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Projeto de investigação
Modeling the response to radiation: DNA repair inhibitors and protectors
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Liposome Formulations for the Strategic Delivery of PARP1 Inhibitors
Publication . Conceição, Carlota J. F.; Moe, Elin; Ribeiro, Paulo A.; Raposo, Maria; DF – Departamento de Física; CeFITec – Centro de Física e Investigação Tecnológica; LIBPhys-UNL; Instituto de Tecnologia Química e Biológica António Xavier (ITQB); MDPI AG
The development of a lipid nano-delivery system was attempted for three specific poly (ADP-ribose) polymerase 1 (PARP1) inhibitors: Veliparib, Rucaparib, and Niraparib. Simple lipid and dual lipid formulations with 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1′-glycerol) sodium salt (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocoline (DPPC) were developed and tested following the thin-film method. DPPG-encapsulating inhibitors presented the best fit in terms of encapsulation efficiency (>40%, translates into concentrations as high as 100 µM), zeta potential values (below −30 mV), and population distribution (single population profile). The particle size of the main population of interest was ~130 nm in diameter. Kinetic release studies showed that DPPG-encapsulating PARP1 inhibitors present slower drug release rates than liposome control samples, and complex drug release mechanisms were identified. DPPG + Veliparib/Niraparib presented a combination of diffusion-controlled and non-Fickian diffusion, while anomalous and super case II transport was verified for DPPG + Rucaparib. Spectroscopic analysis revealed that PARP1 inhibitors interact with the DPPG lipid membrane, promoting membrane water displacement from hydration centers. A preferential membrane interaction with lipid carbonyl groups was observed through hydrogen bonding, where the inhibitors’ protonated amine groups may be the major players in the PARP1 inhibitor encapsulation mode.
PARP1
Publication . Conceição, Carlota J.F.; Moe, Elin; Ribeiro, Paulo A.; Raposo, Maria; Instituto de Tecnologia Química e Biológica António Xavier (ITQB); LIBPhys-UNL; Faculdade de Ciências e Tecnologia (FCT); Elsevier
The Poly (ADP-ribose) polymerase-1 (PARP1) enzyme is involved in several signalling pathways related to homologous repair (HR), base excision repair (BER), and non-homologous end joining (NHEJ). Studies demonstrated that the deregulation of PARP1 function and control mechanisms can lead to cancer emergence. On the other side, PARP1 can be a therapeutic target to maximize cancer treatment. This is done by molecules that can modulate radiation effects, such as DNA repair inhibitors (PARPi). With this approach, tumour cell viability can be undermined by targeting DNA repair mechanisms. Thus, treatment using PARPi represents a new era for cancer therapy, and even new horizons can be attained by coupling these molecules with a nano-delivery system. For this, drug delivery systems such as liposomes encompass all the required features due to its excellent biocompatibility, biodegradability, and low toxicity. This review presents a comprehensive overview of PARP1 biological features and mechanisms, its role in cancer development, therapeutic implications, and emerging cancer treatments by PARPi-mediated therapies. Although there are a vast number of studies regarding PARP1 biological function, some PARP1 mechanisms are not clear yet, and full-length PARP1 structure is missing. Nevertheless, literature reports demonstrate already the high usefulness and vast possibilities offered by combined PARPi cancer therapy.
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Fundação para a Ciência e a Tecnologia
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PD/BD/142765/2018