Preclinical evaluation of taxane-binding peptide-modified polymeric micelles loaded with docetaxel in an orthotopic breast cancer mouse model.
We developed a novel taxane-binding peptide (TBP) modified, biodegradable polymeric micelle that overcomes limitations of drug loading and poor serum stability typically seen with particle delivery, leading to enhanced pharmacokinetics and tumor distribution of docetaxel (DTX). The use of the taxane-binding peptide to increase docetaxel loading is particularly compelling as it takes advantage of a known intracellular binding mechanism in a new way. Docetaxel is a potent chemotherapeutic with a therapeutic index often limited by the toxicity of the excipients that are necessary to enhance its solubility for intravenous delivery. Our polymeric micelle has terminal furan groups that enable facile antibody Fab conjugation by Diels-Alder chemistry for targeted delivery. Compared to the conventional ethanolic polysorbate 80 formulation (Free DTX), our nanoparticle (NP DTX) formulation exhibited a two-fold increase in exposure and tumor accumulation. Notably, the reduced toxicity of the NP DTX formulation increased the therapeutic index and allowed for higher dosing regimens, with a maximum tolerated dose (MTD) 1.6-fold higher than that of the Free DTX formulation, which is significant and similar to enhancements observed in clinical products for docetaxel and other drugs. These improved properties led to enhanced mouse survival in an orthotopic model of breast cancer; however, the targeted formulation of Fab-NP DTX did not further improve efficacy. Together, these results clearly demonstrate the benefits of the TBP-modified polymeric micelles as promising carriers for docetaxel.
Terrence Donnelly Centre for Cellular and Biomolecular Research, Department of Chemical Engineering & Applied Chemistry, Institute of Biomaterials & Biomedical Engineering, University of Toronto, Room 514, 160 College Street, Toronto, ON M5S 3E1, Canada.
Jennifer
J
Logie
Terrence Donnelly Centre for Cellular and Biomolecular Research, Department of Chemical Engineering & Applied Chemistry, Institute of Biomaterials & Biomedical Engineering, University of Toronto, Room 514, 160 College Street, Toronto, ON M5S 3E1, Canada.
Ahil N
AN
Ganesh
Medicinal Chemistry, Ontario Institute for Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
Ahmed M
AM
Aman
Medicinal Chemistry, Ontario Institute for Cancer Research, 101 College Street, Toronto, ON M5G 1L7, Canada.
Rima S
RS
Al-Awar
Terrence Donnelly Centre for Cellular and Biomolecular Research, Department of Chemical Engineering & Applied Chemistry, Institute of Biomaterials & Biomedical Engineering, University of Toronto, Room 514, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada. Electronic address: molly.shoichet@utoronto.ca.
Molly S
MS
Shoichet
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004353:Drug Evaluation, Preclinical; D004655:Emulsions; D005260:Female; D051379:Mice; D008823:Micelles; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D011485:Protein Binding; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004655:Emulsions; D008823:Micelles; D053769:Nanocapsules; D010455:Peptides; D011108:Polymers; D043823:Taxoids; D000077143:Docetaxel
Breast cancer; Docetaxel; Drug targeting; Nanomedicine; Polymeric micelles