Evaluation of drug loading, pharmacokinetic behavior, and toxicity of a cisplatin-containing hydrogel nanoparticle

• Published in: Journal of controlled release 2015-04, Vol.204, p.70-77
• Main Authors: Kai, Marc P., Keeler, Amanda W., Perry, Jillian L., Reuter, Kevin G., Luft, J. Christopher, O'Neal, Sara K., Zamboni, William C., DeSimone, Joseph M.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Cell Line, Tumor; Cell Survival - drug effects; Cisplatin; Cisplatin - administration & dosage; Cisplatin - pharmacokinetics; Cisplatin - pharmacology; Cisplatin - toxicity; Cytotoxicity; Drug Carriers - chemistry; Drug Compounding; Hydrogels - chemistry; Maximum Tolerated Dose; Mice, Inbred C57BL; Nanoparticles - chemistry; Neoplasms, Experimental - drug therapy; PEGylation; Pharmacokinetics; PRINT
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2015.03.001

Cisplatin is a cytotoxic drug used as a first-line therapy for a wide variety of cancers. However, significant renal and neurological toxicities limit its clinical use. It has been documented that drug toxicities can be mitigated through nanoparticle formulation, while simultaneously increasing tumor accumulation through the enhanced permeation and retention effect. Circulation persistence is a key characteristic for exploiting this effect, and to that end we have developed long-circulating, PEGylated, polymeric hydrogels using the Particle Replication In Non-wetting Templates (PRINT®) platform and complexed cisplatin into the particles (PRINT-Platin). Sustained release was demonstrated, and drug loading correlated to surface PEG density. A PEG Mushroom conformation showed the best compromise between particle pharmacokinetic (PK) parameters and drug loading (16wt.%). While the PK profile of PEG Brush was superior, the loading was poor (2wt.%). Conversely, the drug loading in non-PEGylated particles was better (20wt.%), but the PK was not desirable. We also showed comparable cytotoxicity to cisplatin in several cancer cell lines (non-small cell lung, A549; ovarian, SKOV-3; breast, MDA-MB-468) and a higher MTD in mice (10mg/kg versus 5mg/kg). The pharmacokinetic profiles of drug in plasma, tumor, and kidney indicate improved exposure in the blood and tumor accumulation, with concurrent renal protection, when cisplatin was formulated in a nanoparticle. PK parameters were markedly improved: a 16.4-times higher area-under-the-curve (AUC), a reduction in clearance (CL) by a factor of 11.2, and a 4.20-times increase in the volume of distribution (Vd). Additionally, non-small cell lung and ovarian tumor AUC was at least twice that of cisplatin in both models. These findings suggest the potential for PRINT-Platin to improve efficacy and reduce toxicity compared to current cisplatin therapies. [Display omitted]