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.

Scheme 1.

Schematic representation of the Pt-PLGA-b-PEG-Apt-NP construct. Chemical structure of the Pt(IV) prodrug 1 and intracellular reduction for the release of active cisplatin in PSMA expressing human prostate cancer LNCaP cells after receptor mediated endocytosis of Pt-PLGA-b-PEG-Apt-NP.

Fig. 1.

Survival rate of (A) Sprague Dawley rats treated with cisplatin, Pt-PLGA-b-PEG-NPs, and 1 and (B) Swiss Albino mice treated with Pt-PLGA-b-PEG-NPs, and 1.

Fig. 2.

Body weight variations observed for 10 d after intravenous administration of cisplatin, Pt-PLGA-b-PEG-NPs, and Pt(IV) prodrug 1 in male Sprague Dawley rats.

Fig. 3.

Alterations of creatinine, BUN, and AST in rats after treatment with Pt-PLGA-b-PEG-NPs, 1, or cisplatin.

Fig. 4.

Variation of percentage Pt dose in blood (A) and plasma (B) with time following the administration of Pt-PLGA-b-PEG-NPs and Pt prodrug 1 intravenously to rat.

Fig. 5.

Tissue distribution of (A) Pt-PLGA-b-PEG-NPs, and (B) free Pt(IV) prodrug 1 in male rats. Statistical analyses were performed using one-way ANOVA with Tukey post hoc test, p < 0.05 (compared with control).

Fig. 6.

(A) Effect of cisplatin (1 mg/kg), Pt-PLGA-b-PEG-Apt-NP (0.3 mg/kg), PLGA-b-PEG-Apt-NP (20 mg/kg), and saline on the growth of LNCaP tumors inoculated in nude BALB/c mice. Each formulation was administered biweekly by intravenous injection for 30 d. Mean values and standard errors of the mean are presented. Asterisk on day 12 represents significant differences between cisplatin- and Pt-PLGA-b-PEG-Apt-NP-treated tumors according to one-way ANOVA with Tukey post hoc test, p < 0.05. (B) Body weight changes with time of LNCaP tumor-bearing mice treated with cisplatin (1 mg/kg), Pt-PLGA-b-PEG-Apt-NP (0.3 mg/kg), PLGA-b-PEG-Apt-NP (20 mg/kg), and saline. Bars indicate standard deviations.