Co-administration of a charge-conversional dendrimer enhances antitumor efficacy of conventional chemotherapy

Cao, J (Cao, Jun)^[ 1 ] ; Wang, CH (Wang, Chenhong)^[ 2 ] ; Guo, LJ (Guo, Leijia)^[ 1 ] ; Xiao, ZY (Xiao, Zhiyong)^[ 2 ] ; Liu, KL (Liu, Keliang)^[ 2 ] ; Yan, HS (Yan, Husheng)^[ 1,3 ]

EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 2018, 127: 371-377

DOI: 10.1016/j.ejpb.2018.02.035

 WOS:000433650400040

Abstract

Despite extensive investigations, the clinical translation of nanocarrier-based drug delivery systems (NDDS) for cancer therapy is hindered by inefficient delivery and poor tumor penetration. Conventional chemotherapy by administration of free small molecule anticancer drugs remains the standard of care for many cancers. Herein, other than for carrying and releasing drugs, small nanoparticles were used as a potentiator of conventional chemotherapy by co-administration with free chemotherapeutic agents. This strategy avoided the problems associated with drug loading and controlled release encountered in NDDS, and was also much simpler than NDDS. Negatively charged poly(amido amine)-2,3-dimethylmaleic monoamide (PAMAM-DMA) dendrimers were prepared, which possessed low toxicity and can be converted to positively charged PAMAM dendrimers responsive to tumor acidic pH. The in situ formed PAMAM in tumor tissue promoted cellular uptake of co-administered doxorubicin by increasing the cell membrane permeability, and subsequently enhanced the cytotoxicity of doxorubicin. The small size of the dendrimers was favorable for deep penetration in tumor. Co-injection of PAMAM-DMA with doxorubicin into nude mice bearing human tumors almost completely inhibited tumor growth, with a mean tumor weight reducing by 55.9% after the treatment compared with the treatment with doxorubicin alone.