Nanomedicine-based strategies to target and modulate the tumor microenvironment

Funding Information: The authors acknowledge financial support from Fundação para a Ciência e a Tecnologia / Ministério da Ciência, Tecnologia, e Ensino Superior in the framework of PhD grant 2020.06638.BD (to D.P.S.), and from the European Research Council grant agreement No 848325 (J.C. for the ERC Starting Grant). Funding Information: The authors acknowledge financial support from Funda??o para a Ci?ncia e a Tecnologia/ Minist?rio da Ci?ncia, Tecnologia, e Ensino Superior in the framework of PhD grant 2020.06638.BD (to D.P.S.), and from the European Research Council grant agreement No 848325 (J.C. for the ERC Starting Grant). None declared by authors. Publisher Copyright: © 2021 Elsevier Inc.The interest in nanomedicine for cancer theranostics has grown significantly over the past few decades. However, these nanomedicines need to overcome several physiological barriers intrinsic to the tumor microenvironment (TME) before reaching their target. Intrinsic tumor genetic/phenotypic variations, along with intratumor heterogeneity, provide different cues to each cancer type, making each patient with cancer unique. This brings additional challenges in translating nanotechnology-based systems into clinically reliable therapies. To develop efficient therapeutic strategies, it is important to understand the dynamic interactions between TME players and the complex mechanisms involved, because they constitute invaluable targets to dismantle tumor progression. In this review, we discuss the latest nanotechnology-based strategies for cancer diagnosis and therapy as well as the potential targets for the design of future anticancer nanomedicines.publishersversionpublishe

Avaliação da incorporação de levofloxacina em partículas de um biomaterial ortopédico para tratamento da osteomielite

Relatório de projecto no âmbito de Bolsa Universidade de Lisboa/Fundação Amadeu Dias (2010/2011). Universidade de Lisboa. Faculdade de FarmáciaA osteomielite consiste num processo inflamatório associado à destruição óssea, causado por microrganismos infecciosos. O seu tratamento envolve debridamento cirúrgico, remoção dos corpos estranhos e ainda antibioterapia. A necessidade de se atingirem concentrações parentéricas elevadas de antibióticos para que a terapêutica seja efectiva no tecido ósseo, assim como a duração prolongada do tratamento pode conduzir à toxicidade sistémica induzida pelo antibiótico. Este facto vem sublinhar a importância do desenvolvimento de sistemas de drug delivery, de forma a que a libertação dos fármacos no local pretendido, seja feita de modo controlado e por períodos de tempo mais longos. O poli(metilmetacrilato) (PMMA), tratando-se de um polímero biocompatível com valor reconhecido no âmbito das artroplastias, foi considerado como sistema de transporte para a libertação controlada de um antibiótico: a levofloxacina (LEV). O referido antibiótico é uma fluoroquinolona de 3ª geração geralmente utilizada contra Staphylococcus aureus, um dos agentes patogénicos frequentemente associados à osteomielite. Objectivos: 1) Incorporação de LEV em partículas de PMMA; 2) Comparação das características das partículas obtidas por diferentes métodos. Métodos: 1) As partículas de PMMA foram preparadas pelo método da dupla emulsão a/o/a com evaporação do solvente (DESE), quer pela via convencional quer por downscale. Foram avaliados diversos parâmetros como sejam a morfologia, o rendimento de produção, o tamanho, a eficiência de encapsulação (EE), o drug loading (DL), o potencial zeta (PZ) e o perfil de libertação in vitro. Resultados: 1) As partículas apresentaram superfície esférica e regular e tamanhos na gama do micrómetro (µm). Obtiveram-se melhores resultados quer de DL quer de EE, pelo método convencional. Os ensaios de libertação in vitro revelaram concentrações inferiores ao da MIC50 para S. aureus durante toda a duração do ensaio. 2) As partículas produzidas pelo método convencional destacaram-se especialmente das produzidas por downscale no que diz respeito aos seus tamanhos e à dispersão da população. Conclusões: Os valores alcançados revelaram que tanto para o método convencional como para o de downscale é necessário levar a cabo algumas alterações na formulação de forma a melhorar a encapsulação da LEV, a distribuição do tamanho das partículas (essencialmente a nível do downscale) e também os perfis de libertação in vitro

Machine learning for next-generation nanotechnology in healthcare

Funding: The authors acknowledge financial support from FCT Portugal in the framework of PhD grant 2020.06638.BD (to D.P.S.), and the European Research Council grant agreement 848325 (J. Conde for the ERC Starting Grant). T.R. is an Investigador Auxiliar supported by FCT Portugal (CEECIND/ 00684/2018).Nanotechnology for healthcare is coming of age, but automating the design of composite materials poses unique challenges. Although machine learning is supporting groundbreaking discoveries in materials science, new initiatives leveraging learned patterns are required to fully realize the promise of nanodelivery systems and accelerate development pipelines.publishersversionpublishe

Biopolymeric Coatings for Local Release of Therapeutics from Biomedical Implants

Funding Information: S.T., B.M., and J.C. contributed equally to this work. The authors are grateful for funding received from the Australian Research Council Centre of Excellence program (Project Number CE 140100012). J.C. acknowledges the European Research Council Starting Grant (ERC‐StG‐2019‐848325). S.N. and F.D. acknowledge the financial support of Australian Research Council through DP200102164. Publisher Copyright: © 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.The deployment of structures that enable localized release of bioactive molecules can result in more efficacious treatment of disease and better integration of implantable bionic devices. The strategic design of a biopolymeric coating can be used to engineer the optimal release profile depending on the task at hand. As illustrative examples, here advances in delivery of drugs from bone, brain, ocular, and cardiovascular implants are reviewed. These areas are focused to highlight that both hard and soft tissue implants can benefit from controlled localized delivery. The composition of biopolymers used to achieve appropriate delivery to the selected tissue types, and their corresponding outcomes are brought to the fore. To conclude, key factors in designing drug-loaded biopolymeric coatings for biomedical implants are highlighted.publishersversionepub_ahead_of_prin

Nanodelivery of nucleic acids

Funding: This work was supported by the European Research Council (ERC) Starting Grant (ERC-StG-2019-848325 to J. Conde) and the Fundação para a Ciência e a Tecnologia FCT Grant (PTDC/BTM-MAT/4738/2020 to J. Conde). J.S. acknowledges US National Institute of Health (NIH) grants (R01CA200900, R01HL156362 and R01HL159012), the US DoD PRCRP Idea Award with Special Focus (W81XWH1910482), the Lung Cancer Discovery Award from the American Lung Association and the Innovation Discovery Grants award from the Mass General Brigham. H.L., D.Y. and X.Z. were supported by the National Key R&D Program of China (no. 2020YFA0710700), the National Natural Science Foundation of China (nos 21991132, 52003264, 52021002 and 52033010) and the Fundamental Research Funds for the Central Universities (no. WK2060000027).There is growing need for a safe, efficient, specific and non-pathogenic means for delivery of gene therapy materials. Nanomaterials for nucleic acid delivery offer an unprecedented opportunity to overcome these drawbacks; owing to their tunability with diverse physico-chemical properties, they can readily be functionalized with any type of biomolecules/moieties for selective targeting. Nucleic acid therapeutics such as antisense DNA, mRNA, small interfering RNA (siRNA) or microRNA (miRNA) have been widely explored to modulate DNA or RNA expression Strikingly, gene therapies combined with nanoscale delivery systems have broadened the therapeutic and biomedical applications of these molecules, such as bioanalysis, gene silencing, protein replacement and vaccines. Here, we overview how to design smart nucleic acid delivery methods, which provide functionality and efficacy in the layout of molecular diagnostics and therapeutic systems. It is crucial to outline some of the general design considerations of nucleic acid delivery nanoparticles, their extraordinary properties and the structure–function relationships of these nanomaterials with biological systems and diseased cells and tissues.publishersversionpublishe

Multicomponente particulates for immune modulation

Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2018Although immune checkpoint therapy improved the clinical outcomes of melanoma treatment, low response rate, severe side effects, and acquired resistance have been observed in patients. To overcome these limitations, complementary strategies that inhibit tumor immunosuppressive pathways and enhance immunity are urgently needed. We hypothesized that the anticancer activity of the combination of anti-PD-1, for immunosuppression blockade, with the monoclonal anti-OX40 agonist, for T-cell stimulation and expansion, could be improved by cancer vaccination. For this purpose, we designed, synthesized and characterized mannose-grafted poly(lactic coglycolic acid) and poly(lactic acid) (PLGA/PLA) nano-vaccines, containing both melan- A/MART-1 peptides and immune potentiators. These nanoparticle-based vaccines can amplify antitumor immune response by increasing tumor-associated antigen recognition, processing, and presentation to effector T cells. The nanoparticles were shown to have a spherical shape with an average diameter of 170 nm, displaying narrow polydispersity index and near-neutral surface charge. Immunization with these nano-vaccines induced splenocyte activation and antigen specific cytotoxic T-cell activity against melanoma cells ex vivo. Treatment with the combination of the prophylactic nano-vaccines and PD-1/OX40 antibodies in vivo led to maximal tumor growth inhibition, with minimal systemic toxicity. Whereas treatment with anti-PD-1/anti-OX40 alone led to 20% survival 42 days following tumor inoculation, the combination approach with the mannose-PLGA/PLA prophylactic nano-vaccine resulted in 100% survival for the same period. Moreover, the latter presented a survival rate of 50% two months following tumor inoculation and recapitulated a T-cell inflamed tumor microenvironment. On the other hand, the combination of therapeutic mannose-PLGA/PLA nanovaccines with PD-1/OX40 immune checkpoint therapy failed to show benefit in comparison with PD-1/OX40 immune checkpoint in monotherapy. This result seems to be related to infiltration of MDSC into the tumor microenvironment, over time, which may have overcome the effect of CD8+ T cell stimulation, inhibiting T cell infiltration and cytotoxic activity. Altogether, these findings reveal important aspects on the synergism of immune checkpoint targeting with polymeric cancer nano-vaccines, as well as the effect on the modulation of tumor-infiltrating immune cells in melanoma. Therefore, polymeric nanovaccines emerge as a potential strategy to improve clinical outcomes of melanoma treatment.Fundação para a Ciência e a Tecnologia (FCT), projetos SAICTPAC/0019/2015, Pest-OE/SAU/UI4013/2011; EuroNanoMed-II, projeto ENMed/0051/2016; European Structural & Investment Funds (ESIF); Programa Operacional Factores de Competitividade (COMPETE

Revisiting gene delivery to the brain: Silencing and editing

Neurodegenerative disorders, ischemic brain diseases, and brain tumors are debilitating diseases that severely impact a person\u27s life and could possibly lead to their demise if left untreated. Many of these diseases do not respond to small molecule therapeutics and have no effective long-Term therapy. Gene therapy offers the promise of treatment or even a cure for both genetic and acquired brain diseases, mediated by either silencing or editing disease-specific genes. Indeed, in the last 5 years, significant progress has been made in the delivery of non-coding RNAs as well as gene-editing formulations to the brain. Unfortunately, the delivery is a major limiting factor for the success of gene therapies. Both viral and non-viral vectors have been used to deliver genetic information into a target cell, but they have limitations. Viral vectors provide excellent transduction efficiency but are associated with toxic effects and have limited packaging capacity; however, non-viral vectors are less toxic and show a high packaging capacity at the price of low transfection efficiency. Herein, we review the progress made in the field of brain gene therapy, particularly in the design of non-Toxic and trackable non-viral vectors, capable of controlled release of genes in response to internal/external triggers, and in the delivery of formulations for gene editing. The application of these systems in the context of various brain diseases in pre-clinical and clinical tests will be discussed. Such promising approaches could potentially pave the way for clinical realization of brain gene therapies. This journal i

Erratum: Revisiting gene delivery to the brain: Silencing and editing (Biomaterials Science (2021) DOI: 10.1039/D0BM01278C)

The authors regret the incorrect version of Fig. 2 was included in the original manuscript. The correct version of Fig. 2 is as shown below, where ref. 188, 189, 190, 138 and 177 from the original article, are shown as ref. 1–5, respectively.(Figure Presented).The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers

Challenges and strategies

Nucleic acid-based therapy emerges as a powerful weapon for the treatment of tumors thanks to its direct, effective, and lasting therapeutic effect. Encouragingly, continuous nucleic acid-based drugs have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite the tremendous progress, there are few nucleic acid-based drugs for brain tumors in clinic. The most challenging problems lie on the instability of nucleic acids, difficulty in traversing the biological barriers, and the off-target effect. Herein, nucleic acid-based therapy for brain tumor is summarized considering three aspects: (i) the therapeutic nucleic acids and their applications in clinical trials; (ii) the various administration routes for nucleic acid delivery and the respective advantages and drawbacks. (iii) the strategies and carriers for improving stability and targeting ability of nucleic acid drugs. This review provides thorough knowledge for the rational design of nucleic acid-based drugs against brain tumor.publishersversionepub_ahead_of_prin

A Fluorinated BODIPY-Based Zirconium Metal-Organic Framework for In Vivo Enhanced Photodynamic Therapy.

Publication status: PublishedPhotodynamic therapy (PDT), an emergent noninvasive cancer treatment, is largely dependent on the presence of efficient photosensitizers (PSs) and a sufficient oxygen supply. However, the therapeutic efficacy of PSs is greatly compromised by poor solubility, aggregation tendency, and oxygen depletion within solid tumors during PDT in hypoxic microenvironments. Despite the potential of PS-based metal-organic frameworks (MOFs), addressing hypoxia remains challenging. Boron dipyrromethene (BODIPY) chromophores, with excellent photostability, have exhibited great potential in PDT and bioimaging. However, their practical application suffers from limited chemical stability under harsh MOF synthesis conditions. Herein, we report the synthesis of the first example of a Zr-based MOF, namely, 69-L2, exclusively constructed from the BODIPY-derived ligands via a single-crystal to single-crystal post-synthetic exchange, where a direct solvothermal method is not applicable. To increase the PDT performance in hypoxia, we modify 69-L2 with fluorinated phosphate-functionalized methoxy poly(ethylene glycol). The resulting 69-L2@F is an oxygen carrier, enabling tumor oxygenation and simultaneously acting as a PS for reactive oxygen species (ROS) generation under LED irradiation. We demonstrate that 69-L2@F has an enhanced PDT effect in triple-negative breast cancer MDA-MB-231 cells under both normoxia and hypoxia. Following positive results, we evaluated the in vivo activity of 69-L2@F with a hydrogel, enabling local therapy in a triple-negative breast cancer mice model and achieving exceptional antitumor efficacy in only 2 days. We envision BODIPY-based Zr-MOFs to provide a solution for hypoxia relief and maximize efficacy during in vivo PDT, offering new insights into the design of promising MOF-based PSs for hypoxic tumors