title: Rationally engineered polymeric cisplatin nanoparticles for improved antitumor efficacy.
abstract: The use of cisplatin, a first line chemotherapy for most cancers, is dose-limited due to nephrotoxicity. While this toxicity can be addressed through nanotechnology, previous attempts at engineering cisplatin nanoparticles have been limited by the impact on the potency of cisplatin. Here we report the rational engineering of a novel cisplatin nanoparticle by harnessing a novel polyethylene glycol-functionalized poly-isobutylene-maleic acid (PEG-PIMA) copolymer, which can complex with cis-platinum (II) through a monocarboxylato and a coordinate bond. We show that this complex self-assembles into a nanoparticle, and exhibits an IC(50) = 0.77 ± 0.11 µM comparable to that of free cisplatin (IC(50) = 0.44 ± 0.09 µM). The nanoparticles are internalized into the endolysosomal compartment of cancer cells, and release cisplatin in a pH-dependent manner. Furthermore, the nanoparticles exhibit significantly improved antitumor efficacy in a 4T1 breast cancer model in vivo, with limited nephrotoxicity, which can be explained by preferential biodistribution in the tumor with reduced kidney concentrations. Our results suggest that the PEG-PIMA-cisplatin nanoparticle can emerge as an attractive solution to the challenges in cisplatin chemotherapy.
authors.affiliation: BWH-HST Center for Biomedical Engineering, Harvard Medical School, Cambridge, MA 02139, USA.
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Paraskar
authors.forename: Shivani
authors.initials: S
authors.lastname: Soni
authors.forename: Sudipta
authors.initials: S
authors.lastname: Basu
authors.forename: Chitra J
authors.initials: CJ
authors.lastname: Amarasiriwardena
authors.forename: Nicola
authors.initials: N
authors.lastname: Lupoli
authors.forename: Shyam
authors.initials: S
authors.lastname: Srivats
authors.forename: Rituparna Sinha
authors.initials: RS
authors.lastname: Roy
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D051379:Mice; D053758:Nanoparticles / Q000627:therapeutic use* / Q000648:ultrastructure; D036103:Nanotechnology / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy*; D009929:Organ Size / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011108:Polymers; C002189:polyelectrolyte 60; D011092:Polyethylene Glycols; D002945:Cisplatin