title: Targeted delivery of platinum-taxane combination therapy in ovarian cancer.
abstract: Biodegradable polypeptide-based nanogels have been developed from amphiphilic block copolymers, poly(ethylene glycol)-b-poly(L-glutamic acid)-b-poly(L-phenylalanine), which effectively co-incorporate cisplatin and paclitaxel, the clinically used drug combination for the treatment of advanced ovarian cancer. In order to target both drugs selectively to the tumor cells, we explored the benefits of ligand-mediated drug delivery by targeting folate receptors, which are overexpressed in most ovarian cancers. Drug-loaded nanogels were surface-functionalized with folic acid (FA) with the help of a PEG spacer without affecting the ligand binding affinity and maintaining the stability of the carrier system. FA-decorated nanogels significantly suppressed the growth of intraperitoneal ovarian tumor xenografts outperforming their nontargeted counterparts without extending their cytotoxicity to the normal tissues. We also confirmed that synchronized co-delivery of the platinum-taxane drug combination via single carrier to the same targeted cells is more advantageous than a combination of targeted single drug formulations administered at the same drug ratio. Lastly, we demonstrated that the same platform can also be used for localized chemotherapy. Our data indicate that intraperitoneal administration can be more effective in the context of targeted combination therapy. Our findings suggest that multifunctional nanogels are promising drug delivery carriers for improvement of current treatment for ovarian cancer.
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198-5830, USA.
authors.forename: Swapnil S
authors.initials: SS
authors.lastname: Desale
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198-5830, USA.
authors.forename: Kruti S
authors.initials: KS
authors.lastname: Soni
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198-5830, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Romanova
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-3135, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, 985830 Nebraska Medical Center, Omaha, NE 68198-5830, USA. Electronic address: tbronich@unmc.edu.
authors.forename: Tatiana K
authors.initials: TK
authors.lastname: Bronich
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D002945:Cisplatin / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers; D005260:Female; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism; D058972:Folic Acid Transporters / Q000378:metabolism; D005782:Gels; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008819:Mice, Nude; D053758:Nanoparticles; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011099:Polyglutamic Acid / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D004337:Drug Carriers; D058972:Folic Acid Transporters; D005782:Gels; D010455:Peptides; D011108:Polymers; D011099:Polyglutamic Acid; C012001:polyphenylalanine; D011092:Polyethylene Glycols; D005492:Folic Acid; D017239:Paclitaxel; D002945:Cisplatin
keywords: Cisplatin; Combination drug delivery; Nanogels; Ovarian cancer; Paclitaxel; Receptor targeting