title: Dual-layer surface coating of PLGA-based nanoparticles provides slow-release drug delivery to achieve metronomic therapy in a paclitaxel-resistant murine ovarian cancer model.
abstract: Development of drug resistance is a central challenge to the treatment of ovarian cancer. Metronomic chemotherapy decreases the extent of drug-free periods, thereby hindering development of drug resistance. Intraperitoneal chemotherapy allows for treatment of tumors confined within the peritoneum, but achieving sustained tumor-localized chemotherapy remains difficult. We hypothesized that modulating the surface properties of poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles could enhance their drug retention ability and extend their release profile, thereby enabling metronomic, localized chemotherapy in vivo. Paclitaxel was encapsulated in particles coated with a layer of polydopamine and a subsequent layer of poly(ethylene glycol) (PEG). These particles achieved a 3.8-fold higher loading content compared to that of nanoparticles formulated from linear PLGA-PEG copolymers. In vitro release kinetic studies and in vivo drug distribution profiles demonstrate sustained release of paclitaxel. Although free drug conferred no survival advantage, low-dose intraperitoneal administration of paclitaxel-laden surface-coated nanoparticles to drug-resistant ovarian tumor-bearing mice resulted in significant survival benefits in the absence of any apparent systemic toxicity.
authors.affiliation: Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute , Boston, Massachusetts 02215, United States.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Amoozgar
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Tania
authors.initials: T
authors.lastname: Brandstoetter
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Wallis
authors.forename: Erin M
authors.initials: EM
authors.lastname: Wilson
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goldberg
mesh_terms: D059250:Administration, Metronomic; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013499:Surface Properties
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D017239:Paclitaxel