Journal Home > Volume 12 , Issue 4
Nano Research 2019, 12(4): 837-844 https://doi.org/10.1007/s12274-019-2301-3
Research Article | Issue | Published: 29 January 2019

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

Show Author's Information 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( ),  Hai-Quan Mao1,2,5,9( )
Department of Biomedical Engineering,Johns Hopkins School of Medicine,Baltimore,MD 21218,USA;
Institute for NanoBioTechnology,Johns Hopkins University,Baltimore,MD 21218,USA;
W. Harry Feinstone Department of Molecular Microbiology & Immunology, and the Malaria Research Institute,Johns Hopkins Bloomberg School of Public Health,Baltimore,MD 21205,USA;
Emerging Pathogens Institute, Department of Infectious Diseases & Immunology,College of Veterinary Medicine, University of Florida,Gainesville,FL 32611,USA;
Department of Materials Science and Engineering,Whiting School of Engineering, Johns Hopkins University,Baltimore,FL 21218,USA;
Johns Hopkins School of Nursing,Baltimore,FL 21205,USA;
Department of Molecular and Comparative Pathobiology,Johns Hopkins School of Medicine,Baltimore,MD 21205,USA;
Department of Biomedical Engineering,Yale University,New Haven,CT 06520,USA;
Translational Tissue Engineering Center,Johns Hopkins University School of Medicine,Baltimore,MD 21231,USA;
Keywords:
vaccine delivery, biodegradable nanoparticle, lymph node trafficking, nanoparticle size, antigen presenting cells, in vivo imaging
Topics:
Antigens Immune systemInfrared devices MammalsNanoparticlesVaccines
Cite this article:
Howard GP, Verma G, Ke X, et al. Critical size limit of biodegradable nanoparticles for enhanced lymph node trafficking and paracortex penetration. Nano Research, 2019, 12(4): 837-844. https://doi.org/10.1007/s12274-019-2301-3
Download citation
EndNote(RIS)
BibTeX

537

Views

20

Downloads

Citations

74

Crossref

N/A

WoS

69

Scopus

0

CSCD

Abstract Full text Electronic supplementary material About this article

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.


menu
Abstract
Full text
Outline
Electronic supplementary material
About this article

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

Show Author's information 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( ), Hai-Quan Mao1,2,5,9( )
Department of Biomedical Engineering,Johns Hopkins School of Medicine,Baltimore,MD 21218,USA;
Institute for NanoBioTechnology,Johns Hopkins University,Baltimore,MD 21218,USA;
W. Harry Feinstone Department of Molecular Microbiology & Immunology, and the Malaria Research Institute,Johns Hopkins Bloomberg School of Public Health,Baltimore,MD 21205,USA;
Emerging Pathogens Institute, Department of Infectious Diseases & Immunology,College of Veterinary Medicine, University of Florida,Gainesville,FL 32611,USA;
Department of Materials Science and Engineering,Whiting School of Engineering, Johns Hopkins University,Baltimore,FL 21218,USA;
Johns Hopkins School of Nursing,Baltimore,FL 21205,USA;
Department of Molecular and Comparative Pathobiology,Johns Hopkins School of Medicine,Baltimore,MD 21205,USA;
Department of Biomedical Engineering,Yale University,New Haven,CT 06520,USA;
Translational Tissue Engineering Center,Johns Hopkins University School of Medicine,Baltimore,MD 21231,USA;

Abstract

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.

Keywords: vaccine delivery, biodegradable nanoparticle, lymph node trafficking, nanoparticle size, antigen presenting cells, in vivo imaging

References(35)

1

Trevaskis, N. L.; Kaminskas, L. M.; Porter, C. J. H. From sewer to saviour-targeting the lymphatic system to promote drug exposure and activity. Nat. Rev. Drug Discov. 2015, 14, 781–803.
DOI Google Scholar
2

Willard-Mack, C. L. Normal structure, function, and histology of lymph nodes. Toxicol. Pathol. 2006, 34, 409–424.
DOI Google Scholar
3

Wilson, N. S.; El-Sukkari, D.; Belz, G. T.; Smith, C. M.; Steptoe, R. J.; Heath, W. R.; Shortman, K.; Villadangos, J. A. Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood 2003, 102, 2187–2194.
DOI Google Scholar
4

Swartz, M. A.; Hubbell, J. A.; Reddy, S. T. Lymphatic drainage function and its immunological implications: From dendritic cell homing to vaccine design. Semin. Immunol. 2008, 20, 147–156.
DOI Google Scholar
5

Tostanoski, L. H.; Chiu, Y. -C.; Gammon, J. M.; Simon, T.; Andorko, J. I.; Bromberg, J. S.; Jewell, C. M. Reprogramming the local lymph node microenvironment promotes tolerance that is systemic and antigen specific. Cell Rep. 2016, 16, 2940–2952.
DOI Google Scholar
6

Supsersaxo, A.; Hein, W. R.; Steffen, H. Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm. Res. 1990, 7, 167–169.
DOI Google Scholar
7

Oussoren, C.; Storm, G. Liposomes to target the lymphatics by subcutaneous administration. Adv. Drug Deliv. Rev. 2001, 50, 143–156.
DOI Google Scholar
8

Kaminskas, L. M.; Porter, C. J. H. Targeting the lymphatics using dendritic polymers (dendrimers). Adv. Drug Deliv. Rev. 2011, 63, 890–900.
DOI Google Scholar
9

Reddy, S. T.; Rehor, A.; Schmoekel, H. G.; Hubbell, J. A.; Swartz, M. A. In vivo targeting of dendritic cells in lymph nodes with poly(propylene sulfide) nanoparticles. J. Control. Release 2006, 112, 26–34.
DOI Google Scholar
10

Reddy, S. T.; van der Vlies, A. J.; Simeoni, E.; Angeli, V.; Randolph, G. J.; O'Neil, C. P.; Lee, L. K.; Swartz, M. A.; Hubbell, J. A. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat. Biotechnol. 2007, 25, 1159–1164.
DOI Google Scholar
11

Mottram, P. L.; Leong, D.; Crimeen-Irwin, B.; Gloster, S.; Xiang, S. D.; Meanger, J.; Ghildyal, R.; Vardaxis, N.; Plebanski, M. Type 1 and 2 immunity following vaccination is influenced by nanoparticle size: Formulation of a model vaccine for respiratory syncytial virus. Mol. Pharm. 2007, 4, 73–84.
DOI Google Scholar
12

Fifis, T.; Gamvrellis, A.; Crimeen-Irwin, B.; Pietersz, G. A.; Li, J.; Mottram, P. L.; McKenzie, I. F.; Plebanski, M. Size-dependent immunogenicity: Therapeutic and protective properties of nano-vaccines against tumors. J. Immunol. 2004, 173, 3148–3154.
DOI Google Scholar
13

Kumar, S.; Anselmo, A. C.; Banerjee, A.; Zakrewsky, M.; Mitragotri, S. Shape and size-dependent immune response to antigen-carrying nanoparticles. J. Control. Release 2015, 220, 141–148.
DOI Google Scholar
14

Manolova, V.; Flace, A.; Bauer, M.; Schwarz, K.; Saudan, P.; Bachmann, M. F. Nanoparticles target distinct dendritic cell populations according to their size. Eur. J. Immunol. 2008, 38, 1404–1413.
DOI Google Scholar
15

Randolph, G. J.; Angeli, V.; Swartz, M. A. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat. Rev. Immunol. 2005, 5, 617–628.
DOI Google Scholar
16

Li, X. R.; Sloat, B. R.; Yanasarn, N.; Cui, Z. R. Relationship between the size of nanoparticles and their adjuvant activity: Data from a study with an improved experimental design. Eur. J. Pharm. Biopharm. 2011, 78, 107–116.
DOI Google Scholar
17

Chaney, E. J.; Tang, L.; Tong, R.; Cheng, J. J.; Boppart, S. A. Lymphatic biodistribution of polylactide nanoparticles. Mol. Imaging 2010, 9, 153–162.
DOI Google Scholar
18

Rao, D. A.; Forrest, M. L.; Alani, A. W. G.; Kwon, G. S.; Robinson, J. R. Biodegradable PLGA based nanoparticles for sustained regional lymphatic drug delivery. J. Pharm. Sci. 2010, 99, 2018–2031.
DOI Google Scholar
19

Zheng, S. S.; Qin, T.; Lu, Y.; Huang, Y. F.; Luo, L.; Liu, Z. G.; Bo, R. N.; Hu, Y. L.; Liu, J. G.; Wang, D. Y. Maturation of dendritic cells in vitro and immunological enhancement of mice in vivo by pachyman-and/or OVA-encapsulated poly(D, L-lactic acid) nanospheres. Int. J. Nanomedicine 2018, 13, 569–583.
DOI Google Scholar
20

Zhang, W. F.; Wang, L. Y.; Liu, Y.; Chen, X. M.; Liu, Q.; Jia, J. L.; Yang, T. Y.; Qiu, S. H.; Ma, G. H. Immune responses to vaccines involving a combined antigen-nanoparticle mixture and nanoparticle-encapsulated antigen formulation. Biomaterials 2014, 35, 6086–6097.
DOI Google Scholar
21

Maldonado, R. A.; LaMothe, R. A.; Ferrari, J. D.; Zhang, A. H.; Rossi, R. J.; Kolte, P. N.; Griset, A. P.; O'Neil, C.; Altreuter, D. H.; Browning, E. et al. Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc. Natl. Acad. Sci. USA 2015, 112, E156–E165.
DOI Google Scholar
22

Johnson, B. K.; Prud'homme, R. K. Mechanism for rapid self-assembly of block copolymer nanoparticles. Phys. Rev. Lett. 2003, 91, 118302.
DOI Google Scholar
23

Saad, W. S.; Prud'homme, R. K. Principles of nanoparticle formation by flash nanoprecipitation. Nano Today 2016, 11, 212–227.
DOI Google Scholar
24

Xiang, S. D.; Scholzen, A.; Minigo, G.; David, C.; Apostolopoulos, V.; Mottram, P. L.; Plebanski, M. Pathogen recognition and development of particulate vaccines: Does size matter?. Methods 2006, 40, 1–9.
DOI Google Scholar
25

Harrell, M. I.; Iritani, B. M.; Ruddell, A. Lymph node mapping in the mouse. J. Immunol. Methods 2008, 332, 170–174.
DOI Google Scholar
26

Reddy, S. T.; Berk, D. A.; Jain, R. K.; Swartz, M. A. A sensitive in vivo model for quantifying interstitial convective transport of injected macromolecules and nanoparticles. J. Appl. Physiol. 2006, 101, 1162– 1169.
DOI Google Scholar
27

Tomura, M.; Hata, A.; Matsuoka, S.; Shand, F. H. W.; Nakanishi, Y.; Ikebuchi, R.; Ueha, S.; Tsutsui, H.; Inaba, K.; Matsushima, K. et al. Tracking and quantification of dendritic cell migration and antigen trafficking between the skin and lymph nodes. Sci. Rep. 2014, 4, 6030.
DOI Google Scholar
28

Thomas, S. N.; Schudel, A. Overcoming transport barriers for interstitial-, lymphatic-, and lymph node-targeted drug delivery. Curr. Opin. Chem. Eng. 2015, 7, 65–74.
DOI Google Scholar
29

Sixt, M.; Kanazawa, N.; Selg, M.; Samson, T.; Roos, G.; Reinhardt, D. P.; Pabst, R.; Lutz, M. B.; Sorokin, L. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 2005, 22, 19–29.
DOI Google Scholar
30

Roozendaal, R.; Mempel, T. R.; Pitcher, L. A.; Gonzalez, S. F.; Verschoor, A.; Mebius, R. E.; von Andrian, U. H.; Carroll, M. C. Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Immunity 2009, 30, 264–276.
DOI Google Scholar
31

Phan, T. G.; Grigorova, I.; Okada, T.; Cyster, J. G. Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nat. Immunol. 2007, 8, 992–1000.
DOI Google Scholar
32

Kang, S.; Ahn, S.; Lee, J.; Kim, J. Y.; Choi, M.; Gujrati, V.; Kim, H.; Kim, J.; Shin, E. C.; Jon, S. Effects of gold nanoparticle-based vaccine size on lymph node delivery and cytotoxic T-lymphocyte responses. J. Control. Release 2017, 256, 56–67.
DOI Google Scholar
33

Kim, H.; Uto, T.; Akagi, T.; Baba, M.; Akashi, M. Amphiphilic poly(amino acid) nanoparticles induce size-dependent dendritic cell maturation. Adv. Funct. Mater. 2010, 20, 3925–3931.
DOI Google Scholar
34

Hirosue, S.; Kourtis, I. C.; van der Vlies, A. J.; Hubbell, J. A.; Swartz, M. A. Antigen delivery to dendritic cells by poly(propylene sulfide) nanoparticles with disulfide conjugated peptides: Cross-presentation and T cell activation. Vaccine 2010, 28, 7897–7906.
DOI Google Scholar
35

Jiang, H.; Wang, Q.; Sun, X. Lymph node targeting strategies to improve vaccination efficacy. J. Control. Release 2017, 267, 47–56.
DOI Google Scholar
File
12274_2019_2301_MOESM1_ESM.pdf (3.6 MB)
Publication history
Copyright
Acknowledgements

Publication history

Received: 13 November 2018
Revised: 14 January 2019
Accepted: 15 January 2019
Published: 29 January 2019
Issue date: April 2019

Copyright

© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Acknowledgements

Acknowledgements

This work was funded by support from the National Institutes of Health (Nos. R01-AI114609 and T32-OD11089) and NSF GRFP (No. DGE1746891). Partial support was received from the University of Florida Emerging Pathogens Institute.

Return