Anticancer polymeric nanomedicine bearing synergistic drug combination is superior to a mixture of individually-conjugated drugs

• Published in: Journal of controlled release Vol. 187; pp. 145 - 157
• Main Authors: Markovsky, Ela, Baabur-Cohen, Hemda, Satchi-Fainaro, Ronit
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.08.2014
• Subjects: Adenocarcinoma - drug therapy; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Cancer treatment; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Combination therapy; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Drug Combinations; Drug Synergism; Drug-polymer conjugates; Female; Humans; Mammary Neoplasms, Animal - drug therapy; Mice, Nude; Nanomedicine; Paclitaxel - administration & dosage; Paclitaxel - chemistry; Polyglutamic acid; Polyglutamic Acid - administration & dosage; Polyglutamic Acid - chemistry; Polymeric nanomedicines; Polymers - chemistry; Chemotherapy; Polyglutamic acid; Combination therapy; Drug-polymer conjugates; Cancer treatment; Polymeric nanomedicines
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2014.05.025

Paclitaxel and doxorubicin are potent anticancer drugs used in the clinic as mono-therapies or in combination with other modalities to treat various neoplasms. However, both drugs suffer from side effects and poor pharmacokinetics. These two drugs have dissimilar physico-chemical properties, pharmacokinetics and distinct mechanisms of action, toxicity and drug resistance. In order to target both drugs selectively to the tumor site, we conjugated them at a synergistic ratio to a biocompatible and biodegradable polyglutamic acid (PGA) backbone. Drugs conjugation to a nano-sized polymer enabled preferred tumor accumulation by passive targeting, making use of the enhanced permeability and retention (EPR) effect. The rational design presented here resulted in co-delivery of combination of the drugs and their simultaneous release at the tumor site. PGA–paclitaxel–doxorubicin nano-sized conjugate exhibited superior anti-tumor efficacy and safety compared to the combination of the free drugs or a mixture of the drugs conjugated to separate polymer chains, at equivalent concentrations. This novel polymer-based multi-drug nano-sized conjugate allowed for true combination therapy since it delivered both drugs to the same target site at the ratio required for synergism. Using mice bearing orthotopic mammary adenocarcinoma, we demonstrate here the advantage of a combined polymer therapeutic bearing two synergistic drugs on the same polymer backbone, compared to each drug bound separately to the backbone. [Display omitted]