Research Article


2019, 12(4): 837–844


Critical size limit of biodegradable nanoparticles for enhanced lymph node trafficking and paracortex penetration

Gregory P. Howard1,2, Garima Verma3,4, Xiyu Ke2,5, Winter M. Thayer6, Timothy Hamerly4, Victoria K. Baxter3,7, John E. Lee8, Rhoel R. Dinglasan3,4 (*), and Hai-Quan Mao1,2,5,9 (*)

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1 Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore MD 21218, USA
2 Institute for NanoBioTechnology, Johns Hopkins University, Baltimore MD 21218, USA
3 W. Harry Feinstone Department of Molecular Microbiology & Immunology, and the Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore MD 21205, USA
4 Emerging Pathogens Institute, Department of Infectious Diseases & Immunology, College of Veterinary Medicine, University of Florida, Gainesville FL 32611, USA
5 Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore MD 21218, USA
6 Johns Hopkins School of Nursing, Baltimore MD 21205, USA
7 Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore MD 21205, USA
8 Department of Biomedical Engineering, Yale University, New Haven CT 06520, USA
9 Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore MD 21231, USA

Keywords: biodegradable nanoparticle, lymph node trafficking, vaccine delivery, nanoparticle size, antigen presenting cells, in vivo imaging
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  • Abstract
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Lymph node (LN) targeting through interstitial drainage of nanoparticles (NPs) is an attractive strategy to stimulate a potent immune response, as LNs are the primary site for lymphocyte priming by antigen presenting cells (APCs) and triggering of an adaptive immune response. NP size has been shown to influence the efficiency of LN-targeting and retention after subcutaneous injection. For clinical translation, biodegradable NPs are preferred as carrier for vaccine delivery. However, the selective “size gate” for effective LN-drainage, particularly the kinetics of LN trafficking, is less well defined. This is partly due to the challenge in generating size-controlled NPs from biodegradable polymers in the sub-100-nm range. Here, we report the preparation of three sets of poly(lactic-co-glycolic)-b-poly(ethylene-glycol) (PLGA-b-PEG) NPs with number average diameters of 20-, 40-, and 100-nm and narrow size distributions using flash nanoprecipitation. Using NPs labeled with a near-infrared dye, we showed that 20-nm NPs drain rapidly across proximal and distal LNs following subcutaneous inoculation in mice and are retained in LNs more effectively than NPs with a number average diameter of 40-nm. The drainage of 100-nm NPs was negligible. Furthermore, the 20-nm NPs showed the highest degree of penetration around the paracortex region and had enhanced access to dendritic cells in the LNs. Together, these data confirmed that small, size-controlled PLGA-b-PEG NPs at the lower threshold of about 30-nm are most effective for LN trafficking, retention, and APC uptake after s.c. administration. This report could inform the design of LN-targeted NP carrier for the delivery of therapeutic or prophylactic vaccines.
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Critical size limit of biodegradable nanoparticles for enhanced lymph node trafficking and paracortex penetration. Nano Res. 2019, 12(4): 837–844

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