title: Core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin.
abstract: Doxorubicin (DOX) is clinically applied in cancer therapy, but its use is associated with dose limiting severe side effects. Core-crosslinked biodegradable polymeric micelles composed of poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lac(n))) diblock copolymers have shown prolonged circulation in the blood stream upon intravenous administration and enhanced tumor accumulation through the enhanced permeation and retention (EPR) effect. However a (physically) entrapped anticancer drug (paclitaxel) was previously shown to be rapidly eliminated from the circulation, likely because the drug was insufficiently retained in the micelles. To fully exploit the EPR effect for drug targeting, a DOX methacrylamide derivative (DOX-MA) was covalently incorporated into the micellar core by free radical polymerization. The structure of the doxorubicin derivative is susceptible to pH-sensitive hydrolysis, enabling controlled release of the drug in acidic conditions (in either the intratumoral environment and/or the endosomal vesicles). 30-40% w/w of the added drug was covalently entrapped, and the micelles with covalently entrapped DOX had an average diameter of 80 nm. The entire drug payload was released within 24 h incubation at pH 5 and 37 degrees C, whereas only around 5% release was observed at pH 7.4. DOX micelles showed higher cytotoxicity in B16F10 and OVCAR-3 cells compared to DOX-MA, likely due to cellular uptake of the micelles via endocytosis and intracellular drug release in the acidic organelles. The micelles showed better anti-tumor activity than free DOX in mice bearing B16F10 melanoma carcinoma. The results presented in this paper show that mPEG-b-p(HPMAm-Lac(n)) polymeric micelles with covalently entrapped doxorubicin is a system highly promising for the targeted delivery of cytostatic agents.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands.
authors.forename: Marina
authors.initials: M
authors.lastname: Talelli
authors.forename: Maryam
authors.initials: M
authors.lastname: Iman
authors.forename: Amir K
authors.initials: AK
authors.lastname: Varkouhi
authors.forename: Cristianne J F
authors.initials: CJ
authors.lastname: Rijcken
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Schiffelers
authors.forename: Tomas
authors.initials: T
authors.lastname: Etrych
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.forename: Cornelus F
authors.initials: CF
authors.lastname: van Nostrum
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D006801:Humans; D007773:Lactates / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008422:Materials Testing; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D015394:Molecular Structure; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D015996:Survival Rate
chemical_list: D000903:Antibiotics, Antineoplastic; D001672:Biocompatible Materials; D004337:Drug Carriers; D007773:Lactates; D008823:Micelles; D011108:Polymers; D011092:Polyethylene Glycols; D004317:Doxorubicin