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PLGA nanodepots co-encapsulating prostratin and anti-CD25 enhance primary natural killer cell antiviral and antitumor function

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Abstract

Natural killer (NK) cells are attractive effector cells of the innate immune system against human immunodeficiency virus (HIV) and cancer. However, NK cell therapies are limited by the fact that target cells evade NK cells, for example, in latent reservoirs (in HIV) or through upregulation of inhibitory signals (in cancer). To address this limitation, we describe a biodegradable nanoparticlebased “priming” approach to enhance the cytotoxic efficacy of peripheral blood mononuclear cell-derived NK cells. We present poly(lactic-co-glycolic acid) (PLGA) nanodepots (NDs) that co-encapsulate prostratin, a latency-reversing agent, and anti-CD25 (aCD25), a cell surface binding antibody, to enhance primary NK cell function against HIV and cancer. We utilize a nanoemulsion synthesis scheme to encapsulate both prostratin and aCD25 within the PLGA NDs (termed Pro-aCD25-NDs). Physicochemical characterization studies of the NDs demonstrated that our synthesis scheme resulted in stable and monodisperse Pro-aCD25- NDs. The NDs successfully released both active prostratin and anti-CD25, and with controllable release kinetics. When Pro-aCD25-NDs were administered in an in vitro model of latent HIV and acute T cell leukemia using J-Lat 10.6 cells, the NDs were observed to prime J-Lat cells resulting in significantly increased NK cell-mediated cytotoxicity compared to free prostratin plus anti-CD25, and other controls. These findings demonstrate the feasibility of using our Pro-aCD25-NDs to prime target cells for enhancing the cytotoxicity of NK cells as antiviral or antitumor agents.

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References

  1. Mikulak, J.; Oriolo, F.; Zaghi, E.; Di Vito, C.; Mavilio, D. Natural killer cells in HIV-1 infection and therapy. AIDS2017, 31, 2317–2330.

    CAS  Google Scholar 

  2. Guillerey, C.; Huntington, N. D.; Smyth, M. J. Targeting natural killer cells in cancer immunotherapy. Nat. Immunol.2016, 17, 1025–1036.

    CAS  Google Scholar 

  3. Breunig, M.; Lungwitz, U.; Liebl, R.; Goepferich, A. Breaking up the correlation between efficacy and toxicity for nonviral gene delivery. Proc. Natl. Acad. Sci. USA2007, 104, 14454–14459.

    CAS  Google Scholar 

  4. Daher, M.; Rezvani, K. Next generation natural killer cells for cancer immunotherapy: The promise of genetic engineering. Curr. Opin. Immunol.2018, 51, 146–153.

    CAS  Google Scholar 

  5. Florea, B. I.; Meaney, C.; Junginger, H. E.; Borchard, G. Transfection efficiency and toxicity of polyethylenimine in differentiated Calu-3 and nondifferentiated COS-1 cell cultures. AAPS PharmSci2002, 4, 1–11.

    Google Scholar 

  6. Kafil, V.; Omidi, Y. Cytotoxic impacts of linear and branched polyethylenimine nanostructures in a431 cells. Bioimpacts2011, 1, 23–30.

    CAS  Google Scholar 

  7. De Maria, A.; Fogli, M.; Costa, P.; Murdaca, G.; Puppo, F.; Mavilio, D.; Moretta, A.; Moretta, L. The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44). Eur. J. Immunol.2003, 33, 2410–2418.

    Google Scholar 

  8. Katz, J. D.; Mitsuyasu, R.; Gottlieb, M. S.; Lebow, L. T.; Bonavida, B. Mechanism of defective NK cell activity in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. II. Normal antibody-dependent cellular cytotoxicity (ADCC) mediated by effector cells defective in natural killer (NK) cytotoxicity. J. Immunol.1987, 139, 55–60.

    CAS  Google Scholar 

  9. Cheng, J. J.; Teply, B. A.; Sherifi, I.; Sung, J.; Luther, G.; Gu, F. X.; Levy-Nissenbaum, E.; Radovic-Moreno, A. F.; Langer, R.; Farokhzad, O. C. Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery. Biomaterials2007, 28, 869–876.

    CAS  Google Scholar 

  10. Li, Y. P.; Pei, Y. Y.; Zhang, X. Y.; Gu, Z. H.; Zhou, Z. H.; Yuan, W. F.; Zhou, J. J.; Zhu, J. H.; Gao, X. J. PEGylated PLGA nanoparticles as protein carriers: Synthesis, preparation and biodistribution in rats. J. Control. Release2001, 71, 203–211.

    CAS  Google Scholar 

  11. Gdowski, A.; Ranjan, A.; Mukerjee, A.; Vishwanatha, J. Development of biodegradable nanocarriers loaded with a monoclonal antibody. Int. J. Mol. Sci.2015, 16, 3990–3995.

    CAS  Google Scholar 

  12. Langer, R.; Folkman, J. Polymers for the sustained release of proteins and other macromolecules. Nature1976, 263, 797–800.

    CAS  Google Scholar 

  13. Spivak, A. M.; Planelles, V. Novel latency reversal agents for HIV-1 cure. Annu. Rev. Med.2018, 69, 421–436.

    CAS  Google Scholar 

  14. Kulkosky, J.; Culnan, D. M.; Roman, J.; Dornadula, G.; Schnell, M.; Boyd, M. R.; Pomerantz, R. J. Prostratin: Activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood2001, 98, 3006–3015.

    CAS  Google Scholar 

  15. Desimio, M. G.; Giuliani, E.; Ferraro, A. S.; Adorno, G.; Doria, M. In vitro exposure to prostratin but not bryostatin-1 improves natural killer cell functions including killing of CD4+ T cells harboring reactivated human immunodeficiency virus. Front. Immunol.2018, 9, 1514.

    Google Scholar 

  16. Makadia, H. K.; Siegel, S. J. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers2011, 3, 1377–1397.

    CAS  Google Scholar 

  17. Danhier, F.; Ansorena, E.; Silva, J. M.; Coco, R.; Le Breton, A.; Préat, V. PLGA-based nanoparticles: An overview of biomedical applications. J. Control. Release2012, 161, 505–522.

    CAS  Google Scholar 

  18. Español, L.; Larrea, A.; Andreu, V.; Mendoza, G.; Arruebo, M.; Sebastian, V.; Aurora-Prado, M. S.; Kedor-Hackmann, E. R. M.; Santoro, M. I. R. M.; Santamaria, J. Dual encapsulation of hydrophobic and hydrophilic drugs in PLGA nanoparticles by a single-step method: Drug delivery and cytotoxicity assays. RSC Adv.2016, 6, 111060–111069.

    Google Scholar 

  19. Goldberg, M. S. Immunoengineering: How nanotechnology can enhance cancer immunotherapy. Cell2015, 161, 201–204.

    CAS  Google Scholar 

  20. Martínez Rivas, C. J.; Tarhini, M.; Badri, W.; Miladi, K.; Greige- Gerges, H.; Nazari, Q. A.; Galindo Rodríguez, S. A.; Román, R. Á.; Fessi, H.; Elaissari, A. Nanoprecipitation process: From encapsulation to drug delivery. Int. J. Pharm.2017, 532, 66–81.

    Google Scholar 

  21. Astete, C. E.; Sabliov, C. M. Synthesis and characterization of PLGA nanoparticles. J. Biomat. Sci., Polym Ed.2006, 17, 247–289.

    CAS  Google Scholar 

  22. Wang, W.; Erbe, A. K.; Hank, J. A.; Morris, Z. S.; Sondel, P. M. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Front. Immunol.2015, 6, 368.

    Google Scholar 

  23. Ramilo, O.; Bell, K. D.; Uhr, J. W.; Vitetta, E. S. Role of CD25+ and CD25- T cells in acute HIV infection in vitro.J. Immunol.1993, 150, 5202–5208.

    CAS  Google Scholar 

  24. Arce Vargas, F.; Furness, A. J. S.; Solomon, I.; Joshi, K.; Mekkaoui, L.; Lesko, M. H.; Miranda Rota, E.; Dahan, R.; Georgiou, A.; Sledzinska, A. et al. Fc-optimized Anti-CD25 depletes tumorinfiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors. Immunity2017, 46, 577–586.

    CAS  Google Scholar 

  25. Flynn, M. J.; Hartley, J. A. The emerging role of anti-CD25 directed therapies as both immune modulators and targeted agents in cancer. Brit. J. Haematol.2017, 179, 20–35.

    CAS  Google Scholar 

  26. Jordan, A.; Bisgrove, D.; Verdin, E. HIV reproducibly establishes a latent infection after acute infection of T cells in vitro.EMBO J.2003, 22, 1868–1877.

    CAS  Google Scholar 

  27. Chen, M. S.; Ouyang, H. C.; Zhou, S. Y.; Li, J. Y.; Ye, Y. B. PLGA-nanoparticle mediated delivery of anti-OX40 monoclonal antibody enhances anti-tumor cytotoxic T cell responses. Cell. Immunol.2014, 287, 91–99.

    CAS  Google Scholar 

  28. Sousa, F.; Cruz, A.; Pinto, I. M.; Sarmento, B. Nanoparticles provide long-term stability of bevacizumab preserving its antiangiogenic activity. Acta Biomater.2018, 78, 285–295.

    CAS  Google Scholar 

  29. Feczkó, T.; Tóth, J.; Dósa, G.; Gyenis, J. Optimization of protein encapsulation in PLGA nanoparticles. Chem. Eng. Process.2011, 50, 757–765.

    Google Scholar 

  30. Son, S.; Lee, W. R.; Joung, Y. K.; Kwon, M. H.; Kim, Y. S.; Park, K. D. Optimized stability retention of a monoclonal antibody in the PLGA nanoparticles. Int. J. Pharm.2009, 368, 178–185.

    CAS  Google Scholar 

  31. Lee, Y. H.; Lai, Y. H. Synthesis, characterization, and biological evaluation of anti-HER2 indocyanine green-encapsulated PEGcoated PLGA nanoparticles for targeted phototherapy of breast cancer cells. PLoS One2016, 11, e0168192.

    Google Scholar 

  32. Lee, Y. H.; Chang, D. S. Fabrication, characterization, and biological evaluation of anti-HER2 indocyanine green-doxorubicin-encapsulated PEG-b-PLGA copolymeric nanoparticles for targeted photochemotherapy of breast cancer cells. Sci. Rep.2017, 7, 46688.

    Google Scholar 

  33. Sainz, V.; Peres, C.; Ciman, T.; Rodrigues, C.; Viana, A. S.; Afonso, C. A. M.; Barata, T.; Brocchini, S.; Zloh, M.; Gaspar, R. S. et al. Optimization of protein loaded PLGA nanoparticle manufacturing parameters following a quality-by-design approach. RSC Adv.2016, 6, 104502–104512.

    CAS  Google Scholar 

  34. Fonte, P.; Soares, S.; Costa, A.; Andrade, J. C.; Seabra, V.; Reis, S.; Sarmento, B. Effect of cryoprotectants on the porosity and stability of insulin-loaded PLGA nanoparticles after freeze-drying. Biomatter.2012, 2, 329–339.

    Google Scholar 

  35. Hines, D. J.; Kaplan, D. L. Poly(lactic-co-glycolic) acid-controlledrelease systems: Experimental and modeling insights. Crit. Rev. Ther. Drug. Carrier Syst.2013, 30, 257–276.

    CAS  Google Scholar 

  36. Fredenberg, S.; Wahlgren, M.; Reslow, M.; Axelsson, A. The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems-a review. Int. J. Pharm.2011, 415, 34–52.

    CAS  Google Scholar 

  37. Jeong, B.; Bae, Y. H.; Kim, S. W. Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers. J. Control. Release2000, 63, 155–163.

    CAS  Google Scholar 

  38. Faisant, N.; Siepmann, J.; Richard, J.; Benoit, J. P. Mathematical modeling of drug release from bioerodible microparticles: Effect of gamma-irradiation. Eur. J. Pharm. Biopharm.2003, 56, 271–279.

    CAS  Google Scholar 

  39. Williams, S. A.; Chen, L. F.; Kwon, H.; Fenard, D.; Bisgrove, D.; Verdin, E.; Greene, W. C. Prostratin antagonizes HIV latency by activating NF-?B. J. Biol. Chem.2004, 279, 42008–42017.

    CAS  Google Scholar 

  40. Spina, C. A.; Anderson, J.; Archin, N. M.; Bosque, A.; Chan, J.; Famiglietti, M.; Greene, W. C.; Kashuba, A.; Lewin, S. R.; Margolis, D. M. et al. An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients. PLoS Pathog.2013, 9, e1003834.

    Google Scholar 

  41. Lv, S. X.; Tang, Z. H.; Li, M. Q.; Lin, J.; Song, W. T.; Liu, H. Y.; Huang, Y. B.; Zhang, Y. Y.; Chen, X. S. Co-delivery of doxorubicin and paclitaxel by PEG-polypeptide nanovehicle for the treatment of non-small cell lung cancer. Biomaterials2014, 35, 6118–6129.

    CAS  Google Scholar 

  42. Guo, S. T.; Lin, C. M.; Xu, Z. H.; Miao, L.; Wang, Y. H.; Huang, L. Co-delivery of cisplatin and rapamycin for enhanced anticancer therapy through synergistic effects and microenvironment modulation. ACS Nano2014, 8, 4996–5009.

    CAS  Google Scholar 

  43. Wang, Y.; Gao, S. J.; Ye, W. H.; Yoon, H. S.; Yang, Y. Y. Codelivery of drugs and DNA from cationic core-shell nanoparticles self-assembled from a biodegradable copolymer. Nat. Mater.2006, 5, 791–796.

    CAS  Google Scholar 

  44. Fujisaki, H.; Kakuda, H.; Shimasaki, N.; Imai, C.; Ma, J.; Lockey, T.; Eldridge, P.; Leung, W. H.; Campana, D. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res.2009, 69, 4010–4017.

    CAS  Google Scholar 

  45. Cho, D.; Campana, D. Expansion and activation of natural killer cells for cancer immunotherapy. Korean J. Lab. Med.2009, 29, 89–96.

    CAS  Google Scholar 

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Acknowledgements

Research reported in this publication was supported in part by the George Washington Cancer Center and by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R21AI136102. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Elizabeth E. Sweeney and Preethi B. Balakrishnan contributed equally to this work.

Authors and Affiliations

  1. The George Washington Cancer Center, The George Washington University, Washington, DC, 20052, USA

    Elizabeth E. Sweeney, Preethi B. Balakrishnan, Allan Bowen, Rachel A. Burga, C. Russell Y. Cruz & Rohan Fernandes

  2. Center for Cancer and Immunology Research, Children’s National Health System, Washington, DC, 20010, USA

    Allison B. Powell & C. Russell Y. Cruz

  3. Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington, DC, 20052, USA

    Indra Sarabia & Alberto Bosque

  4. Infectious Disease Division, Weill Cornell Medical College, New York, NY, 10065, USA

    R. Brad Jones

  5. Department of Medicine, The George Washington University, Washington, DC, 20052, USA

    Rohan Fernandes

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  1. Elizabeth E. Sweeney
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Correspondence to Rohan Fernandes.

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PLGA nanodepots co-encapsulating prostratin and anti-CD25 enhance primary natural killer cell antiviral and antitumor function

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Sweeney, E.E., Balakrishnan, P.B., Powell, A.B. et al. PLGA nanodepots co-encapsulating prostratin and anti-CD25 enhance primary natural killer cell antiviral and antitumor function. Nano Res. 13, 736–744 (2020). https://doi.org/10.1007/s12274-020-2684-1

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