Characterization and Mathematical Modeling of Alginate/Chitosan-Based Nanoparticles Releasing the Chemokine CXCL12 to Attract Glioblastoma Cells

Abstract

Chitosan (Chit) currently used to prepare nanoparticles (NPs) for brain application can be complexed with negatively charged polymers such as alginate (Alg) to better entrap positively charged molecules such as CXCL12. A sustained CXCL12 gradient created by a delivery system can be used, as a therapeutic approach, to control the migration of cancerous cells infiltrated in peri-tumoral tissues similar to those of glioblastoma multiforme (GBM). For this purpose, we prepared Alg/Chit NPs entrapping CXCL12 and characterized them. We demonstrated that Alg/Chit NPs, with an average size of ~250 nm, entrapped CXCL12 with ~98% efficiency for initial mass loadings varying from 0.372 to 1.490 µg/mg NPs. The release kinetic profiles of CXCL12 were dependent on the initial mass loading, and the released chemokine from NPs after seven days reached 12.6%, 32.3%, and 59.9% of cumulative release for initial contents of 0.372, 0.744, and 1.490 µg CXCL12/mg NPs, respectively. Mathematical modeling of released kinetics showed a predominant diffusive process with strong interactions between Alg and CXCL12. The CXCL12-NPs were not toxic and did not promote F98 GBM cell proliferation, while the released CXCL12 kept its chemotaxis effect. Thus, we developed an efficient and tunable CXCL12 delivery system as a promising therapeutic strategy that aims to be injected into a hydrogel used to fill the cavity after surgical tumor resection. This system will be used to attract infiltrated GBM cells prior to their elimination by conventional treatment without affecting a large zone of healthy brain tissue.

Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma

“…A different approach that utilizes CXCR4 overexpression in glioma cells without directly interfering in the pathway was recently proposed by Gascon et al [117]. The use of nanoparticles as a delivery system for CXCL12 to GBM cells was established in vitro [117].…”

“…A different approach that utilizes CXCR4 overexpression in glioma cells without directly interfering in the pathway was recently proposed by Gascon et al [117]. The use of nanoparticles as a delivery system for CXCL12 to GBM cells was established in vitro [117]. There, authors enclosed CXCL12 in nanoparticles which, upon delivery, released CXCL12 to GBM cells, without promoting proliferation but keeping its chemotactic capabilities [117].…”

“…The use of nanoparticles as a delivery system for CXCL12 to GBM cells was established in vitro [117]. There, authors enclosed CXCL12 in nanoparticles which, upon delivery, released CXCL12 to GBM cells, without promoting proliferation but keeping its chemotactic capabilities [117]. The aim for the future is, to inject these CXCL12-carrying nanoparticles into a hydrogel which could be used to fill up the cavity after tumor resection, thus attracting disseminated tumor cells.…”

“…The aim for the future is, to inject these CXCL12-carrying nanoparticles into a hydrogel which could be used to fill up the cavity after tumor resection, thus attracting disseminated tumor cells. These tumor cells would then be targeted by standard therapeutic approaches while having the benefit of not affecting the surrounding healthy brain tissue [117].…”

Targeted Drug Delivery System; Nanoparticle Based Combination of Chitosan and Alginate for Cancer Therapy: A Review

“…And it has also been proven that the Ch/Alg folic acid conjugate is able to perform a better antitumor therapeutic effect than the free drug because of the selective affinity of Ch/Alg to intestinal cells [77,78]. Gascon et al developed modified CXCL12-conjugated Ch/Alg nanoparticles for the treatment of brain and spinal cancer because the IL-13RA2 receptor (also known as cluster of differentiation 213A2, is a membrane-bound protein is highly expressed in glioblastoma cancer tissue and is not present in normal brain tissue [74]. CXCL12 conjugated into nanoparticles was able to significantly increase drug accumulation at the cancer site, thereby enhancing the therapeutic effect.…”