Modularity of RBC hitchhiking with polymeric nanoparticles: testing the limits of non-covalent adsorption

Abstract

Red blood cell (RBC) hitchhiking has great potential in enhancing drug therapy, by improving targeting and reducing rapid clearance of nanoparticles (NPs). However, to improve the potential for clinical translation of RBC hitchhiking, a more thorough understanding of the RBC-NP interface is needed. Here, we evaluate the effects of NP surface parameters on the success and biocompatibility of NP adsorption to extracted RBCs from various species. Major differences in RBC characteristics between rabbit, mouse and human were proven to significantly impact NP adsorption outcomes. Additionally, the effects of NP design parameters, including NP hydrophobicity, zeta potential, surfactant concentration and drug encapsulation, on RBC hitchhiking are investigated. Our studies demonstrate the importance of electrostatic interactions in balancing NP adsorption success and biocompatibility. We further investigated the effect of varying the anti-coagulant used for blood storage. The results presented here offer new insights into the parameters that impact NP adsorption on RBCs that will assist researchers in experimental design choices for using RBC hitchhiking as drug delivery strategy.

Advances in Drug Delivery Systems Based on Red Blood Cells and Their Membrane-Derived Nanoparticles

“…Compared to plain PLGA NPs, those loaded with paclitaxel and dexamethasone increase adsorption efficiency onto human RBCs without causing agglutination, while significantly decreasing hemolysis. 185 However, the underlying mechanisms of this phenomenon are not elucidated in this study. It is also important to evaluate the behaviors of the system after repeated treatments.…”

“…For example, the positively charged polyethylenimine (PEI) PLGA NPs (average zeta potential = 17.3 ± 0.4 mV) exhibit a 2-fold increase in binding efficiency on the negatively charged human RBCs compared to plain PLGA NPs (average zeta potential = −25.9 ± 0.2 mV), indicating the significant contribution of electrostatic force to adsoption. 185 Similarly, the positively charged magnetic NPs coated with chitosan (average zeta potential = 42.1 ± 8.8 mV) are also tightly bound to RBCs even after three washes. 9 By contrast, the partially hydrophobic, negatively charged NPs of the same size coated with polyethylene glycol α-,ω-diphosphate (average zeta potential = −35.3 ± 11.6 mV) exhibit initial high binding strength but desorb almost 30% after washing.…”

“…9 In addition, it is crucial to balance the binding efficiency and adverse effects caused by increased attraction force, especially at high RBC:nanoparticle ratios, which may result in agglutination or aggregates in the arteries, leading to pulmonary emboli. 185 Therefore, optimization of the influential parameters may help to minimize damages to RBCs due to attached NPs so that the system can deliver drugs efficiently to the target sites without posing severe side effects. Adverse immunological responses are another safety concern to be carefully evaluated.…”

“…Despite having the highest level of adsorption, rabbit RBCs pose a serious issue of aggregation upon binding of NPs. 185 These results call for careful considerations regarding adsorption success and biocompatibility when choosing animal models and formulations for RBC-hitchhiking systems.…”

Nanodiamonds for Biomedical Applications – Features of Interaction with Blood Components and Behavior in the Circulatory System [Review]

“…This facilitates the drug delivery in the brain and the crossing of the BBB [66,74]. Mostly polymeric NP are usually used [75]. However, it also was demonstrated that ND can attach to RBC membrane (Fig.…”