title: Targeted nanogels: a versatile platform for drug delivery to tumors.
abstract: Although nanoparticle-based drug delivery formulations can improve the effectiveness and safety of certain anticancer drugs, many drugs, due to their chemical composition, are unsuitable for nanoparticle loading. Here, we describe a targeted nanogel drug delivery platform that can (i) encapsulate a wide range of drug chemotypes, including biological, small molecule, and cytotoxic agents; (ii) display targeting ligands and polymeric coatings on the surface; (iii) enhance drug retention within the nanogel core after photo-cross-linking; and (iv) retain therapeutic activity after lyophilization allowing for long-term storage. For therapeutic studies, we used integrin αvβ3-targeted lipid-coated nanogels with cross-linked human serum albumin in the core for carrying therapeutic cargoes. These particles exhibited potent activity in tumor cell viability assays with drugs of distinct chemotype, including paclitaxel, docetaxel, bortezomib, 17-AAG, sorafenib, sunitinib, bosutinib, and dasatinib. Treatment of orthotopic breast and pancreas tumors in mice with taxane-loaded nanogels produced a 15-fold improvement in antitumor activity relative to Abraxane by blocking both primary tumor growth and spontaneous metastasis. With a modifiable surface and core, the lipid-coated nanogel represents a platform technology that can be easily adapted for specific drug delivery applications to treat a wide range of malignant diseases.
authors.affiliation: UCSD NanoTumor Center, Department of Pathology, Moores Cancer Center, University of California at San Diego, La Jolla, California, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Murphy
authors.forename: Bharat K
authors.initials: BK
authors.lastname: Majeti
authors.forename: Rajesh
authors.initials: R
authors.lastname: Mukthavaram
authors.forename: Lisette M
authors.initials: LM
authors.lastname: Acevedo
authors.forename: Leo A
authors.initials: LA
authors.lastname: Barnes
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000008:administration & dosage; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005612:Freeze Drying / Q000379:methods; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D000080385:Nanogels; D017239:Paclitaxel / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry*; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D008055:Lipids; D000080385:Nanogels; D011108:Polymers; D043823:Taxoids; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D017239:Paclitaxel