology, General Hospital of Southern Theater Command, People’s Liberation Army, Guangzhou 510010, China
Jianing Chi
Department of Geriatric Cardiology, General Hospital of Southern Theater Command, People’s Liberation Army, Guangzhou 510010, China
Wei Zhang
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China
Linping Zhao
Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
Hong Cheng
Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, China
Ali Chen
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, China
Shiying Li
Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China
Lin Xu
Department of Geriatric Cardiology, General Hospital of Southern Theater Command, People’s Liberation Army, Guangzhou 510010, China
Chemotherapy-induced side effects restrain anti-tumor efficiency, with hyperlipidemia being the most common accompanying disease to cause treatment failure. In this work, a chimeric peptide-engineered nanomedicine (designated as PRS) was fabricated for the synergistic suppression of tumor growth and therapy-induced hyperlipidemia. Within this nanomedicine, the tumor matrix-targeting peptide palmitic-K(palmitic)CREKA can self-assemble into a nano-micelle to encapsulate Rapamycin (mTOR inhibitor) and SBC-115076 (PCSK9 inhibitor). This PRS nanomedicine exhibits a uniform nano-distribution with good stability which enhances intracellular drug delivery and tumor-targeting delivery. Also, PRS was found to synergistically inhibit tumor cell proliferation by interrupting the mTOR pathway and reducing Rapamycin-induced hyperlipidemia by increasing the production of LDLR. In vitro and in vivo results demonstrate the superiority of PRS for systematic suppression of tumor growth and the reduction of hyperlipidemia without initiating any other toxic side effects. This work proposes a sophisticated strategy to inhibit tumor growth and also provides new insights for cooperative management of chemotherapy-induced side effects.
