Delivery of SN-38 in pediatric solid tumors

Resumen

Delivery and distribution of SN-38, a potent topoisomerase I inhibitor, have been evaluated in preclinical models of pediatric solid tumors obtained from tumor fresh tumor samples of patients from Sant Joan de Deu Barcelona Hospital to generate patient-derived xenografts (PDX). The new combined microdialysis – tumor homogenate method for SN-38 sampling was a must to determine the compartmental SN-38 distribution (vascular, extra- and intracellular) in subcutaneous paired PDX of neuroblastoma, Ewing’s sarcoma and rhabdomyosarcoma at different stages as well as it was useful to characterize new polymeric drug delivery systems for the administration of both local (polymeric nanofiber matrices) or systemic (polymeric nanoparticles) SN-38. A main goal was to study the distribution profile of SN-38 after the administration of its prodrug irinotecan in immunodeficient mice after the implantation of 8 paired xenografts models from early and latestage tumor samples from 4 pediatric patients. SN-38 showed reduced penetration to the intracellular compartment in late-stage tumor (chemoresistant) when compared to the early-stage tumor (sensitive) obtained from the same patient at different stages of the disease. Polymeric drug delivery systems for SN-38 delivery to the tumor tissue were also developed and characterized. Polymeric drug delivery systems allow administering potent anti-tumor drugs that are not suitable for systemic administration because of its high hydrophobicity. First, we developed poly(lactic) acid nanofiber matrices with SN-38 microcrystals that showed sustained release of the drug over 48 h post-administration. SN-38 released from polymeric matrices showed localized distribution and effect, as determined by microdialysis and the efficacy studies, reducing systemic exposition drastically. It is important to consider though, that drugs released from locally implanted delivery systems may have limited diffusion throughout the alive tissue as determined from the microdialysis studies and that could be the reason of the failure of previously developed local drug delivery systems. For this reason, our proposal for clinical translation would be that this therapy should only be applied for the local control of the disease after successful tumor resection or in patients with microscopic tumor residues. Nanoparticles are also a good platform for the administration of hydrophobic drugs. Polymeric nanoparticles with SN-38 intended for systemic administration and targeting of neuroblastoma cells via GD2 ganglioside, actively expressed on neuroblastoma cells, were also developed. Poly(lactic-co-glycolic) nanoparticles with polyethylene glycol, to avoid rapid opsonization, and decorated with anti-GD2 murine 3F8 monoclonal antibody were characterized in vitro and in vivo. Both targeted and non-targeted nanoparticles showed sustained release of the drug over 48 h. Microdialysis studies showed longer tumor exposition to SN-38 when it was administered as nanoparticulate formulation instead as irinotecan. Moreover, with targeted nanoparticles (active targeting) we observed longer tumor exposition to free SN-38 when compared with the administration of non-targeted nanoparticles (passive targeting) and this was correlated with improved efficacy. Thus, in an administration schedule of Monday and Thursday for three weeks at equimolar doses, SN-38 administered as nanoparticulate formulation showed improved delayed tumor growth, and this effect was even better when administering targeted nanoparticles. Remarkably in this context, 6 administrations of targeted SN-38 showed better antitumor activity than the conventional 10 administrations of irinotecan at equimolar dose for one cycle of the standard treatment. This thesis work demonstrates the importance of microdialysis technique in drug delivery and distribution studies and innovatively for the characterization of drug delivery systems. In addition, drug delivery systems developed and characterized through this project showed to be a promising platform for the administration of the potent SN-38, limiting systemic exposure and localizing the drug at the tumor site while delaying tumor growth.