Juan Li1, Lei Zheng2, Rongmei Wang1, Deqing Sun1, Shuang Liang3, Jing Wu1, Yongqing Liu1, Xiaona Tian1, Tingting Li4, Yang Yang5, Leiqiang Han1. 1. Department of Clinical Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, People's Republic of China. 2. Department of Pharmacy, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250031, People's Republic of China. 3. School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China. 4. Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA. 5. China National Center for Biotechnology Development, Beijing 100039, People's Republic of China.
Abstract
BACKGROUND: The development of paclitaxel (PTX) resistance seriously restricts its clinical efficacy. An attractive option for combating resistance is inhibiting the expression of P-glycoprotein (P-gp) in tumor cells. We have reported that flavokawain A (FKA) inhibited P-gp protein expression in PTX-resistant A549 (A549/T) cells, indicating that FKA combined with PTX may reverse PTX resistance. However, due to the variable pharmacokinetics of FKA and PTX, the conventional cocktail combination in clinics may cause uncertainty of treatment efficacy in vivo. MATERIALS AND METHODS: To synergistically elevate the anti-cancer activity of PTX and FKA in vivo, the national medical products administration (NMPA) approved sodium aescinate (Aes) was utilized to stabilize hydrophobic PTX and FKA to form polymer-free twin like PTX-A nanoparticles (NPs) and FKA-A NPs. RESULTS: The resulting nanoparticles prepared simply by nanoprecipitation possessed similar particle size, good stability and ultrahigh drug loadings of up to 50%. With the aid of Aes, these two drugs accumulated in tumor tissue by passive targeting and were efficiently taken up by A549/T cells; this resulted in significant suppression of tumor growth in A549/T homograft mice at a low PTX dose (2.5 mg·kg-1). Synergistic effects and reversed PTX resistance were achieved by the combination of PTX-A NPs and FKA-A NPs by inhibiting P-gp expression in tumor cells. CONCLUSION: Using NMPA-approved Aes to prepare twin-like nanoparticles without introducing any new materials provides an efficient platform for combination chemotherapy and clinical translation.
BACKGROUND: The development of paclitaxel (PTX) resistance seriously restricts its clinical efficacy. An attractive option for combating resistance is inhibiting the expression of P-glycoprotein (P-gp) in tumor cells. We have reported that flavokawain A (FKA) inhibited P-gp protein expression in PTX-resistant A549 (A549/T) cells, indicating that FKA combined with PTX may reverse PTX resistance. However, due to the variable pharmacokinetics of FKA and PTX, the conventional cocktail combination in clinics may cause uncertainty of treatment efficacy in vivo. MATERIALS AND METHODS: To synergistically elevate the anti-cancer activity of PTX and FKA in vivo, the national medical products administration (NMPA) approved sodium aescinate (Aes) was utilized to stabilize hydrophobic PTX and FKA to form polymer-free twin like PTX-A nanoparticles (NPs) and FKA-A NPs. RESULTS: The resulting nanoparticles prepared simply by nanoprecipitation possessed similar particle size, good stability and ultrahigh drug loadings of up to 50%. With the aid of Aes, these two drugs accumulated in tumor tissue by passive targeting and were efficiently taken up by A549/T cells; this resulted in significant suppression of tumor growth in A549/T homograft mice at a low PTX dose (2.5 mg·kg-1). Synergistic effects and reversed PTX resistance were achieved by the combination of PTX-A NPs and FKA-A NPs by inhibiting P-gp expression in tumor cells. CONCLUSION: Using NMPA-approved Aes to prepare twin-like nanoparticles without introducing any new materials provides an efficient platform for combination chemotherapy and clinical translation.
Authors: Sander Pronk; Szilárd Páll; Roland Schulz; Per Larsson; Pär Bjelkmar; Rossen Apostolov; Michael R Shirts; Jeremy C Smith; Peter M Kasson; David van der Spoel; Berk Hess; Erik Lindahl Journal: Bioinformatics Date: 2013-02-13 Impact factor: 6.937