Albumin based-nanoparticles as a platform for oral and intravenous delivery of monoclonal antibodies

Resumen

This research was centred on the hypothesis that the use of albumin serum nanoparticles (NP) decorated with various pharmaceutical excipients, such as polyethylene glycol and dextrans, has the potential to significantly enhance the delivery of therapeutic proteins via both oral and intravenous routes. For oral administration due to the challenge of this route for therapeutic proteins, we propose that encapsulating bevacizumab (used as model of therapeutic protein) within PEG-coated albumin NP, with the inclusion of permeation enhancers, can facilitate the delivery of the monoclonal antibody to the epithelial surface. This encapsulation approach is expected to enhance the oral bioavailability of bevacizumab. For intravenous administration, to enhance the accumulation of monoclonal antibodies within tumor we are persuaded that encapsulating therapeutic proteins in dextran-coated albumin NP may promote their accumulation in the tumor mass leading to enhance its efficacy while minimizing potential side effects. Albumin NP (containing either DS or DOCU) were successfully prepared by desolvation and, then, coated with poly(ethylene glycol) 35,000 (PEG). Diffusion mucus studies showed increased diffusivity for DS-NP-P while in vivo fluorescence imaging in rats demonstrated the ability of PEG-coated NP to reach the intestinal surface. In C. elegans FT63, DS and DOCU, free or encapsulated, disrupted the integrity of the intestinal epithelium, without affecting the overall survival of the worms. A hydrophobic ion pairing complex between bevacizumab and DS or DOCU were successfully formed being the complex formation efficiency higher for the B-DOCU. The bevacizumab HIP complexes were successfully encapsulated in albumin NP, particularly those based on DS. The release of bevacizumab from NP was characterized by an important burst effect in SGF; although in SIF, NP containing the bevacizumab complexes displayed lower released rates. Finally, the PK study of the oral administration of B-DS-NP-P allowed to confirm an oral bioavailability of bevacizumab up to 3.7%. Albumin NP coated with dextran 40,000 (DEX) were prepared by a desolvation method. The encapsulation of bevacizumab in DEX-coated NP produced an encapsulation efficiency higher than 80%. The pharmacokinetic profile of B-NP-DEX was characterized by a rapid increase in the plasma levels and a plateau for 23 hours, the AUC was lower than free bevacizumab. The effect of bevacizumab either free or encapsulated in NP (B-NP-DEX) was evaluated in a xenograft model of colorectal cancer. B-NP-DEX caused a reduction in tumor growth of approximately 40% compared to the control and free bevacizumab. Levels of the monoclonal antibody in tumor were 2.5-times higher in animals treated with B-NP-DEX. VEGF expression in tumor showed a significant reduction in mice treated with B-NP-DEX. The effect of bevacizumab encapsulated in DEX-coated NP (B-NP-DEX) plus intravenous PTX was evaluated in an in vivo model of colorectal cancer. B-NP-DEX+PTX exhibited a higher reduction rate in tumor growth. Regarding proliferation by ki67 and VEGF levels a significant reduction was observed for B-NP-DEX+PTX. The effect of IV bevacizumab plus oral paclitaxel NP was also evaluated. Some similar outcomes with free BEVA+PTX had been observed considering the different routes of administration of PTX (IV vs oral). These outcomes might open an alternative route for paclitaxel administration upgrading the existing treatments. This research provides valuable insights into the use of albumin nanoparticles coated with different excipients to improve the delivery of therapeutic proteins, with the potential to enhance their bioavailability and efficacy in the treatment of cancer.