title: Osteotropic therapy via targeted layer-by-layer nanoparticles.
abstract: Current treatment options for debilitating bone diseases such as osteosarcoma, osteoporosis, and bone metastatic cancer are suboptimal and have low efficacy. New treatment options for these pathologies require targeted therapy that maximizes exposure to the diseased tissue and minimizes off-target side effects. This work investigates an approach for generating functional and targeted drug carriers specifically for treating primary osteosarcoma, a disease in which recurrence is common and the cure rate has remained around 20%. This approach utilizes the modularity of Layer-by-Layer (LbL) assembly to generate tissue-specific drug carriers for systemic administration. This is accomplished via surface modification of drug-loaded nanoparticles with an aqueous polyelectrolyte, poly(acrylic acid) (PAA), side-chain functionalized with alendronate, a potent clinically used bisphosphonate. Nanoparticles coated with PAA-alendronate are observed to bind and internalize rapidly in human osteosarcoma 143B cells. Encapsulation of doxorubicin, a front-line chemotherapeutic, in an LbL-targeted liposome demonstrates potent toxicity in vitro. Active targeting of 143B xenografts in NCR nude mice with the LbL-targeted doxorubicin liposomes promotes enhanced, prolonged tumor accumulation and significantly improved efficacy. This report represents a tunable approach towards the synthesis of drug carriers, in which LbL enables surface modification of nanoparticles for tissue-specific targeting and treatment.
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering Institute for Soldier Nanotechnologies 77 Massachusetts Avenue, Cambridge, MA, 02139.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Morton
authors.forename: Nisarg J
authors.initials: NJ
authors.lastname: Shah
authors.forename: Mohiuddin A
authors.initials: MA
authors.lastname: Quadir
authors.forename: Zhou J
authors.initials: ZJ
authors.lastname: Deng
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Poon
authors.forename: Paula T
authors.initials: PT
authors.lastname: Hammond
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D019386:Alendronate / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000737:chemistry; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D012516:Osteosarcoma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D011859:Radiography; D014183:Transplantation, Heterologous
chemical_list: D000180:Acrylic Resins; D050071:Bone Density Conservation Agents; D004337:Drug Carriers; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; C006903:carbopol 940; D004317:Doxorubicin; D019386:Alendronate
keywords: bisphosphonate; bone; cancer therapy; layer-by-layer