title: Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy.
abstract: Nanoscale drug delivery vehicles have been extensively studied as carriers for cancer chemotherapeutics. However, the formulation of platinum chemotherapeutics in nanoparticles has been a challenge arising from their physicochemical properties. There are only a few reports describing oxaliplatin nanoparticles. In this study, we derivatized the monomeric units of a polyisobutylene maleic acid copolymer with glucosamine, which chelates trans-1,2-diaminocyclohexane (DACH) platinum (II) through a novel monocarboxylato and O --> Pt coordination linkage. At a specific polymer to platinum ratio, the complex self-assembled into a nanoparticle, where the polymeric units act as the leaving group, releasing DACH-platinum in a sustained pH-dependent manner. Sizing was done using dynamic light scatter and electron microscopy. The nanoparticles were evaluated for efficacy in vitro and in vivo. Biodistribution was quantified using inductively coupled plasma atomic absorption spectroscopy (ICP-AAS). The PIMA-GA-DACH-platinum nanoparticle was found to be more active than free oxaliplatin in vitro. In vivo, the nanoparticles resulted in greater tumor inhibition than oxaliplatin (equivalent to 5 mg kg⁻¹ platinum dose) with minimal nephrotoxicity or body weight loss. ICP-AAS revealed significant preferential tumor accumulation of platinum with reduced biodistribution to the kidney or liver following PIMA-GA-DACH-platinum nanoparticle administration as compared with free oxaliplatin. These results indicate that the rational engineering of a novel polymeric nanoparticle inspired by the bioactivation of oxaliplatin results in increased antitumor potency with reduced systemic toxicity compared with the parent cytotoxic. Rational design can emerge as an exciting strategy in the synthesis of nanomedicines for cancer chemotherapy.
authors.affiliation: Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Cambridge, MA 02139, USA.
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Paraskar
authors.forename: Shivani
authors.initials: S
authors.lastname: Soni
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Roy
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Papa
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D005260:Female; D005944:Glucosamine / Q000737:chemistry; D006801:Humans; D008298:Maleates / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077150:Oxaliplatin; D011090:Polyenes / Q000737:chemistry; D011108:Polymers / Q000737:chemistry
chemical_list: C554217:((1R,2R)-1,2-diaminocyclohexane)platinum(II); D000970:Antineoplastic Agents; D008298:Maleates; D009944:Organoplatinum Compounds; D011090:Polyenes; D011108:Polymers; D000077150:Oxaliplatin; C008967:polyisobutylene; C030272:maleic acid; D005944:Glucosamine