Issue 22, 2015

A pH-responsive natural cyclopeptide RA-V drug formulation for improved breast cancer therapy

Abstract

The natural plant cyclopeptide RA-V, which was isolated from the roots of Rubia yunnanensis, was discovered to be a novel anti-cancer candidate. However, the cyclic hexapeptide exhibited poor solubility in physiological conditions, limiting its application for cancer therapy in vivo. To solve this problem, pH-sensitive polymers were developed for targeted RA-V delivery into tumor sites and for acid-triggered drug release. The poly(β-amino ester)s (PAE) copolymers self-assembled into micelle-like nanoparticles in an aqueous solution at pH 7.4, and the solubility of RA-V was enhanced by loading the drug into the hydrophobic cores of micelles. The near-infrared (NIR) fluorescent probe squaraine (SQ) dye, as an imaging probe, could also be encapsulated into polymer micelles simultaneously. The diameters of the RA-V/SQ loaded micelles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM), which proved that the micelles with sizes of 35–60 nm were suitable as anti-cancer drug nano-vehicles. The drug-loading capacity and drug release profiles of RA-V-loaded micelles were calculated and monitored by high performance liquid chromatography (HPLC) measurements. The RA-V/SQ loaded micelles were stable at a neutral pH, and drug release could be greatly accelerated by the acid-triggered ionization of copolymer chains. Similarly, with free RA-V cyclopeptide, the RA-V/SQ loaded micelles exhibited high anti-cancer efficiency toward MCF-7 cells and Hela cells, while the intact polymer micelles and SQ-loaded micelles are non-toxic. Moreover, the endocytosis pathway and mitochondria-regulated apoptosis of RA-V/SQ loaded micelles were proved by lysosome colocalization and JC-1 assay, respectively. Finally, biodistribution and tumor growth inhibition were evaluated in MCF-7 cell-xenografted nude mice, demonstrating that RA-V/SQ loaded micelles could realize tumor imaging and effectively and simultaneously inhibit tumor growth. Therefore, the RA-V/SQ loaded micelles may find use as potential nano-scaled cancer therapeutics and imaging agents.

Graphical abstract: A pH-responsive natural cyclopeptide RA-V drug formulation for improved breast cancer therapy

Supplementary files

Article information

Article type
Paper
Submitted
11 Mar 2015
Accepted
27 Apr 2015
First published
29 Apr 2015

J. Mater. Chem. B, 2015,3, 4514-4523

Author version available

A pH-responsive natural cyclopeptide RA-V drug formulation for improved breast cancer therapy

Z. Qiao, D. Zhang, C. Hou, S. Zhao, Y. Liu, Y. Gao, N. Tan and H. Wang, J. Mater. Chem. B, 2015, 3, 4514 DOI: 10.1039/C5TB00445D

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