Academic literature on the topic 'Combinatory therapy'

Integrating multi-modal therapies into one platform could show great promise in overcoming the drawbacks of conventional single-modal therapy and achieving improved therapeutic efficacy in cancer. In this study, we prepared pheophorbide a (Pheo a)/targeting ligand (epitope analog of oncoprotein E7, EAE7)-conjugated poly(γ-glutamic acid) (γ-PGA)/poly(lactide-co-glycolide)-block-poly(ethylene glycol) methyl ether (MPEG-PLGA)/hyaluronic acid (PPHE) polymeric nanoparticles via self-assembly and encapsulation method for the photodynamic therapy (PDT)/cold atmospheric plasma (CAP) combinatory treatment of human papillomavirus (HPV)-positive cervical cancer, thereby enhancing the therapeutic efficacy. The synthesized PPHE polymeric nanoparticles exhibited a quasi-spherical shape with an average diameter of 80.5 ± 17.6 nm in an aqueous solution. The results from the in vitro PDT efficacy assays demonstrated that PPHE has a superior PDT activity on CaSki cells due to the enhanced targeting ability. In addition, the PDT/CAP combinatory treatment more effectively inhibited the growth of cervical cancer cells by causing elevated intracellular reactive oxygen species generation and apoptotic cell death. Moreover, the three-dimensional cell culture model clearly confirmed the synergistic therapeutic efficacy of the PDT and the CAP combination therapy using PPHE on CaSki cells. Overall, these results indicate that the PDT/CAP combinatory treatment using PPHE is a highly effective new therapeutic modality for cervical cancer.

A potent therapy for the infectious coronavirus disease COVID-19 is urgently required with, at the time of writing, research in this area still ongoing. This study aims to evaluate the in vitro anti-viral activities of combinations of certain commercially available drugs that have recently formed part of COVID-19 therapy. Dual combinatory drugs, namely; Lopinavir-Ritonavir (LOPIRITO)-Clarithromycin (CLA), LOPIRITO-Azithromycin (AZI), LOPIRITO-Doxycycline (DOXY), Hydroxychloroquine (HCQ)-AZI, HCQ-DOXY, Favipiravir (FAVI)-AZI, HCQ-FAVI, and HCQ-LOPIRITO, were prepared. These drugs were mixed at specific ratios and evaluated for their safe use based on the cytotoxicity concentration (CC50) values of human umbilical cord mesenchymal stem cells. The anti-viral efficacy of these combinations in relation to Vero cells infected with SARS-CoV-2 virus isolated from a patient in Universitas Airlangga hospital, Surabaya, Indonesia and evaluated for IC50 24, 48, and 72 hours after viral inoculation was subsequently determined. Observation of the viral load in qRT-PCR was undertaken, the results of which indicated the absence of high levels of cytotoxicity in any samples and that dual combinatory drugs produced lower cytotoxicity than single drugs. In addition, these combinations demonstrated considerable effectiveness in reducing the copy number of the virus at 48 and 72 hours, while even at 24 hours, post-drug incubation resulted in low IC50 values. Most combination drugs reduced pro-inflammatory markers, i.e. IL-6 and TNF-α, while increasing the anti-inflammatory response of IL-10. According to these results, the descending order of effective dual combinatory drugs is one of LOPIRITO-AZI>LOPIRITO-DOXY>HCQ-AZI>HCQ-FAVI>LOPIRITO-CLA>HCQ-DOX. It can be suggested that dual combinatory drugs, e.g. LOPIRITO-AZI, can potentially be used in the treatment of COVID-19 infectious diseases.

Antimicrobial photodynamic therapy (aPDT) has become a fundamental tool in modern therapeutics, notably due to the expanding versatility of photosensitizers (PSs) and the numerous possibilities to combine aPDT with other antimicrobial treatments to combat localized infections. After revisiting the basic principles of aPDT, this review first highlights the current state of the art of curative or preventive aPDT applications with relevant clinical trials. In addition, the most recent developments in photochemistry and photophysics as well as advanced carrier systems in the context of aPDT are provided, with a focus on the latest generations of efficient and versatile PSs and the progress towards hybrid-multicomponent systems. In particular, deeper insight into combinatory aPDT approaches is afforded, involving non-radiative or other light-based modalities. Selected aPDT perspectives are outlined, pointing out new strategies to target and treat microorganisms. Finally, the review works out the evolution of the conceptually simple PDT methodology towards a much more sophisticated, integrated, and innovative technology as an important element of potent antimicrobial strategies.

Lung cancer remains a leading cause of cancer-related mortality worldwide with the poor prognosis. Encouragingly, immune checkpoint blockade targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has dramatically changed the landscape for treatments in patients with non-small-cell lung cancer (NSCLC). However, only a small proportion of NSCLC patients responded to monotherapy of anti-PD-1/PDL1 agents; together, the development of resistance to anti-PD-1/PD-L1 therapy that leads to failure of anti-PD-1/PD-L1 therapy has significantly limited a broad applicability of the findings in clinical practices. Nowadays, several companion diagnostic assays for PDL1 expression have been introduced for identifying patients who may benefit the immunotherapy. In addition, results from clinical trials explored combinatory therapeutic strategies with conventional and/or targeted therapy reported a higher efficacy with an acceptable safety profile in NSCLC treatments, as compared to the monotherapy of these agents alone. In this review article, we summarized several anti-PD-1/PD-L1 agents licensed for NSCLC treatment, with a focus on predictive biomarkers and companion diagnostic assays for identification of NSCLC patients for immunotherapy anti-PD-1/PDL1 antibodies. Of a great interest, potentials of the combinatory therapy of anti-PD-1/PDL1 therapy with a conventional or targeted therapy, or other immunotherapy such as CAR-T cell therapy were emphasized in the article.

A number of epidemiological studies have associated anticancer therapy with an increased risk of cardiovascular disease in later life, a concern for patient long-term survival. Survivors of childhood cancer, previously administered radiotherapy, display chronic arterial damage including endothelial cell dysfunction, a defining feature of atherosclerosis (Brouwer et al., 2013). This thesis aimed to characterise the effects of radiation therapy (X-rays) and the cardiotoxic chemotherapeutic drug doxorubicin, alone or in combination, on coronary artery endothelial cell viability and function. The role of stress-activated c-Jun N-terminal kinase (JNK) in therapy-mediated endothelial cell dysfunction was also elucidated. Survival assays, employed to assess the effects of single-agent therapy, demonstrated that doxorubicin causes concentration-dependent death of human coronary artery endothelial cells (HCAECs) and X-irradiation inhibits HCAEC clonogenic survival dose-dependently. Using fluorescence-activated cell sorting (FACS), the ability of doxorubicin to arrest HCAECs in the radiosensitive G2/M phase of the cell cycle after a period of 24 hours was identified. Nonetheless, when doxorubicin and X-rays were used in combination, synergy between the two agents was not observed, an additive effect on HCAEC clonogenic survival was detected at the specific concentration (1 μM doxorubicin) and dose (1 Gy X-rays) studied. JNK was moderately activated by doxorubicin and played a partial role in the G2/M arrest of HCAECs by doxorubicin. Surprisingly, X-irradiation poorly activated JNK, thus JNK does not appear to play a major role in endothelial cell dysfunction post-therapy with these anticancer agents. The data collated in this thesis provides an insight into the endothelial cell dysfunction and death elicited by anticancer agents, doxorubicin and X-rays, contributing to vascular wall destruction and development of atherosclerosis post-cancer therapy.

In Europa, la sopravvivenza a 5 anni dei pazienti affetti da leucemia mieloide acuta (LMA) è solo del 20%. La duplicazione interna in tandem del gene FLT3 (FLT3-ITD), che codifica per il recettore della tirosina chinasi FLT3, è la mutazione più frequente (~ 25%) nella LMA con cariotipo normale, dove porta all'attivazione costitutiva della chinasi FLT3. Nonostante risultati iniziali molto promettenti con inibitori di FLT3 (FLT3i) nei pazienti con questa mutazione, pochi pazienti hanno remissioni prolungate, evidenziando la necessità di nuove e più efficaci terapie. La persistenza delle cellule staminali leucemiche guida la leucemogenesi della LMA ed è responsabile della resistenza ai farmaci e della ricaduta dopo chemioterapia convenzionale. L'attivazione costitutiva di FLT3 porta all’attivazione del signaling a valle, e in particolare della via PI3K/AKT/mTOR, una cascata di segnale fortemente associata alla sopravvivenza delle cellule staminali leucemiche e al crosstalk tra le cellule staminali leucemiche e le cellule stromali associate al microambiente tumorale midollare. La nicchia midollare fornisce protezione alle cellule leucemiche FLT3-ITD nei confronti degli inibitori FLT3. Pertanto, la via PI3K/AKT/mTOR può rappresentare un bersaglio terapeutico nella AML FLT3-ITD. Questo studio mira a verificare l'ipotesi che l'inibizione di PI3K/AKT/mTOR sensibilizzi le cellule AML FLT3-ITD alla terapia mirata con RTKi utilizzando linee cellulari AML umane e blasti di pazienti primari. In particolare, ho definito il profilo fenotipico delle linee cellulari FLT3-ITD rispetto a quelle FLT3 wildtype dopo trattamento con un pannello di FLT3i o PI3K/AKT/mTORi che non hanno dimostrato sufficiente efficacia clinica se utilizzato come monoterapia. Successivamente, ho valutato l’effetto del farmaco sulla crescita cellulare e sul ciclo cellulare e l'apoptosi. I risultati ottenuti dimostrano che BAY-806946 (pan PI3Ki) e PF-04691502 (inibitore duale PI3K/mTORi) sono in grado di inibire la crescita poiché causano arresto del ciclo cellular in fase G1 e apoptosi, un effetto che appare indipendente dallo stato mutazionale di FLT3. Dimostrano inoltre che l’arresto della crescita cellulare indotto dall’inibitore di FLT3 (FLT3i) quizartinib è causato principalmente dall’induzione di apoptosi. Tuttavia l’efficacia rimane inferiore rispetto al trattamento con chemioterpia convenzionale (AraC). Inoltre, la proof of concept per l’utilizzo della combinazione del quizartinib con BAY-806946 è stata ottenuta in linee cellulari AML FLT3-ITD e blasti primari da paziente. Nel valutare i blasti primari da paziente, è stato considerato il ruolo protettivo delle cellule stromali mesenchimali in co-coltura, e dei fattori di crescita per riprodurre le condizioni del microambiente midollare. Pertanto, blasti primari da paziente LAM sono stati mantenuti in co-coltura con cellule stromali MS5 in presenza di concentrazioni fisiologiche di fattori di crescita quali IL-3, TPO e GM-CSF. Come atteso, il BAY-806946 potenzia l’effetto citostatico e citotossico del quizartinib nelle cellule MOLM-13 e nei blasti primari da paziente con mutazione FLT3-ITD in condizione di co-coltura. E’ importante sottolineare l’incremento di apoptosi osservato anche nella sottopopolazione staminale leucemica CD34+CD38-. Infine, ho valutato il profilo delle citochine e delle fosfoproteine persistenti come bersagli putativi dopo il trattamento di combinazione. Complessivamente, questo studio dimostra il potenziale di PI3Ki per migliorare l'efficacia di RTKi quizartinib nel trattamento della LMA FLT3-ITD.
Acute myeloid leukemia (AML) has a very poor 5-year survival of ~20% in Europe. The internal tandem duplication (ITD) mutation of the Fms-like receptor tyrosine kinase 3 (FLT3) (FLT3-ITD) is the most frequent mutation (~25%) in normal karyotype AML. In recent clinical studies, few patients display prolonged remissions with receptor tyrosine kinase (RTK) inhibitors, such as FLT3 inhibitors (FLT3i) therapy, highlighting a substantial unmet need for novel effective treatment. Persistence of leukemia stem cells (LSC) drive AML leukemogenesis, responsible for drug resistance and disease relapse following conventional chemotherapy. Growing evidence recognizes that FLT3-ITD mutation leads to the constitutive activation of FLT3 kinase and its downstream pathways, including PI3K/AKT/mTOR signaling, strongly associated with LSC survival and crosstalk between LSC and stromal cells associated bone marrow (BM) tumor environment (TME). The TME provides protection of FLT3-ITD AML cells against FLT3 inhibitors. Thus, the PI3K/AKT/mTOR pathway may represent as a putative target for FLT3-ITD AML. This study aims to test the hypothesis that PI3K/AKT/mTOR inhibition could sensitize FLT3-ITD AML cells to RTKi-lead targeted therapy using human AML cell lines and primary patient blasts. First, I uncover the phenotypic profile of FLT3-ITD versus FLT3 wildtype cell lines following treatment with selected FLT3i or PI3K/AKT/mTORi that have failed treatment of AML as monotherapy in clinical studies. More specifically, I determine the drug efficacy by means of cell growth measurement and assessment of cell cycle status and apoptosis. I was able to demonstrate that BAY-806946 (pan PI3Ki) and PF-04691502 (dual PI3K/mTORi) exerted growth inhibitory activity caused by G1 cell cycle arrest and apoptosis, and this effect was irrespective of FLT3 status. Quizartinib (FLT3i) selectively inhibited cell growth in FLT3-ITD AML and this effect was mainly caused by apoptosis. The observed drug-induced apoptotic effect was however not as efficient as chemotherapy. Next, I provide proof-of-concept for the combination of quizartinib and BAY-806946 using both FLT3-ITD AML cell lines and primary patient blasts. When evaluating on primary patient blasts, I take into consideration the protective role of mesenchymal stromal cells and physiological growth factors to mimic the BM microenvironment. Hereby, I co-cultured FLT3-ITD AML blasts with stromal cell line MS-5 and added growth factors essential for AML survival and differentiation such as IL-3, TPO and G-CSF at physiological concentration. As expected, treatment with BAY-806946 enhanced both cytostatic and cytotoxic effect of quizartinib in FLT3-ITD AML cell line MOLM-13 as well as primary patient blasts in co-culture. More importantly, enhanced apoptosis was measured in the stem cell like CD34+CD38- population. Lastly, I elucidate the cytokine profile and persistent phosphoproteins as putative targets following combination treatment. Ultimately, this study demonstrates the potential of PI3K/AKT/mTORi to enhance the efficacy of RTKi quizartinib for the treatment of FLT3-ITD AML.

En nanomédecine, une nouvelle approche consiste à développer des vecteurs synthétiques pour co-délivrer au sein d’une cellule tumorale, un anticancéreux ainsi qu’un siARN, capable de supprimer l’expression d’une protéine impliquée dans les mécanismes de résistance. Les travaux décrits dans ce manuscrit ont été consacrés à la synthèse de nano-vecteurs micellaires pour la délivrance simultanée de ces deux agents thérapeutiques. Une première partie décrit la synthèse et la formulation de micelles nanométriques diacétyléniques photopolymérisables conçues pour délivrer efficacement un siARN. Les propriétés d’encapsulation et de délivrance de ces micelles ont ensuite été étudiées in vitro et in vivo pour une application en thérapie combinatoire. Enfin, une dernière partie présente la fonctionnalisation par interaction électrostatique de ces vecteurs cationiques avec des anticorps préalablement modifiés par des oligonucléotides anioniques pour réaliser un ciblage actif des cellules tumorales
In the nanomedecine field, a new approach consists in developing synthetic vectors able to co-deliver into a cancer cell, an antitumoral drug and siRNAs that target protein(s) involved in MDR. The work described in this manuscript was dedicated to the development of micellar nanovectors for the intracellular co-delivery of these two therapeutic agents. The first part details the synthesis and the formulation of nanometric photopolymerized diacetylenic micelles adapted for the delivery and intracellular release of the siRNA. Then, the encapsulation and delivery properties of these micelles, bearing histidine polar heads have been investigated in vitro and in vivo for the application of combination therapy. Finally, the last part presents the functionalization by electrostatic interaction of these cationic vectors with antibodies, priorly modified by anionic oligonucleotides. This original and versatile system allowed achieving an active targeting of tumoral cells

Dissertação de Mestrado em Biotecnologia Farmacêutica apresentada à Faculdade de Farmácia
O cancro é uma das causas mais significativas de mortalidade em todo o mundo. O impacto de fatores ambientais e a crescente adoção de comportamentos de risco têm contribuído para a alta incidência de cancro, especialmente em países subdesenvolvidos, onde o acesso ao diagnóstico precoce, ao tratamento ou aos cuidados paliativos é limitado. Além disso, a elevada heterogeneidade e a complexidade biológica das células tumorais tornam a resistência à terapia um problema emergente. Uma das alternativas para combater o problema das resistências é encontrar estratégias terapêuticas alternativas de baixo custo que não envolvam todas as etapas do processo complexo e oneroso da investigação e desenvolvimento de novos fármacos. O desenvolvimento de novas terapias combinatórias, uma abordagem que aumenta a eficácia e reduz a probabilidade de resistência aos fármacos, é uma solução frequentemente utilizada e relativamente acessível, que requer menos ensaios clínicos em comparação com o desenvolvimento de novos medicamentos. A ascensão de tecnologias Ómicas de elevado rendimento possibilitaram a aquisição de grandes quantidades de dados, desde a génomica, transcriptómica, proteómica até à metabolómica, que têm permitindo caracterizar as células tumorais do ponto de vista biológico e funcional. No entanto, lidar com esta enorme quantidade de dados, de modo a que possam ser extraídos conhecimentos biológicas proveitosos que possam ajudar no desenvolvimento de terapias mais direcionadas, é uma tarefa complexa. Os métodos de Aprendizagem Computacional (AC) são abordagens cada vez mais populares e baratas, para a análise de dados de Ómicas e na integração desse conhecimento com outros dados relacionados com o cancro.Neste trabalho, propomos um novo modelo de AC para a previsão de novas soluções de terapias combinatórias, recorrendo para isso a dados de Ómicas que caracterizam as linhas celulares de tumores (especificamente para dados de expressão, metilação e variação do número de cópias) e às propriedades físico-químicas e estruturais de fármacos aprovados pela FDA para quimioterapia no cancro. A abordagem com melhor desempenho, um Ensemble Model composto por uma Deep Neural Network, uma Random Forest e uma Support Vector Machine, obteve uma accuracy de 0.74, precision de 0.75 e recall de 0.90. Este modelo possibilitou a previsão de novas combinações terapêuticas através da realização de ensaios de screening de fármacos conducentes à eliminação de candidatos menos vantajosos. Além disso fomos mais ambiciosos e desenvolvemos uma nova base de dados de Proteínas Membranares (os alvos mais comuns para a quimioterapia) que contém as suas principais características e das suas interfaces. Esta base de dados é uma ferramenta importante para estudos futuros no âmbito deste trabalho.
Cancer is one of the more significant causes of mortality worldwide. The impact of environmental factors and the growing adoption of risk behaviours have contributed to the high incidence of cancer, especially in low-income countries, where access to screening, early diagnosis, treatment or palliative care is limited. Furthermore, the high tumour heterogeneity and biological complexity make drug-resistance an overwhelming problem. Overcoming this problem can be achieved by finding new and low-cost therapeutic alternatives that do not involve taking the extremely pricy path of original drug R&D. The development of new combinatory therapies is a commonly used cheaper solution that requires fewer clinical experiments when compared to the development process of new drugs, and that often increases the efficacy and reduces the probability of drug resistance. In the last years, the rises of new high-throughput OMICs technologies have made possible the acquisition of large amounts of OMICs data, allowing the unprecedented characterization of cancer biology and behaviour. Dealing with these massive amounts of data so that prolific biological interpretations can be extracted that may aid in the development of more targeted therapies has been a daunting task. Machine Learning (ML) methods are increasingly popular cheaper and faster approaches used to analyse OMICs and integrate this knowledge with other cancer-related data. In this work, we propose a new ML model for the prediction of an innovative combinatory therapeutic solution, developed using OMICs data that characterize cancer cell lines (specifically expression, methylation and copy number variation) and structural and physico-chemical properties of drugs approved by the FDA for cancer chemotherapy. The best performing approach, an ensemble model comprising a Deep Neural Network, a Random Forest and a Support Vector Machine, achieved 0.74 accuracy, 0.75 precision and 0.90 recall and was suited for the prediction of new combinations for chemotherapy by reliably performing drug screening assays and eliminating less advantageous candidates. We went further ahead and developed also a new database of Membrane Proteins, the most common targets for chemotherapy, and analyse their main interfacial features and characteristics. This database is indeed an important tool for future studies regarding the subject of this work.

Nanomaterials have been widely investigated for improving the treatment of diseases acting as vectors for diverse therapies and as diagnostic tools. Iron-based nanowires possess promising potential for biomedical applications due to their outstanding properties. The combination of different therapeutic and diagnostic strategies into one single platform is an approach for more efficient and safer treatments. In this thesis, I investigate the application of iron-iron oxide core-shell nanowires as therapeutic agents for cancer treatment. In particular, a novel method for multimodal cancer cell destruction was developed combining the optical, magneto-mechanical and chemotherapeutic properties of functionalized nanowires. By functionalizing the nanowires with doxorubicin through a pH-sensitive linker, the first treatment modality was achieved by selective intracellular drug release. The second treatment modality utilizes the mechanical disturbance exerted by the nanowires upon the application of a low-power alternating magnetic field. The third treatment modality exploits the capability of the nanowires to transform optical energy, absorbed from near-infrared irradiation, into heat. The efficiency of the three treatment modalities both independently and combined were tested in breast cancer cells with near complete cell death (90%). The combination of the different strategies can potentially reduce side effects and treatment time. Additionally, I studied the potential of these iron-iron oxide core-shell nanowires as diagnostic tools, included in the Appendix of this dissertation. Specifically, I studied their capability to act as magnetic resonance imaging contrast agents for cell labeling, detection and tracking. Therein, a high performance as T2 contrast agents was confirmed evaluating the effect of oxidation and surface coatings on the T2 contrast in the tailored transverse relaxivities. The detection of nanowire-labeled cancer cells was demonstrated in T2-weighted images of cells implanted in tissue-mimicking phantoms and in mouse brain. Labeling the cells with nanowires enabled high-resolution cell detection after in vivo implantation (~10 cells) over a minimum of 40 days. The capability of these magnetic nanowires of being remotely controllable and detectable make them an attractive option in the treatment and diagnosis of cancer and in cell therapy. Future directions include preclinical studies for testing the nanowire-based photothermal therapy for tumor ablation.

Valutazione dell'attività antineoplastica di prodotti derivanti da piante di olivo su vari tipi di tumore. Studio del trattamento combinato tra agenti naturali e chemioterapici. Evaluation of antineoplastic activity of olive derivatives towards several types of cancers. Study of combinatory treatment based on the use of natural compounds in association with chemotherapy

This chapter focuses on Beckett's media environments and his experimentation with technology in relation to the complex contemporary media culture. Beckett explored some cardinal aspects of technology and wrote texts that deployed media so as to create dramatic effects and simultaneously challenged the limitations of the artistic medium. Breath is intrinsically intermedial given that is operates in-between realities, in-between the boundaries of artistic media, the verbal and the visual, the audible and the scenic, in-between visibility and invisibility, absence and emptiness, embodiment and ambiguity of corporeal experience. Intermediality is examined as a combinatory structure of syntactical elements that come from more than one medium, but are combined into one and are thereby transformed into a new entity