Direct Comparison of B Cell Surface Receptors as Therapeutic Targets for Nanoparticle Delivery of BTK Inhibitors
| Autor: | Rabib Chaudhury, Brenda M. Calderon, Jung Seok Lee, Sean Bickerton, Anjelica L. Gonzalez, Patrick Han, Amanda S. Pellowe, Shihan N. Khan, Tarek M. Fahmy |
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| Rok vydání: | 2021 |
| Předmět: |
media_common.quotation_subject
education Antigens CD19 Pharmaceutical Science Receptors Antigen B-Cell Receptors Cell Surface 02 engineering and technology Lymphocyte Activation 030226 pharmacology & pharmacy CD19 03 medical and health sciences Mice 0302 clinical medicine immune system diseases Cell surface receptor hemic and lymphatic diseases Drug Discovery medicine Bruton's tyrosine kinase Animals Receptor Internalization Protein Kinase Inhibitors health care economics and organizations B cell media_common Cell Proliferation B-Lymphocytes biology Chemistry technology industry and agriculture In vitro toxicology 021001 nanoscience & nanotechnology Mice Inbred C57BL medicine.anatomical_structure biology.protein Biophysics Molecular Medicine Leukocyte Common Antigens Nanoparticles Female 0210 nano-technology Tyrosine kinase Signal Transduction |
| Zdroj: | Molecular pharmaceutics. 18(3) |
| ISSN: | 1543-8392 |
| Popis: | Targeting different cell surface receptors with nanoparticle (NP)-based platforms can result in differential particle binding properties that may impact their localization, bioavailability, and, ultimately, the therapeutic efficacy of an encapsulated payload. Conventional in vitro assays comparing the efficacy of targeted NPs often do not adequately control for these differences in particle-receptor binding, potentially confounding their therapeutic readouts and possibly even limiting their experimental value. In this work, we characterize the conditions under which NPs loaded with Bruton's Tyrosine Kinase (BTK) inhibitor differentially suppress primary B cell activation when targeting either CD19 (internalizing) or B220 (noninternalizing) surface receptors. Surface binding of fluorescently labeled CD19- and B220-targeted NPs was analyzed and quantitatively correlated with the number of bound particles at given treatment concentrations. Using this binding data, suppression of B cell activation was directly compared for differentially targeted (CD19 vs B220) NPs loaded with a BTK inhibitor at a range of particle drug loading concentrations. When NPs were loaded with lower amounts of drug, CD19-mediated internalization demonstrated increased inhibition of B cell proliferation compared with B220 NPs. However, these differences were mitigated when particles were loaded with higher concentrations of BTK inhibitor and B220-mediated "paracrine-like" delivery demonstrated superior suppression of cellular activation when cells were bound to lower overall numbers of NPs. Taken together, these results demonstrate that inhibition of B cell activation can be optimized for NPs targeting either internalizing or noninternalizing surface receptors and that particle internalization is likely not a requisite endpoint when designing particles for delivery of BTK inhibitor to B cells. |
| Databáze: | OpenAIRE |
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