Red Blood Cells-Derived Vesicles for Delivery of Lipophilic Drug Camptothecin.

Abstract

Recently, cell membrane-derived nanoparticles, particularly of RBCs, have been explored for delivery of hydrophilic solutes of varied size and complexities. So far, these naturally derived nanoparticles show a significant overlap with liposomes in terms of stability, solute encapsulation, and release. Unlike hydrophilic molecules, which are loaded inside the aqueous core, hydrophobic moieties largely partition inside the lipophilic shell, hence fate of these nanocarriers may be different. Since vesicles have more complex membrane architecture (due to natural lipids and additional proteins and glycoproteins), ease of loading hydrophobic drug, its release pattern, and overall particle stability cannot be compared to those of synthetic lipid-based carriers. Therefore, we derived nanovesicles (NVEs) from RBC membrane, loaded with hydrophobic drug camptothecin (CPT) and labeled noncovalently with amphiphilic fluorophore (CM-DiI). Although both CPT and CM-DiI are known to partition inside the membrane, the overall stability of NVEs and composition of membrane proteins, particularly CD47, "marker of self", did not change. Additionally, the developed NVEs were found to be nonphagocytic even in the presence of serum and showed minimal stimulation of macrophages to release cytokines. Further, this system showed slow release but strong retention of CPT and CM-DiI, respectively, over 24 h, hence appropriate for theranostic applications. Also, NVEs were internalized by lung carcinoma cells and possessed slightly higher toxicity than free CPT. When injected intravenously in balb/c mice, these nanovesicles showed higher retention in blood over 48 h and insignificant accumulation in vital organs like heart and kidneys, thus suggesting its potential for in vivo application. We believe that this system has superior stealth and comparable physicochemical properties to synthetic lipid-based nanocarriers; hence, it can be further developed as personalized medicine.