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Development of polypeptide-based therapeutics for topical delivery

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Development of polypeptide-based therapeutics for topical delivery

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dc.contributor.advisor	Vicent Docón, María Jesús
dc.contributor.advisor	Nebot Carda, Vicent Josep
dc.contributor.author	Dolz Pérez, Irene
dc.contributor.other	Facultat de Química	es_ES
dc.date.accessioned	2019-11-18T10:52:49Z
dc.date.available	2019-11-19T05:45:05Z
dc.date.issued	2019	es_ES
dc.date.submitted	26-11-2019	es_ES
dc.identifier.uri	https://hdl.handle.net/10550/72220
dc.description.abstract	Topical administration represents the main route to attain local therapeutic activity of bioactive agents in several organs, such as the skin or the heart by means of devices that enhance drug transport through the endothelium acting as a reservoir. The complex structure of the skin protects the human body against potentially harmful external agents; however, this protective mechanism inhibits the penetration of topically administering bioactive agents employed for the treatment of skin diseases. Unfortunately, many of the topical drugs currently used or under evaluation in clinical trials lack the appropriate physico-chemical characteristics required for delivery through the skin. However, various rational strategies have been employed in an attempt to improve the physico-chemical properties of bioactive agents according to the features of the desired site of action, thereby improving topical delivery and stability. The research carried out in this thesis describes the application of polymer therapeutics, a nanomedicinal approach, to improve the physico-chemical properties and increase both the penetration of bioactive agents through the skin and retention time at the desired site of action. Well-defined polypeptide-based polymer therapeutic approaches offer particular advantages for dermal applications such as biodegradability, versatility, multivalence, and high drug loading capacity. The development of new polypeptide-drug conjugates employing stimuli-responsive linking moieties, as well as novel hybrid polypeptide-based carriers to enhance drug delivery through the skin, can improve transdermal drug delivery into the skin, thereby improving the effectiveness of topical treatments for skin diseases, such as psoriasis. Furthermore, we believe that our newly developed platforms may find wider use, and we also explore polypeptide-drug combinations as an approach to enhance wound healing and treat ischemia/reperfusion injury following myocardial infarction. The knowledge base regarding the pathogenesis of human psoriasis has recently widened thanks to the development of accurate ex vivo and in vivo models. We present the detailed characterization of an inflammatory ex vivo human skin model, including the assessment of tissue viability, immunohistopathology, and the quantification of pro-inflammatory cytokines release. Additionally, we developed an in vivo preclinically relevant imiquimod (IMQ)-induced model of psoriasis that reflects the critical features of the human disease. Our findings demonstrated the suitability of this murine model to mimic the main hallmarks of human psoriasis, including inflamed skin and the presence of increased levels of psoriasis-associated inflammatory cytokines in tissue and serum. Finally, we applied the knowledge acquired from the development of polymer-drug conjugates for the treatment of skin inflammation to the development of novel wound healing approaches via the PGA-conjugation of the omega-3 polyunsaturated fatty acid didocosahexaenoic acid (diDHA). PGA conjugation enhanced diDHA stability and decreased degradation, which promoted improved therapeutic activity for the conjugate when compared to free diDHA both in skin wound healing and in the treatment of ischemia-reperfusion injury in the mouse heart following myocardial infarction. Overall, our findings highlight the suitability of polymer therapeutic approaches, and polypeptide conjugation in particular, to form drug delivery systems for dermal applications. Specifically, PGA-drug conjugates enhance the skin penetration of drugs, while bioresponsive linkers promote the specific release of the drug in the desired skin layer. Moreover, PGA conjugation of fatty acids has also demonstrated the improvement of both safety and effectiveness of the treatment in skin wound healing and in ischemia-reperfusion injury in the heart.	es_ES
dc.format.extent	344 p.	es_ES
dc.language.iso	en	es_ES
dc.subject	polymer therapeutics	es_ES
dc.subject	polymer-drug conjugates	es_ES
dc.subject	topical delivery	es_ES
dc.subject	skin diseases	es_ES
dc.subject	tissue healing	es_ES
dc.title	Development of polypeptide-based therapeutics for topical delivery	es_ES
dc.type	doctoral thesis	es_ES
dc.subject.unesco	UNESCO::QUÍMICA	es_ES
dc.embargo.terms	0 days	es_ES