title: The tumor accumulation and therapeutic efficacy of doxorubicin carried in calcium phosphate-reinforced polymer nanoparticles.
abstract: A mineral (calcium phosphate, CaP)-reinforced core-shell-corona micelle was evaluated as a nanocarrier of doxorubicin (DOX) for cancer therapy. The polymer micelles of poly(ethylene glycol)-b-poly(L-aspartic acid)-b-poly(L-phenylalanine) (PEG-PAsp-PPhe) in the aqueous phase provided the three distinct functional domains: the hydrated PEG outer corona for prolonged circulation, the anionic PAsp middle shell for CaP mineralization, and the hydrophobic PPhe inner core for DOX loading. CaP mineralization was performed by initial electrostatic localization of calcium ions at anionic PAsp shells, and the consequent addition of phosphate anions to trigger the growth of CaP. The mineralization did not affect the micelle size or the spherical morphology. The CaP-mineralized micelles exhibited enhanced serum stability. The DOX release from the DOX-loaded mineralized micelles (DOX-CaP-PM) at physiological pH was efficiently inhibited, whereas at an endosomal pH (pH 4.5), DOX release was facilitated due to the rapid dissolution of the CaP mineral layers in the middle shell domains. The in vivo tissue distribution and tumor accumulation of the DOX-CaP-PM that were labeled with a near-infrared fluorescent (NIRF) dye, Cy5.5, were monitored in MDA-MB231 tumor-bearing mice. Non-invasive real-time optical imaging results indicated that the DOX-CaP-PM exhibited enhanced tumor specificity due to the prolonged stable circulation in the blood and an enhanced permeation and retention (EPR) effect compared with the DOX-loaded nonmineralized polymer micelles (DOX-NPM). The DOX-CaP-PM exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with free DOX and DOX-NPM. The CaP mineralization on assembled nanoparticles may serve as a useful guide for enhancing the antitumor therapeutic efficacy of various polymer micelles and nano-aggregates.
authors.affiliation: Department of Life and Nanopharmaceutical Science, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Kyung Hyun
authors.initials: KH
authors.lastname: Min
authors.forename: Hong Jae
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.forename: Seo Young
authors.initials: SY
authors.lastname: Jeong
authors.forename: Sang Cheon
authors.initials: SC
authors.lastname: Lee
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002130:Calcium Phosphates / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D051379:Mice; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D002130:Calcium Phosphates; D004337:Drug Carriers; D008823:Micelles; D010455:Peptides; C017645:polyaspartate; C012001:polyphenylalanine; D011092:Polyethylene Glycols; D004317:Doxorubicin; C020243:calcium phosphate