Publicação
Development of ROS Sensitive Traceless Linkers for Drug Delivery
| datacite.subject.fos | Ciências Médicas::Medicina Básica | pt_PT |
| dc.contributor.advisor | Góis, Pedro M. P. | |
| dc.contributor.advisor | Bernardes, Gonçalo J. L. | |
| dc.contributor.author | Carvalho, Joana | |
| dc.date.accessioned | 2023-06-28T11:20:19Z | |
| dc.date.embargo | 2026-07 | |
| dc.date.issued | 2022-06 | |
| dc.date.submitted | 2022-02 | |
| dc.description.abstract | Cancer disease is the second most common cause of death in the world, being responsible for more than 25.8% of the total number of deaths. Over the last decades, a considerable effort has been made to bring new therapeutic alternatives and consequently increase survival rates in oncological disease. Due to therapeutic innovation, various cancer types can be managed as chronic and complex diseases. In spite of positive prospects, more compelling and less harmful medicines are required. With the innovative advance of chemistry and biology, it has ended up conceivable to apply precision medicine’s basis to drug development. Targeted therapies are the expression of this paradigm-changing. Antibody drugs conjugate (ADC) consists of a biotherapeutic class that combines cytotoxic drugs and monoclonal antibodies, allying potent therapeutic activity with precision. The development of ADCs is complex and requires the correct tuning of its components – antibody, payload, linker and bioconjugation. Despite the challenging process, eleven ADCs are approved for clinical treatment. Linker chemistry plays an important role in ADC design and may compromise its pharmacokinetics and therapeutic effect. Boronic acid (BA) derivatives have been used to develop reversible chemistries with application in targeted technologies. Due to the reversible nature of boron, several boron-based scaffolds display selective cleavage in the presence of ROS, GSH levels or at acidic conditions. Considering the chemical features of tumour cells, we started to explore diazaborines (DABs) as ROS-responsive scaffolds. In this work, we developed a ROS-responsive linker based on DAB scaffold to construct ROS-responsive ADCs. In the chapter II, we describe a ROS-responsive linker-payload that proved to be stable in physiological conditions (half-life time of over 130 h). Besides, it was also efficiently activated (a half-life time of 8.1 h) to release the SN-38 payload under oxidative conditions. In the chapter III, these structures were used in the site-selective functionalization of a single-domain antibody fragment (sdAb) and we were able to construct a homogeneous ADC. The obtained ADC presented a high selectivity and potency (IC50=54.1 nM) against the B-cell lymphoma CLBL-1 cell line. In the chapter IV, we present the initial steps for developing other ROS-responsive scaffolds. Benzoxazaborines are boron-based scaffolds containing B-N-C-N, B-N-C-O and B-O-C=N linkages. We identify benzoxazaborines with potential application as stable ROS-responsive linkers during these studies. Overall, this PhD thesis gives valuable insights about ROS-responsive boron scaffolds. In particular, diazaborines prove useful for constructing ROS-responsive ADCs with potential biological application. Besides, ROS-responsive linkers can be applied to other cytotoxic payloads and targets, expanding the disease scope for ROS-responsive ADCs. | pt_PT |
| dc.description.provenance | Submitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2023-05-16T15:05:16Z No. of bitstreams: 1 scnd740778_td_Joana_Carvalho.pdf: 7725750 bytes, checksum: c628310a7d084d81b01ba189fdc6fe58 (MD5) | en |
| dc.description.provenance | Made available in DSpace on 2023-06-28T11:20:19Z (GMT). No. of bitstreams: 1 scnd740778_td_Joana_Carvalho.pdf: 7725750 bytes, checksum: c628310a7d084d81b01ba189fdc6fe58 (MD5) Previous issue date: 2022-06 | en |
| dc.identifier.tid | 101592922 | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10451/58386 | |
| dc.language.iso | eng | pt_PT |
| dc.relation | Design of ROS traceless linkers for drug delivery | |
| dc.subject | conjugados fármaco-anticorpo | pt_PT |
| dc.subject | ácidos borónicos | pt_PT |
| dc.subject | espaçador químico | pt_PT |
| dc.subject | diazaborinas | pt_PT |
| dc.subject | espécies reativas de oxigénio | pt_PT |
| dc.subject | antibody–drug conjugates | pt_PT |
| dc.subject | boronic acids | pt_PT |
| dc.subject | cleavable linkers | pt_PT |
| dc.subject | diazaborines | pt_PT |
| dc.subject | reactive oxygen species | pt_PT |
| dc.title | Development of ROS Sensitive Traceless Linkers for Drug Delivery | pt_PT |
| dc.type | doctoral thesis | |
| dspace.entity.type | Publication | |
| oaire.awardNumber | PD/BD/143124/2019 | |
| oaire.awardTitle | Design of ROS traceless linkers for drug delivery | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT//PD%2FBD%2F143124%2F2019/PT | |
| person.familyName | Coelho Carvalho | |
| person.givenName | Joana Inês | |
| person.identifier.ciencia-id | DA13-D7CB-8031 | |
| person.identifier.orcid | 0000-0002-9848-0203 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.contributor.authoremail | repositorio@reitoria.ulisboa.pt | |
| rcaap.rights | embargoedAccess | pt_PT |
| rcaap.type | doctoralThesis | pt_PT |
| relation.isAuthorOfPublication | c728e761-5c64-4aa2-875a-cc78090e478b | |
| relation.isAuthorOfPublication.latestForDiscovery | c728e761-5c64-4aa2-875a-cc78090e478b | |
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| thesis.degree.name | Tese de doutoramento, Farmácia (Química Farmacêutica e Terapêutica), Universidade de Lisboa, Faculdade de Farmácia, 2022 | pt_PT |