Journal
INTERNATIONAL JOURNAL OF NANOMEDICINE
Volume 17, Issue -, Pages 5081-5097Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/IJN.S381483
Keywords
atherosclerosis; cholesterol efflux; drug delivery; everolimus; proliferation; protein -conjugate
Funding
- German Research Foundation
- [HI1573/2]
- [42268184]
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The conventional techniques for rHDL preparation have limitations, including long process times and harsh preparation conditions. This study presents a novel method to overcome these challenges and proposes a dual mode of action for Eve-rHDL in atherosclerosis and cardiovascular disease.
Purpose: The conventional techniques for the preparation of reconstituted high-density lipoprotein (rHDL) are hampered by long process times, the need for large amounts of starting material, and harsh preparation conditions. Here, we present a novel rHDL preparation method to overcome these challenges. Furthermore, we propose a dual mode of action for rHDL loaded with the immunosuppressant drug everolimus (Eve-rHDL) in the context of atherosclerosis and cardiovascular disease.Methods: We use dual centrifugation for rHDL nanoparticle preparation and characterize the physicochemical properties by NS-TEM, N-PAGE, DLS, AF4, and HPLC. In addition, we determine the biological efficacy in human and murine cell culture with regard to cellular uptake, cholesterol efflux, and proliferation.Results: We confirm the characteristic particle size of 10 nm, discoidal morphology, and chemical composition of the rHDL preparations and identify dual centrifugation as an ideal method for cost-effective aseptic rHDL manufacturing. rHDL can be prepared in approx. 1.5 h with batch sizes as little as 89 mu L. Moreover, we demonstrate the cholesterol efflux capacity and anti-proliferative activity of Eve-rHDL in vitro. The anti-proliferative effects were comparable to free Eve, thus confirming the suitability of rHDL as a capable drug delivery vehicle.Conclusion: Eve-rHDL shows great efficacy in vitro and may further be employed to target atherosclerotic plaques in vivo. Highly effective anti-atherosclerotic therapy might be feasible by reducing both inflammatory-and lipid burden of the plaques. Dual centrifugation is an ideal technique for the efficient application of the rHDL platform in cardiovascular disease and beyond.
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