Enhancement of the blood-circulation time and performance of nanomedicines via the forced clearance of erythrocytes

Abstract

The rapid elimination of nanoparticles from the bloodstream by the mononuclear phagocyte system limits the activity of many nanoparticle formulations. Here, we show that inducing a slight and transient depletion of erythrocytes in mice (~5% decrease in haematocrit) by administrating a low dose (1.25 mg kg−1) of allogeneic anti-erythrocyte antibodies increases the circulation half-life of a range of short-circulating and long-circulating nanoparticle formulations by up to 32-fold. Treatment of the animals with anti-erythrocyte antibodies significantly improved the targeting of CD4+ cells in vivo with fluorescent anti-CD4-antibody-conjugated nanoparticles, the magnetically guided delivery of ferrofluid nanoparticles to subcutaneous tumour allografts and xenografts, and the treatment of subcutaneous tumour allografts with magnetically guided liposomes loaded with doxorubicin and magnetite or with clinically approved ‘stealthy’ doxorubicin liposomes. The transient and partial blocking of the mononuclear phagocyte system may enhance the performance of a wide variety of nanoparticle drugs.

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Fig. 1: Effect of the MPS-cytoblockade on blood circulation of nanoparticles and microparticles.
Fig. 2: Characterizing the mechanism aspects of MPS-cytoblockade.
Fig. 3: Characterizing the functional aspects of MPS-cytoblockade.
Fig. 4: Safety aspects of MPS-cytoblockade.
Fig. 5: Safety aspects of MPS-cytoblockade using blood and urine tests.
Fig. 6: Biomedical applications of the MPS-cytoblockade.

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets are too numerous to be readily shared publicly but can be made available from the corresponding author on reasonable request.

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Acknowledgements

We thank A. F. Topolskov (General Physics Institute, RAS) for engineering assistance; O. A. Kharlova (Diagnostic Centre 6 of Moscow Health Department) and A. В. Schekhter (First Moscow State Medical University) for help with histology; A. M. Sapozhnikov (Institute of Bioorganic Chemistry, RAS) for access to and help with FACScan; and R. I. Yakubovskaya (Moscow Oncology Research Centre) for supplying B16-F1 and LLC cell lines and support with establishing the mouse tumour model. Certain aspects of this multidisciplinary research were partially supported by the Russian Science Foundation grants 16-19-00131 (in vitro phagocytosis study; histology; toxicity and complement studies), 16-12-10543 (development of the MPQ measurement methodology and related detectors; MRI particle biodistribution study) and 17-74-20146 (inflammation study; nanoparticle characterization; RBC biodistribution study).

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M.P.N. conceived the idea, designed the study and supervised the project. I.V.Z. performed all of the in vivo experiments, the toxicity study, and nanoparticle synthesis and characterization. M.P.N. and P.I.N. developed and optimized the MPQ-based technique for nanoparticle circulation measurements. V.O.S. performed all of the in vitro experiments and the cytokine and sepsis studies. I.L.S. performed in vitro phagocytosis studies and MPS-cytoblockade in rats, and co-performed toxicity experiments. M.P.N. co-performed the MRI measurements, in vitro phagocytosis studies and developed doxorubicin–magnetite liposomes. M.P.N., I.V.Z., S.M.D. and P.I.N. analysed data. M.P.N. and P.I.N. wrote the manuscript.

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Correspondence to Maxim P. Nikitin.

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M.P.N., I.V.Z., S.M.D. and P.I.N. are inventors on patent applications (RU2014145276 and PCT/RU2015/000755) and a patent (RU2683020) related to the findings described in this manuscript. P.I.N. is a named inventor on MPQ-related patents (RU2166751 and RU2177611).

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Nikitin, M.P., Zelepukin, I.V., Shipunova, V.O. et al. Enhancement of the blood-circulation time and performance of nanomedicines via the forced clearance of erythrocytes. Nat Biomed Eng 4, 717–731 (2020). https://doi.org/10.1038/s41551-020-0581-2

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