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Author Puigmal Domínguez, Núria |
Abstract The curative potential of immunotherapies to augment or suppress immune responses has shifted the paradigm for managing various diseases including cancer and autoimmune disorders, yet broad implementation has been curtailed by detrimental off-target toxicities. Given the ability of nanomaterials to direct immunomodulators to target tissues, nanomedicine-based delivery platforms formulated in carrier biomaterials could surmount the most pressing needs in the field being cell-specific targeting, local —rather than systemic— administration, and tissue accumulation to ultimately enhance the safety and potency of these therapeutic products. Using poly(β-amino ester)s (PBAEs) as foundational nanocarriers, this thesis proposes to engineer PBAE-based delivery platforms to target the immunologically rich milieu of the skin for local immunomodulation in the contexts of nucleic acid vaccination, cancer immunotherapy and adoptive T cell therapy. First, a novel library of oligopeptide- and mannose-modified PBAEs is presented for refined targeting of dendritic cells (DCs) as primary orchestrators of antigen presentation in the skin. The synergistic potential of oligopeptide and ligand decoration to target dermal DC subsets has been demonstrated as a powerful tool to upgrade delivery vectors for gene vaccination. Nanoparticle- and solvent-free delivery of nucleic acids using PBAEs formulated as polyelectrolyte films (PEMs) has also been confirmed. PBAEs can be successfully integrated in transdermal devices such as microneedles, either as PEMs or as polyplexes, to mediate minimally-invasive gene transfer. Moving to cancer immunotherapy, a hydrogel-based MN platform is presented for delivery of an immunostimulatory drug and retrieval of interstitial skin fluid (ISF) for in situ immune surveillance of the response to therapy. It has been proven that PBAE-loaded MNs suppress tumor growth and modulate the immune signature of the tumor microenvironment, which appears to correlate with that from MN-sampled ISF. Finally, hydrogel MNs are proposed for restoring immune homeostasis in transplanted skin allografts. Recruitment of adoptively-transferred regulatory T cells into the allografts has been achieved by delivering chemoattractant chemokines with the MNs while also monitoring the Treg homing process via ISF sampling, confirming the potential of MNs as a mode of tissue surveillance. In conclusion, this thesis demonstrates the potential of transdermal platforms derived from PBAEs for local immunomodulation. Shifting from hypodermic administration to solvent-free, local, and minimally-invasive approaches, PBAE-based systems have been engineered with microneedles for immunotherapy delivery. |
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Director Ramos Pérez, Víctor |
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Departament IQS SE - Bioenginyeria |
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Date defense 2021-07-15
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