Exploiting supramolecular interactions to produce bevacizumab-loaded nanoparticles for potential mucosal delivery

Abstract

Monoclonal antibody (mAb) delivery is gaining importance for local, systemic, and route-specific targeting. The mucus constitutes the main barrier for this type of delivery. In the present study, we aimed to develop a drug delivery platform by integrating mucus penetrating and mucoadhesive agents into a single system. Our hypothesis is that by combining these opposing functions, this system could have its properties modulated according to specific purposes. Self-assembly studies were conducted using three classes of building blocks: the protein drug bevacizumab (BVZ), mucus-penetrating polyanion dextran sulfate (DS), mucoadhesive polycations trimethylchitosan (TMC) and chitosan oligosaccharides (COS). We obtained two types of nanoparticles by manipulating supramolecular interactions between the components. Binary protein-polyanion (BVZ/DS) nanoparticles showed size of approximately 150 nm and a negative zeta potential. Ternary protein-polyanion-polycation (BVZ/DS/COS) nanoparticles were obtained using COS and exhibited 350 nm and a positive zeta potential. Assisted by calorimetric information, we demonstrated that building stable ternary nanoparticles carrying positive charges were not possible using the polycation TMC due to its thermodynamic constraints. Furthermore, spectroscopy analysis and CAM assay indicated that BVZ continued structurally and functionally stable after its incorporation into the nanoparticles. These two types of nanoparticles exhibited different behaviors when interacting with mucin, as shown by DLS and AFM studies. While the negatively charged particles promoted dispersion of the mucin network, suggesting a mucus penetrating effect of DS, the positively charged particles formed aggregates, probably caused by the mucoadhesive effect of COS. These results highlight the importance of understanding the role of supramolecular interactions, responsible for forming drug delivery systems containing complex molecules, such as proteins and polymers.

Assessment of In-Situ Gelling Microemulsion Systems upon Temperature and Dilution Condition for Corneal Delivery of Bevacizumab

“…The fitting of the CD spectra (Figure 2) reveals the high relative amount of b-strand (ca. 45%), which indeed corresponds with the detailed analysis of the secondary structure of BVZ carried out by Ferreira et al [51] and confirms the relative abundance of the β-sheets (ca. 47%).…”

Organic Nanocarriers for Bevacizumab Delivery: An Overview of Development, Characterization and Applications

“…To avoid the BCZ exposition to organic solvents or to a sonication process, BCZ-coated PLA nanoparticles encapsulated inside porous PLGA microparticles were produced by lyophilization, supercritical infusion, and pressure quench technology [67]. The maintenance of BCZ structure was observed in several reports after nanoencapsulation or surface-conjugation [47,55,62,68,74].…”

“…Ternary protein-polyanion-polycation nanoparticles have been developed using BCZ, dextran sulfate nanoparticles and chitosan oligosaccharides [ 55 ]. Dextran sulfate, a mucus-penetrating polyanion with high water solubility, has hydroxyl groups modulating the incorporation of drugs into its skeleton [ 97 ].…”

“…Dextran sulfate, a mucus-penetrating polyanion with high water solubility, has hydroxyl groups modulating the incorporation of drugs into its skeleton [ 97 ]. Nanoparticles ( d = 346 nm; ζ potential = +40.0 mV, and EE% = 73%) showed mucoadhesion in the presence of mucin [ 55 ]. The secondary and tertiary structures of BCZ were maintained after incorporation into nanoparticles.…”

“…BCZ-loaded dextran sulfate nanoparticles inhibited the angiogenesis in the CAM assay in a way more pronounced and constant reduction over time in blood vessels compared to free BCZ. This formulation was produced for the mucosal delivery [ 55 ].…”