title: Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo.
abstract: Targeted delivery and controlled release of inactive platinum (Pt) prodrugs may offer a new approach to improve the efficacy and tolerability of the Pt family of drugs, which are used to treat 50% of all cancers today. Using prostate cancer (PCa) as a model disease, we previously described the engineering of aptamer (Apt)-targeted poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) encapsulating a Pt(IV) prodrug c,t,c[Pt(NH(3))(2)-(O(2)CCH(2)CH(2)CH(2)CH(2)CH(3))(2)Cl(2)] (1) (Pt-PLGA-b-PEG-Apt-NP), which target the extracellular domain of the prostate specific membrane antigen (PSMA), for enhanced in vitro cytotoxicity. Here we demonstrate enhanced in vivo pharmacokinetics (PK), biodistribution, tolerability, and efficacy of Pt-PLGA-b-PEG-Apt-NP (150 ± 15 nm encapsulating ∼5% wt/wt Pt(IV) prodrug) when compared to cisplatin administered in its conventional form in normal Sprague Dawley rats, Swiss Albino mice, and the PSMA-expressing LNCaP subcutaneous xenograft mouse model of PCa, respectively. The 10-d maximum tolerated dose following a single i.v. injection of Pt-PLGA-b-PEG-NP in rats and mice was determined at 40 mg/kg and 5 mg/kg, respectively. PK studies with Pt-PLGA-b-PEG-NP revealed prolonged Pt persistence in systemic blood circulation and decreased accumulation of Pt in the kidneys, a major target site of cisplatin toxicity. Pt-PLGA-b-PEG-Apt-NPs further displayed the significant dose-sparing characteristics of the drug, with equivalent antitumor efficacy in LNCaP xenografts at 1/3 the dose of cisplatin administered in its conventional form (0.3 mg/kg vs. 1 mg/kg). When considering the simultaneous improvement in tolerability and efficacy, the Pt-PLGA-b-PEG-Apt NP provides a remarkable improvement in the drug therapeutic index.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Shanta
authors.initials: S
authors.lastname: Dhar
authors.forename: Nagesh
authors.initials: N
authors.lastname: Kolishetti
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lippard
authors.forename: Omid C
authors.initials: OC
authors.lastname: Farokhzad
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D002945:Cisplatin