Tissue Compatibility of SN-38-Loaded Anticancer Nanofiber Matrices

Delivery of chemotherapy in the surgical bed has shown preclinical activity to control cancer progression upon subtotal resection of pediatric solid tumors, but whether this new treatment is safe for tumor‐adjacent healthy tissues remains unknown. Here, Wistar rats are used to study the anatomic and functional impact of electrospun nanofiber matrices eluting SN‐38 a potent chemotherapeutic agent on several body sites where pediatric tumors such as neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma arise. Blank and SN‐38‐loaded matrices embracing the femoral neurovascular bundle or in direct contact with abdominal viscera (liver, kidney, urinary bladder, intestine, and uterus) are placed. Foreign body tissue reaction to the implants is observed though no histologic damage in any tissue/organ. Skin healing is normal. Tissue reaction is similar for SN‐38‐loaded and blank matrices, with the exception of the hepatic capsule that is thicker for the former although within the limits consistent with mild foreign body reaction. Tissue and organ function is completely conserved after local treatments, as assessed by the rotarod test (forelimb function), hematologic tests (liver and renal function), and control of clinical signs. Overall, these findings support the clinical translation of SN‐38‐loaded nanofiber matrices to improve local control strategies of surgically resected tumors

Delivery of SN-38 in pediatric solid tumors

[eng] A new combined microdialysis – tumor homogenate method for the determination of compartmental (vascular, extra- and intracellular) SN-38 distribution in patient-derived xenografts (PDX) generated from pediatric solid tumors from fresh tumor samples from patients of Sant Joan de Deu Barcelona Hospital was developed. SN-38 in late-stage (chemoresistant) tumors presented limited distribution into the intracellular compartment while drug distribution into this compartment was significantly higher in early-stage (sensitive) models when SN-38 was administered as its prodrug irinotecan. Furthermore, two polymeric drug delivery systems were developed for the local and systemic administration of SN-38. Poly(lactic) acid electrospun nanofiber matrices with microcrystals of SN-38 were developed for the local administration of SN-38. Matrices showed maintained release of SN-38 over 48 h with local distribution and efficacy delaying tumor growth over PDX models. Dialysates showed limited SN-38 diffusion from the matrices through the tumor tissue, suggesting this therapy could only be useful for the local tumor control after successful surgery of the tumor or where only microscopic tumor seeds are left. Systemic administration of SN-38 was possible by encapsulating the drug into poly(lactic-co-glycolic) acid with polyethylene glycol nanoparticles, which were decorated with 3F8 monoclonal antibody, an anti-GD2 antibody that recognizes the ganglioside GD2 overexpressed on the surface of neuroblastoma cells surface for active targeting. Nanoparticles released SN-38 over 2 days and tumor exposition to SN-38 was increased when compared with the administration of an equimolar dose of irinotecan, and that was correlated with improved efficacy over the conventional irinotecan where 10 administrations of the drug had reduced efficacy compared to the direct administration of SN-38 in the targeted nanoparticles. Both nanofiber matrices and nanoparticles showed to be good platforms for SN-38 administration reducing systemic exposition by localizing SN-38 at the tumor microenvironment and significantly delaying tumor growth as shown in the efficacy studies. Thus, polymeric local drug delivery systems strategy should be of high interest for the potential future treatment of chemoresistant tumor