SN-38-loaded nanofiber matrices for local control of pediatric solid tumors after subtotal resection surgery

Abstract

In addition to surgery, local tumor control in pediatric oncology requires new treatments as an alternative to radiotherapy. SN-38 is an anticancer drug with proved activity against several pediatric solid tumors including neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. Taking advantage of the extremely low aqueous solubility of SN-38, we have developed a novel drug delivery system (DDS) consisting of matrices made of poly(lactic acid) electrospun polymer nanofibers loaded with SN-38 microcrystals for local release in difficultto-treat pediatric solid tumors. To model the clinical scenario, we conducted extensive preclinical experiments to characterize the biodistribution of the released SN-38 using microdialysis sampling in vivo. We observed that the drug achieves high concentrations in the virtual space of the surgical bed and 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 penetrates a maximum distance of 2 mm within the tumor bulk. Subsequently, we developed a model of subtotal tumor resection in clinically relevant pediatric patient-derived xenografts and used such models to provide evidence of the activity of the SN-38 DDS to inhibit tumor regrowth. We propose that this novel DDS could represent a potential future strategy to avoid harmful radiation therapy as a primary tumor control together with surgery.

Targeted drug distribution in tumor extracellular fluid of GD2-expressing neuroblastoma patient-derived xenografts using SN-38-loaded nanoparticles conjugated to the monoclonal antibody 3F8

“…In these experiments, 50,000 cells were plated and the antiproliferative activity of the products was assayed after overnight culture [11]. …”

“…Long-term delivery of SN-38 in tECF was studied in vivo in tumor-bearing mice using intratumoral microdialysis [11, 31]. Briefly, 20 kDa cutoff, 4 mm-length microdialysis probes (CMA, Kista, Sweden) were inserted into subcutaneous HSJD-NB-007 tumors implanted in 13 mice under isoflurane anesthesia, and fixed with sutures to the skin.…”

“…We recently observed that local SN-38 delivery in the surgical bed maximizes exposure to the drug in neuroblastoma patient-derived xenografts (PDX) and achieves improved local tumor control in highly chemoresistant pediatric tumor models, when compared to equimolar irinotecan [11]. Similarly, novel formulations of SN-38 prodrugs designed for intravenous (i.v.)…”

Trabectedin and Campthotecin Synergistically Eliminate Cancer Stem Cells in Cell-of-Origin Sarcoma Models

“…Many of these strategies are based on the combination with compounds that induce DNA damage while also interfering with DNA damage repair mechanisms, such as doxorubicin, cisplatin, PARP inhibitors or campthotecins [1], [8], [21], [26], [27], [28]. Campthotecin (CPT) and its derivatives irinotecan and topotecan are chemotherapeutic drugs with proved activity against several types of sarcoma [29], [30], [31], [32]. CPT targets DNA topoisomerase I and inhibits its resealing activity leading to the stabilization of the transiently-generated SSB which can be converted into toxic DSB by collision with replication or transcription complexes [33], [34].…”

Sustained delivery of vincristine inside an orthotopic mouse sarcoma model decreases tumor growth

“…Monterrubio et al described implanting a matrix loaded with SN-38 after subtotal sarcoma tumor resection in a mouse xenograft model and achieved significantly delayed tumor growth [30]. SN-38 was loaded into a nano-fiber matrix and delivered to the resection bed of sarcomas.…”