Engineering the next generation nanoparticle-cyclosporine A therapy in lupus
Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease that can affect almost every organ in the body. Current treatments for SLE are often inadequate because they involve the chronic use of non-specific, steroidal and cytostatic drugs that are associated with a wide spectrum of side-effects. However, notwithstanding ongoing efforts to develop better therapies, there has only been one new, FDA-approved drug for SLE in more than five decades. In this context, cyclosporine (CsA), a powerful suppressor of both humoral and cell-mediated immune responses can be a potential candidate, but its efficacy as a stand-alone treatment for SLE has never been demonstrated and often used to steroid tampering. Acknowledged reason for the lack of success with the current commercial CsA formulations is due to poor/variable target (lymphoid) tissue bioavailability with consequently differing biological activity and toxic to the kidneys. Targeting the lymphoid tissue potentially enables rational design of therapeutics to modulate the immune system, representing an innovative approach to treating lupus due to the fact that more than 75 percent of immune cells reside in the GUT-associated lymphoid tissues (GALT). Moreover, GALT in lupus is larger compared to the healthy individuals, making it an attractive site for targeting. The proposed study will generate paradigm-shifting, new knowledge in the field of nano-medicines using unique periodic-functional-polyesters (P2s, unlike commercial PLA/PLGA that are terminal functional), and investigate how the ligand density and composition influence the CsA delivery to lymphoid tissue. The work is enabled by previous findings, in which highly potent lymphatic system-targeting nanoparticle-CsA (called P2Ns-GA-CsA) specific to CD71 (transferrin receptor 1, TfR-1) on lymphoid cells (T and B-cells) have outperformed ligand-free controls and commercial CsA product, leading to better therapeutic outcomes. In this project, the technology is further developed by investigating how the spatial size and composition of the spacer molecules affect the intestinal-receptor interaction and transport of the nanoparticles facilitating customized dose-regimens.
- R. Ganugula, M. Arora, D. Zou, S. K. Agarwal, C. Mohan, M. N. V. Ravi Kumar. A highly potent lymphatic system-targeting nanoparticle-cyclosporine prevents glomerulonephritis in mouse model of lupus. Sci. Adv. 6: eabb3900, 2020. Highlighted in Nat Rev Rheumatol 16, 410 (2020). https://doi.org/10.1038/s41584-020-0462-9.
- R. Ganugula, M. Arora, P. Saini, M. Guada, and M. N. V. Ravi Kumar. Next generation precision-polyesters enabling optimization of ligand-receptor stoichiometry for modular drug delivery. J. Am. Chem. Soc. 139: 7203-7216, 2017. (Cover article)
- P. Saini, R. Ganugula, M. Arora, M. N. V. Ravi Kumar. The next generation non-competitive active polyester nanosystems for transferrin receptor-mediated peroral transport utilizing gambogic acid as a ligand. Sci. Rep. 6, 29501, 2016.