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

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 nano¿ber 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 ¿ndings support the clinical translation of SN-38-loaded nano¿ber matrices to improve local control strategies of surgically resected tumorsPostprint (author's final draft

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

Combined Microdialysis-Tumor Homogenate Method for the Study of the Steady State Compartmental Distribution of a Hydrophobic Anticancer Drug in Patient-Derived Xenografts

PURPOSE: To develop a reproducible microdialysis-tumor homogenate method for the study of the intratumor distribution of a highly hydrophobic anticancer drug (SN-38; 7-ethyl-10-hydroxycamptothecin) in neuroblastoma patient-derived xenografts. METHODS: We studied the nonspecific binding of SN-38 to the microdialysis tubing in the presence of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) in the perfusate. We calibrated the microdialysis probes by the zero flow rate (ZFR) method and calculated the enhancement factor (f = extrapolated SN-38 concentration at the ZFR / SN-38 concentration in the dialysed solution) of HPBCD. We characterized the extravasation of HPBCD to tumors engrafted in mice. In vivo microdialysis and terminal homogenate data at the steady state (subcutaneous pump infusions) were used to calculate the volume of distribution of unbound SN-38 (Vu,tumor) in neuroblastoma. RESULTS: HPBCD (10% w/v) in the perfusate prevented the nonspecific binding of SN-38 to the microdialysis probe and enhanced SN-38 recovery (f = 1.86). The extravasation of HPBCD in the tumor during microdialysis was lower than 1%. Vu,tumor values were above 3 mL/g tumor for both neuroblastoma models and suggested efficient cellular penetration of SN-38. CONCLUSIONS: The method contributes to overcome the limitations of the microdialysis technique in hydrophobic drugs and provides a powerful tool to characterize compartmental anticancer drug distribution in xenografts.Fil: Monterrubio, Carles. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; EspañaFil: Paco, Sonia. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; EspañaFil: Vila Ubach, Mónica. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; EspañaFil: Rodríguez, Eva. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; EspañaFil: Glisoni, Romina Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; ArgentinaFil: Lavarino, Cinzia. Technion - Israel Institute of Technology; IsraelFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría ; ArgentinaFil: Sosnik, Alejandro. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; EspañaFil: Mora, Jaume. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; EspañaFil: Carcaboso, Ángel M.. Hospital Sant Joan de Déu Barcelona; España. Fundació Sant Joan de Déu; Españ

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

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 difficult-to-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 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.Fil: Monterrubio, Carles. Fundació Sant Joan de Déu; España. Esplugues de Llobregat; EspañaFil: Pascual Pasto, Guillem. Fundació Sant Joan de Déu; España. Esplugues de Llobregat; EspañaFil: Cano, Francisco. Universidad Politécnica de Catalunya; EspañaFil: Vila Ubach, Monica. Fundació Sant Joan de Déu; España. Esplugues de Llobregat; EspañaFil: Manzanares, Alejandro. Fundació Sant Joan de Déu; España. Esplugues de Llobregat; EspañaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Tornero, Jose A.. Universidad Politécnica de Catalunya; EspañaFil: Sosnik, Alejandro Dario. Technion-Israel Institute of Technology; IsraelFil: Mora, Jaume. Fundació Sant Joan de Déu; España. Esplugues de Llobregat; EspañaFil: Montero Carcaboso, Angel. Fundació Sant Joan de Déu; España. Esplugues de Llobregat; Españ

The influence of psychical research on models of identity and narrative structure in some late Victorian literature

Includes bibliographical referencesAvailable from British Library Document Supply Centre- DSC:D221315 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

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

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 difficult-to-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 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 surgeryIn 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 difficult-to-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 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 surger

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

Preclinical platform of retinoblastoma xenografts recapitulating human disease and molecular markers of dissemination

Translational research in retinoblastoma – a pediatric tumor that originates during the development of the retina – would be improved by the creation of new patient-derived models. Using tumor samples from enucleated eyes we established a new battery of preclinical models that grow in vitro in serum-free medium and in vivo in immunodeficient mice. To examine whether the new xenografts recapitulate human disease and disseminate from the retina to the central nervous system, we evaluated their histology and the presence of molecular markers of dissemination that are used in the clinical setting to detect extraocular metastases. We evaluated GD2 synthase and CRX as such markers and generated a Taqman real-time quantitative PCR method to measure CRX mRNA for rapid, sensitive and specific quantification of local and metastatic tumor burden. This approach was able to detect 1 human retinoblastoma cell in 100.000 mouse brain cells. Our research adds novel preclinical tools for the discovery of new retinoblastoma treatments for clinical translation.Fil: Pascual Pasto, Guillem. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Olaciregui, Nagore G.. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Vila Ubach, Monica. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Paco, Sonia. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Monterrubio, Carles. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Rodriguez, Eva. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Winter, Ursula Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Sant Joan de Deu Barcelona; España. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Batalla Vilacis, Mireia. Fundacio Sant Joan de Deu; EspañaFil: Catala, Jaume. Hospital Sant Joan de Deu Barcelona; EspañaFil: Salvador, Hector. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Parareda, Andreu. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Suñol, Mariona. Hospital Sant Joan de Deu Barcelona; EspañaFil: Mora, Jaume. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Lavarino, Cinzia. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: de Torres, Carmen. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; EspañaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; España. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Carcaboso, Angel M.. Fundacio Sant Joan de Deu; España. Hospital Sant Joan de Deu Barcelona; Españ

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