Pharmacokinetics and antitumor efficacy characterization of cisplatin-loaded PLGA nanoparticles in tumor-bearing mice.
Daniel Moreno1, Sara Zalba1, Iñigo Navarro2, Conchita Tros1, Iñaki F. Trocóniz1, María J Garrido1
1, Department of Pharmacy and Pharmaceutical Technology; 2, Department of Analytical chemistry; University of Navarra; Pamplona. Spain.
Background: Cisplatin (CDDP) shows a significant dose-limiting due to its side effects. Polymeric nano-sized carriers seem to be able to improve the therapeutic index of the encapsulated drug, although that characterization has been in general very empirical.
Objective: The characterization of the antitumor efficacy of CDDP nanoparticles by a semi-mechanistic pharmacokinetic/pharmacodynamic model in tumor-bearing mice.
Methods: CDDP-encapsulated PLGA nanoparticles (NP) [1] were developed to characterize their efficacy in SCID mice xenografted with colorectal adenocarcinoma DHDK12-ProB cells. Animals were divided in five groups to receive: G-I, saline; G-II, unloaded-NP; G-III, 5mg/kg of CDDP i.v.; G-IV, 5mg/kg of CDDP i.p. and G-V, 5mg/kg of CDDP-NP i.p., once a week for three weeks. Blood samples were used to measure Pt plasma concentrations, blood urea nitrogen (BUN) and vascular endothelial growth factor (VEGF). Tumour growth and body weight were recorded daily.
All analysis were performed using the population approach with NONMEM version VI using the FOCE interaction method.
Results: CDDP disposition administered in saline solution was described by a three-compartments model associated with a first order absorption process, however for NP was described by one compartment model with a zero order absorption process. The estimate of the apparent volume of distribution was higher after NP administration than after free-drug. The inter-animal variability could be associated with total plasma clearance.
The tumour growth in saline and unloaded-NP groups, was described by an exponential growth followed by a linear growth, as has been previously reported by Simeoni et al.[2]. In groups treated with CDDP, the inhibition of the tumour growth was related to a factor dependent on CDDP plasma concentrations, which represents the potency of the drug. In addition, a transit compartmental system was also used to model the delay in the process of the cell death, estimated in approximately 5 days.
Finally, the similarity between time profiles of VEGF and tumour growth suggests that this biomarker could be used to model the efficacy of a specific treatment.
Conclusions: The selected model provides a tool to explore in silico, alternative in vitro and in vivo scenarios to optimize the controlled delivery systems of CDDP, new dosing schedule or drug combinations.
References:
[1] Moreno et al. Eur J Pharm Biopharm 68 :503-12 (2008).
[2] Simeoni et al. Cancer Res 64: 1094-1101 (2004).