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.
Highlights
Polymeric-based nanoparticles (NPs) have generated a lot of interest because of their potential as drug delivery systems that can transport molecules across physiological barriers such as the blood-brain barrier [1]
We have developed a tunable and efficient non-cytotoxic Alg/Chit NPs delivery system that can entrap various quantities of CXCL12 at high encapsulation efficiency within an applicable concentration range, while keeping its bioactivity
Alg/Chit NPs can release CXCL12 at specific doses over time depending on the initial mass loading, to control glioblastoma multiforme (GBM) cell invasion without enhancing their proliferation
Summary
Polymeric-based nanoparticles (NPs) have generated a lot of interest because of their potential as drug delivery systems that can transport molecules across physiological barriers such as the blood-brain barrier [1]. It acts on cells through binding to its main receptor CXCR4 It is involved in stem or progenitor cell migration during tissue regeneration and repair [13,14,15]. GBM tumor recurrence is mainly due to the migration of GBM cells into the normal brain parenchyma, which limits conventional cancer therapy efficiency (surgical resection and radiotherapy) [21]. To overcome this challenge, a proposed strategy consists in reversing the migration direction of GBM cells using a chemoattractant gradient and concentrate them to a location where they can be eliminated by conventional treatment without affecting the healthy brain tissue. Rubin et al demonstrated that soluble CXCL12 increases the migration of U87 GBM cells in a dose-dependent manner [23]
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