title: Anticancer polymeric nanomedicine bearing synergistic drug combination is superior to a mixture of individually-conjugated drugs.
abstract: 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.
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ela
authors.initials: E
authors.lastname: Markovsky
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Hemda
authors.initials: H
authors.lastname: Baabur-Cohen
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: ronitsf@post.tau.ac.il.
authors.forename: Ronit
authors.initials: R
authors.lastname: Satchi-Fainaro
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy*; D008819:Mice, Nude; D050997:Nanomedicine; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011099:Polyglutamic Acid / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D011108:Polymers; D011099:Polyglutamic Acid; D004317:Doxorubicin; D017239:Paclitaxel
keywords: Cancer treatment; Chemotherapy; Combination therapy; Drug-polymer conjugates; Polyglutamic acid; Polymeric nanomedicines