Publicação
Trans-BBB peptides for targeting brain metastasis
| Resumo: | Cancer is a heterogeneous and still not well-understood disease, being one of the most significant health problems worldwide. Among women, the most common cancer type is breast cancer. It accounts for 1 in 4 cancer cases and 1 in 6 cancer deaths. There are different breast cancer subtypes according to the histological or molecular profile of cancer biopsies. This differentiation is highly important since they present distinct prevalence, prognosis, and therapeutic protocols. The most aggressive, with less therapeutic options, is the triple-negative breast cancer (TNBC), which lacks the common targeted survival receptors. Thus, traditional chemotherapy remains the only effective treatment. Another major complication associated with TNBC in advanced stages is cancer metastization, being the brain the main metastatic site. Besides the lack of effective therapies, the existence of a physical barrier between blood and brain, the blood-brain barrier (BBB), limits the penetration of drugs, decreasing patients’ prognosis. Taking into consideration the need for new approaches to treat both primary and secondary TNBC, the present work encompasses some innovative therapeutic strategies that consider peptides as biomedical tools. In addition, a full characterization of peptide chemistry, mainly peptide stability, is also presented. Peptides are pharmaceutical molecules with different biochemical and therapeutic properties compared to small-molecule drugs and other biologics. They are easy to design, small in size, easy to synthetize, and some have the ability to penetrate cell membranes. In addition, they also have high activity, specificity and affinity, minimal drug-drug interactions, and biological and chemical diversity. In this work, we focused on the study of anticancer peptides (ACPs) and BBB peptide shuttles (BBBpS). Initially, we investigated the effectiveness of in-house peptides towards TNBC. The most promising peptide presented high activity with significant selectivity, low toxicity and high stability. Unfortunately, this ACP, like most therapeutic molecules, lacks brain penetration capabilities. Thus, like typical strategies in drug discovery directed to small-molecules, we evolved in the direction of multimode pharmacology, and conjugated this ACP to a BBBpS, designing a hybrid peptide. The result was a dual-active peptide capable of crossing the BBB and efficiently eliminate TNBC, with low toxicity and high stability. These relevant results enticed us to further challenge our systems to create other peptide-delivery systems across the BBB. In a side-project, we conjugated the BBBpS to an antibody fragment with successful results. The objective was to understand the capacity of our BBBpS to carry large payloads across the BBB. In the future, we will develop an antibody fragment that recognizes a specific receptor on tumor microenvironment, and will conjugate it to our BBBpS and ACP in order to obtain a promising peptide-antibody conjugate. The use of delivery systems based on peptides is increasing popularity. However, the most relevant disadvantage of peptides is their stability, which is considered poor. Peptide instability has a negative impact in the dissemination of peptides across clinical protocols for decades. To shed light on the properties responsible for peptide stability, in a side project, we collected information related to the stability of published peptides, identified the physicochemical properties related to stability, and proposed a model to predict in silico peptide stability based on peptide sequence. In sum, in this PhD thesis were successfully developed peptide-delivery systems. In addition, it is also delivered some relevant principles related to peptide chemistry that can guide researchers in the development of new molecules presenting better physicochemical properties. |
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| Autores principais: | Cavaco, Marco |
| Assunto: | barreira hematoencefálica cancro da mama triplo negativo metástases cerebrais péptidos sistemas baseados em péptidos blood-brain barrier brain metastasis peptides triple-negative breast cancer peptide-based systems |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Cancer is a heterogeneous and still not well-understood disease, being one of the most significant health problems worldwide. Among women, the most common cancer type is breast cancer. It accounts for 1 in 4 cancer cases and 1 in 6 cancer deaths. There are different breast cancer subtypes according to the histological or molecular profile of cancer biopsies. This differentiation is highly important since they present distinct prevalence, prognosis, and therapeutic protocols. The most aggressive, with less therapeutic options, is the triple-negative breast cancer (TNBC), which lacks the common targeted survival receptors. Thus, traditional chemotherapy remains the only effective treatment. Another major complication associated with TNBC in advanced stages is cancer metastization, being the brain the main metastatic site. Besides the lack of effective therapies, the existence of a physical barrier between blood and brain, the blood-brain barrier (BBB), limits the penetration of drugs, decreasing patients’ prognosis. Taking into consideration the need for new approaches to treat both primary and secondary TNBC, the present work encompasses some innovative therapeutic strategies that consider peptides as biomedical tools. In addition, a full characterization of peptide chemistry, mainly peptide stability, is also presented. Peptides are pharmaceutical molecules with different biochemical and therapeutic properties compared to small-molecule drugs and other biologics. They are easy to design, small in size, easy to synthetize, and some have the ability to penetrate cell membranes. In addition, they also have high activity, specificity and affinity, minimal drug-drug interactions, and biological and chemical diversity. In this work, we focused on the study of anticancer peptides (ACPs) and BBB peptide shuttles (BBBpS). Initially, we investigated the effectiveness of in-house peptides towards TNBC. The most promising peptide presented high activity with significant selectivity, low toxicity and high stability. Unfortunately, this ACP, like most therapeutic molecules, lacks brain penetration capabilities. Thus, like typical strategies in drug discovery directed to small-molecules, we evolved in the direction of multimode pharmacology, and conjugated this ACP to a BBBpS, designing a hybrid peptide. The result was a dual-active peptide capable of crossing the BBB and efficiently eliminate TNBC, with low toxicity and high stability. These relevant results enticed us to further challenge our systems to create other peptide-delivery systems across the BBB. In a side-project, we conjugated the BBBpS to an antibody fragment with successful results. The objective was to understand the capacity of our BBBpS to carry large payloads across the BBB. In the future, we will develop an antibody fragment that recognizes a specific receptor on tumor microenvironment, and will conjugate it to our BBBpS and ACP in order to obtain a promising peptide-antibody conjugate. The use of delivery systems based on peptides is increasing popularity. However, the most relevant disadvantage of peptides is their stability, which is considered poor. Peptide instability has a negative impact in the dissemination of peptides across clinical protocols for decades. To shed light on the properties responsible for peptide stability, in a side project, we collected information related to the stability of published peptides, identified the physicochemical properties related to stability, and proposed a model to predict in silico peptide stability based on peptide sequence. In sum, in this PhD thesis were successfully developed peptide-delivery systems. In addition, it is also delivered some relevant principles related to peptide chemistry that can guide researchers in the development of new molecules presenting better physicochemical properties. |
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