title: Functionalized nanospheres for targeted delivery of paclitaxel.
abstract: Targeted delivery of anti-cancer agents to cancer cells is a mature line of investigation that has yet to realize its full potential. In this study we report on the development of a delivery platform with the future goal of merging two thus far parallel methods for selective elimination of cancer cells: targeted nanospheres and pretargeted radioimmunotherapy. Several clinical trials have shown the promise of pretargeted radioimmunotherapy, which leverages the specificity of antibodies for targeted cell populations and delivers a localized dose of a biotinylated radionuclide that is most often administered following binding of a biotinylated antibody and streptavidin (StA) to the target cells. The work presented here describes the development of biotinylated nanospheres based on an ABA-type copolymer comprised of a tyrosine-derived oligomer as the B-block and poly(ethylene glycol) (PEG) A-blocks. The biotinylated nanospheres encapsulate paclitaxel (PTX) to the same extent as unbiotinylated nanospheres. Efficacy of targeting was shown on CD44 positive cells in the SUM159 breast cancer cell line by incubating the cells sequentially with a biotinylated anti-CD44 antibody, StA and the biotinylated nanospheres encapsulating PTX. Targeted nanospheres achieved the half maximal inhibitory concentration of PTX on SUM159 cells at a 5-10 fold lower concentration than that of PTX applied in either non-targeted nanospheres or free drug approaches. Moreover, targeted nanospheres selectively eliminated CD44 positive SUM159 cells compared to free PTX and untargeted nanospheres. This new generation of nano-sized carrier offers a versatile platform that can be adopted for a wide variety of drug and target specific applications and has the potential to be combined with the clinically emerging method of pretargeted radioimmunotherapy.
authors.affiliation: New Jersey Center for Biomaterials and Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 145 Bevier Road, Piscataway, NJ 08854, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Bushman
authors.forename: Asa
authors.initials: A
authors.lastname: Vaughan
authors.forename: Larisa
authors.initials: L
authors.lastname: Sheihet
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Marius
authors.initials: M
authors.lastname: Costache
authors.forename: Joachim
authors.initials: J
authors.lastname: Kohn
mesh_terms: D055910:Antibodies, Immobilized / Q000737:chemistry / Q000276:immunology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D019921:Biotinylation; D001940:Breast / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D054118:Nanospheres / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*; D019809:Streptavidin / Q000737:chemistry
chemical_list: D055910:Antibodies, Immobilized; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D011092:Polyethylene Glycols; D019809:Streptavidin; D017239:Paclitaxel
keywords: 4-dimethylaminopyridinium-p-toluene sulfate; Biotinylation; Breast cancer; CTAB; DCC; DIPC; DMF; DPTs; DTO; EPR; ESA; GPC; HOBT; Kd; N,N′-dicyclohexylcarbodiimide; N-hydroxysuccinimide; NHS; NMR; Nanosphere; Oligo(DTO-SA); PBS; PEG; PTX; Paclitaxel; Pretargeted radioimmunotherapy; SA; StA; THF; Targeting; Tyr-NSP; Tyr-NSP-PTX; anti-CD44 antibody; bTyr-NSP; bTyr-NSP-PTX; biotinylated tyrosine-derived nanospheres; biotinylated tyrosine-derived nanospheres loaded with paclitaxel; cetyltrimethylammonium bromide; desaminotyrosyl tyrosine octyl ester; diisopropylcarbodiimide; dimethylformamide; dissociation constant; enhanced permeability and retention; epithelial-specific antigen; gel permeation chromatography; hydroxybenzotriazole; nuclear magnetic resonance; oligomers of desaminotyrosyl tyrosine octyl ester and suberic acid; paclitaxel; phosphate buffered saline; poly(ethylene glycol); streptavidin; suberic acid; tetrahydrofuran; tyrosine derived nanospheres loaded with paclitaxel; tyrosine-derived nanospheres; αCD44