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Description
Glioblastoma (GBM) is the most common (60-70% of primary brain tumours) and the most malignant of the glial tumours. Although current therapies remain palliative, they have been proved to prolong overall survival. The effectiveness of temozolomide (TMZ) chemotherapy is limited by the serious systemic and dose-related side effects. Therefore, the primary goal of the presented studies was the design, fabrication, and preliminary characterization of the biopolymeric-based materials serving as a system for the local delivery of TMZ. The only clinically approved to date implantable therapeutic formulation for GBM therapy is Gliadel which releases carmustine, however, there are no analogous products containing TMZ available. The proposed approach can increase TMZ concentration at the desired site simultaneously reducing adverse systemic complications.
The major constituent of the obtained material is a lyophilized form of a hydrogel, crosslinked with a genipin matrix based on three biopolymers: collagen, lysine-modified hyaluronic acid (HAmod), and chitosan. Ionically gelled with tripolyphosphate chitosan particles loaded with TMZ were incorporated into the polymeric sol, which upon formation of covalent bonds formed biomaterial. For such a system several experiments were conducted like- swelling, degradation and the TMZ release study. To prove the possibility of a tuneable TMZ release profile two modifications of the presented material were tested. The former concerns the additional functionalization of chitosan particles with HAmod, whereas the second is related to attaching the TMZ molecules to the chitosan chains using EDC/NHS chemistry, which demands the transformation of TMZ into its derivative, TMZ-COOH. Fabricated carriers were characterized in terms of their morphology, size, and stability by means of the scanning electron microscope (SEM), dynamic light scattering technique, and zeta potential measurements, respectively. The encapsulation efficiency was estimated based on UV-Vis spectra. The products synthesized within the second modification were characterized by FTIR and NMR spectroscopies.
SEM microphotographs revealed that both types of particles are embedded into the porous polymeric matrix. An increase in the carriers’ size from approx. 100nm for chitosan ones to over 350nm for those modified with HAmod along with changes in their potential zeta values confirmed the desired functionalization. UV-Vis spectra enabled the verification of the TMZ content in the carriers. It was demonstrated that by playing with material composition and applying the lyophilization process the swelling ratio of the obtained products can be tuneable to potentially reduce the “mass effect” in the brain. The presence of the drug in the whole system was confirmed, however, TMZ encapsulated in the chitosan particles placed into the matrix exhibited the burst release. NMR and FTIR analyses identified the product of TMZ transformation as TMZ-COOH and verified its further immobilization to the chitosan.
Our findings suggest that the presented herein lyophilized hydrogel-based material could pose a reasonable starting point for the development of a novel local delivery system of TMZ, which has tuneable physicochemical characteristics. It is believed the proposed two modifications will help to achieve a more favourable, controlled release profile of TMZ.
Authors acknowledge the financial support of National Science Centre, Poland, grant OPUS 21, No UMO-2021/41/B/NZ7/03816.
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