Alginate hydrogel improves anti-angiogenic bevacizumab activity in cancer therapy

Abstract

Anti-vascular endothelial growth factor (anti-VEGF) therapy applied to solid tumors is a promising strategy, yet, the challenge to deliver these agents at high drug concentrations together with the maintenance of therapeutic doses locally, at the tumor site, minimizes its benefits. To overcome these obstacles, we propose the development of a bevacizumab-loaded alginate hydrogel by electrostatic interactions to design a delivery system for controlled and anti-angiogenic therapy under tumor microenvironmental conditions. The tridimensional hydrogel structure produced provides drug stability and a system able to be introduced as a flowable solution, stablishing a depot after local administration. Biological performance by the chick embryo chorioallantoic membrane (CAM) assay indicated a pH-independent improved anti-angiogenic activity (∼50%) compared to commercial available anti-VEGF drug. Moreover, there was a considerable regression in tumor size when treated with this system. Immunohistochemistry highlighted a reduced number and disorganization of microscopic blood vessels resulting from applied therapy. These results suggest that the developed hydrogel is a promising approach to create an innovative delivery system that offers the possibility to treat different solid tumors by intratumoral administration.

Hydrogels as Potential Nano-, Micro- and Macro-Scale Systems for Controlled Drug Delivery

“…The divalent ions interfered with the binding between DOX and dextran sulphate, promoting prolonged release of the active substance from the HG and thereby providing a sustained chemotherapeutic effect for destroying cancer cells. Alginate (sodium alginate, SA)-based HGs with immobilized bevacizumab were also examined [233]. Anti-angiogenic active ingredients were released at prolonged and elevated levels to cancerous and neighbouring cells.…”

Recent advances in smart hydrogels for biomedical applications: From self-assembly to functional approaches

“…Therefore, pH-responsive systems that effectively deliver anticancer drugs might carry and stabilize the therapeutic agent at physiological pH, in addition to releasing the drug at this condition [189]. Numerous hydrogel systems have been proposed in this sense, particularly for local administration, where antitumor drugs can be directly transported to the cancer microenvironment [122,[190][191][192].…”

“…In acidic environments, according to the polymer pKa, alginate chains represent a matrix surrounded by negative charges, which are able to interact with positively charged drugs through supramolecular interactions. The acid environment makes these polyelectrolyte complexes stronger and more stable, which results in different drug release profiles, according to the pH changes at the tumor environment [190,194].…”

3D tumor angiogenesis models: recent advances and challenges

“…Alginate is frequently used as a bioink with calcium chloride that acts as a support material as well as a cross-linking agent. For example, Ferreira et al ., constructed bevacizumab loaded alginate hydrogel which inhibited tumor angiogenesis by a pH-dependent controlled release of bevacizumab in CAM assay (Ferreira et al 2017 ). Similarly, Fischbach et al ., used RGD (an integrin recognition site) bound alginate hydrogel to demonstrate enhanced secretion of IL-8 and VEGF by OSCC-3, MDA-MB-231 and glioblastoma cell line U87, whose blockage significantly reduced tumor angiogenesis and growth (Fischbach et al 2009 ).…”