title: Nanoparticle encapsulation of mitaplatin and the effect thereof on in vivo properties.
abstract: Nanoparticle (NP) therapeutics have the potential to significantly alter the in vivo biological properties of the pharmaceutically active agents that they carry. Here we describe the development of a polymeric NP, termed M-NP, comprising poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-PEG), stabilized with poly(vinyl alcohol) (PVA), and loaded with a water-soluble platinum(IV) [Pt(IV)] prodrug, mitaplatin. Mitaplatin, c,c,t-[PtCl2(NH3)2(OOCCHCl2)2], is a compound designed to release cisplatin, an anticancer drug in widespread clinical use, and the orphan drug dichloroacetate following chemical reduction. An optimized preparation of M-NP by double emulsion and its physical characterization are reported, and the influence of encapsulation on the properties of the platinum agent is evaluated in vivo. Encapsulation increases the circulation time of Pt in the bloodstream of rats. The biodistribution of Pt in mice is also affected by nanoparticle encapsulation, resulting in reduced accumulation in the kidneys. Finally, the efficacy of both free mitaplatin and M-NP, measured by tumor growth inhibition in a mouse xenograft model of triple-negative breast cancer, reveals that controlled release of mitaplatin over time from the nanoparticle treatment produces long-term efficacy comparable to that of free mitaplatin, which might limit toxic side effects.
authors.affiliation: Department of Chemistry,Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Johnstone
authors.forename: Nora
authors.initials: N
authors.lastname: Kulak
authors.forename: Eric M
authors.initials: EM
authors.lastname: Pridgen
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D062845:Chloroacetates; D003460:Crystallization / Q000379:methods; D046911:Macromolecular Substances / Q000737:chemistry; D008422:Materials Testing; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D050997:Nanomedicine / Q000379:methods; D009374:Neoplasms, Experimental / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology; D009928:Organ Specificity; D009944:Organoplatinum Compounds; D010316:Particle Size; D011108:Polymers / Q000737:chemistry*; D013499:Surface Properties; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D062845:Chloroacetates; D046911:Macromolecular Substances; D053769:Nanocapsules; D009944:Organoplatinum Compounds; D011108:Polymers; C547058:mitaplatin