scholarly journals Click Activated Protodrugs Against Cancer Increase the Therapeutic Potential of Chemotherapy through Local Capture and Activation

2020 ◽  
Author(s):  
Kui Wu ◽  
Nathan Yee ◽  
Sangeetha Srinivasan ◽  
Amir Mahmoodi ◽  
Michael Zakharian ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Unmet Need ◽  
Sodium Hyaluronate ◽  
Maximum Tolerated Dose ◽  
The Body ◽  
In Vivo Studies ◽  
Tumor Biomarker ◽  
Tumor Site

<div> <div> <div> <p>A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)- modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels-Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapy. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. Studies in rodents show that a single injection of the tetrazine-modified biopolymer, SQL70, efficiently captures SQP33 protodrug doses given at 10.8-times the maximum tolerated dose of conventional doxorubicin with greatly reduced systemic toxicity. </p> </div> </div> </div>

scholarly journals Click Activated Protodrugs Against Cancer Increase the Therapeutic Potential of Chemotherapy through Local Capture and Activation

2020 ◽  
Author(s):  
Kui Wu ◽  
Nathan Yee ◽  
Sangeetha Srinivasan ◽  
Amir Mahmoodi ◽  
Michael Zakharian ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Unmet Need ◽  
Sodium Hyaluronate ◽  
Maximum Tolerated Dose ◽  
The Body ◽  
In Vivo Studies ◽  
Tumor Biomarker ◽  
Tumor Site

<div> <div> <div> <p>A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)- modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels-Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapy. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. Studies in rodents show that a single injection of the tetrazine-modified biopolymer, SQL70, efficiently captures SQP33 protodrug doses given at 10.8-times the maximum tolerated dose of conventional doxorubicin with greatly reduced systemic toxicity. </p> </div> </div> </div>

scholarly journals Click Activated Protodrugs Against Cancer Increase the Therapeutic Potential of Chemotherapy through Local Capture and Activation

2020 ◽  
Author(s):  
Kui Wu ◽  
Nathan Yee ◽  
Sangeetha Srinivasan ◽  
Amir Mahmoodi ◽  
Michael Zakharian ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Unmet Need ◽  
Sodium Hyaluronate ◽  
Maximum Tolerated Dose ◽  
The Body ◽  
In Vivo Studies ◽  
Tumor Biomarker ◽  
Tumor Site

<div> <div> <div> <p>A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)- modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels-Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapy. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. Studies in rodents show that a single injection of the tetrazine-modified biopolymer, SQL70, efficiently captures SQP33 protodrug doses given at 10.8-times the maximum tolerated dose of conventional doxorubicin with greatly reduced systemic toxicity. </p> </div> </div> </div>

Insilico identification of a ferroportin inhibitor for the management of iron-overload condition in Beta Thalassemia major patients.

2021 ◽  
Author(s):  
Yasir Sharif ◽  
Saba Irshad ◽  
Muhammad Hamza Tariq ◽  
Muhammad Nadeem Asghar
Keyword(s):  
Iron Overload ◽  
Therapeutic Potential ◽  
3D Structure ◽  
Thalassemia Major ◽  
The Body ◽  
In Vivo Studies ◽  
Beta Thalassemia ◽  
Beta Thalassemia Major

Abstract The reason of high mortality rate in the patients of beta-thalassemia major is iron overload because it leads to many secondary complications. Condition of iron overload is known as hemochromatosis (HC). HC causes distorted formation of HFE protein that disturbs the whole pathway of HAMP protein synthesis which results in unbounded form of ferroportin and hence iron keeps absorbing in the body, leading to iron accumulation. The current study was conducted to identify a potential phytochemical that could bind to ferroportin and inhibits its iron absorbing activity within the body. The 3D structure of Ferroportin was unavailable in protein data bank PDB, therefore, it was developed by using different bioinformatics tools and best structure was identified through SAVES and RAMPAGE analysis. This best structure was docked with a library of 1010 bioactive phytochemicals by using MOE-2009 software. The top-ten ranked potential inhibitors were then evaluated for drug-like properties through molsoft and Molinspiration server followed by ADMET analysis. Our study demonstrated that “Taxifolin’ showed the maximum binding affinity with Ferroportin and also demonstrates maximum drug-like properties. Thus this compound could be used as a potential inhibitor of ferroportin. However, in-vitro and in-vivo studies must be conducted to validate the therapeutic potential of taxifolin against hemochromatosis.

Preparation and Evaluation of Quercetin-Loaded MPEG-PLA Nanoparticles

2018 ◽  
Vol 14 (5) ◽  
pp. 366-376 ◽  
Author(s):  
Hiraku Onishi ◽  
Masashi Nakamura ◽  
Masanaho Sasatsu
Keyword(s):  
Organic Solvent ◽  
Therapeutic Potential ◽  
In Vitro Release ◽  
Aqueous Solubility ◽  
The Body ◽  
In Vivo Studies ◽  
Water Mixture ◽  
Biodistribution Studies

Background: Quercetin (QE) is one of the flavonoids with various biological functions such as anti-oxidation, anti-inflammatory and antitumor. However, the low aqueous solubility and short half-life in the body reduce its in vivo efficacy. Therefore, the appropriate delivery techniques to solve those problems have drawn much attention. In the present study, methoxypolyethylene glycol- poly-DL-lactic acid (MPEG-PLA) nanoparticles loaded with quercetin (QE), called NP, were prepared, and their antitumor characteristics were investigated in vitro and in vivo. Method: NPs were produced by evaporating organic solvent from the organic solvent-water mixture in four formulations. The particle characteristics and in vitro release were examined for the obtained preparations (NP1 – NP4). The antitumor features were investigated in vivo with different administration schedules using mice inoculated subcutaneously with murine Sarcoma 180. In addition, the efficacy of co-administration of NP with a strong antitumor chemotherapeutic agent, irinotecan hydrochloride (CPT-11), was examined. Biodistribution studies were performed using the same animal models. Result: The NP with the higher drug content (0.58 % (w/w)) and gradual release profile, Preparation NP4, were chosen and used as NP in the in vivo studies. NP suppressed tumor growth better than QE solution in various dosing schedules (total dose = 2 mg/kg). In the combination therapy with CPT-11, NP exhibited antitumor efficacy in a nearly additive manner. No decrease in body weight observed with any administration. NP markedly enhanced the systemic distribution and tumor localization. Conclusion: These results indicated that the present NP should promote the efficacy of QE, and might have useful therapeutic potential in the treatment of solid tumors.

Nanocurcumin: A Double-Edged Sword for Microcancers

2020 ◽  
Vol 26 (45) ◽  
pp. 5783-5792
Author(s):  
Kholood Abid Janjua ◽  
Adeeb Shehzad ◽  
Raheem Shahzad ◽  
Salman Ul Islam ◽  
Mazhar Ul Islam
Keyword(s):  
Intracellular Signaling ◽  
Dosage Forms ◽  
The Body ◽  
In Vivo Studies ◽  
Mrna Levels ◽  
Anticancer Activities ◽  
Road Map ◽  
Anticancer Effects

There is compelling evidence that drug molecules isolated from natural sources are hindered by low systemic bioavailability, poor absorption, and rapid elimination from the human body. Novel approaches are urgently needed that could enhance the retention time as well as the efficacy of natural products in the body. Among the various adopted approaches to meet this ever-increasing demand, nanoformulations show the most fascinating way of improving the bioavailability of dietary phytochemicals through modifying their pharmacokinetics and pharmacodynamics. Curcumin, a yellowish pigment isolated from dried ground rhizomes of turmeric, exhibits tremendous pharmacological effects, including anticancer activities. Several in vitro and in vivo studies have shown that curcumin mediates anticancer effects through the modulation (upregulation and/or downregulations) of several intracellular signaling pathways both at protein and mRNA levels. Scientists have introduced multiple modern techniques and novel dosage forms for enhancing the delivery, bioavailability, and efficacy of curcumin in the treatment of various malignancies. These novel dosage forms include nanoparticles, liposomes, micelles, phospholipids, and curcumin-encapsulated polymer nanoparticles. Nanocurcumin has shown improved anticancer effects compared to conventional curcumin formulations. This review discusses the underlying molecular mechanism of various nanoformulations of curcumin for the treatment of different cancers. We hope that this study will make a road map for preclinical and clinical investigations of cancer and recommend nano curcumin as a drug of choice for cancer therapy.

Medicinal Plants and Bioactive Compounds for Diabetes Management: Important Advances for Drug Discovery

2020 ◽  
Vol 26 ◽  
Author(s):  
Kondeti Ramudu Shanmugam ◽  
Bhasha Shanmugam ◽  
Gangigunta Venkatasubbaiah ◽  
Sahukari Ravi ◽  
Kesireddy Sathyavelu Reddy
Keyword(s):  
Herbal Medicine ◽  
Medicinal Plants ◽  
Bioactive Compounds ◽  
Diabetes Management ◽  
Therapeutic Potential ◽  
Public Health Problem ◽  
In Vivo Studies ◽  
Major Public Health Problem

Background : Diabetes is a major public health problem in the world. It affects each and every part of the human body and also leads to organ failure. Hence, great progress made in the field of herbal medicine and diabetic research. Objectives: Our review will focus on the effect of bioactive compounds of medicinal plants which are used to treat diabetes in India and other countries. Methods: Information regarding diabetes, oxidative stress, medicinal plants and bioactive compounds were collected from different search engines like Science direct, Springer, Wiley online library, Taylor and francis, Bentham Science, Pubmed and Google scholar. Data was analyzed and summarized in the review. Results and Conclusion: Anti-diabetic drugs that are in use have many side effects on vital organs like heart, liver, kidney and brain. There is an urgent need for alternative medicine to treat diabetes and their disorders. In India and other countries herbal medicine was used to treat diabetes. Many herbal plants have antidiabetic effects. The plants like ginger, phyllanthus, curcumin, aswagandha, aloe, hibiscus and curcuma showed significant anti-hyperglycemic activities in experimental models and humans. The bioactive compounds like Allicin, azadirachtin, cajanin, curcumin, querceitin, gingerol possesses anti-diabetic, antioxidant and other pharmacological properties. This review focuses on the role of bioactive compounds of medicinal plants in prevention and management of diabetes. Conclusion: Moreover, our review suggests that bioactive compounds have the potential therapeutic potential against diabetes. However, further in vitro and in vivo studies are needed to validate these findings.

scholarly journals Potential Implantable Nanofibrous Biomaterials Combined with Stem Cells for Subchondral Bone Regeneration

Materials ◽  
2020 ◽  
Vol 13 (14) ◽  
pp. 3087
Author(s):  
Rana Smaida ◽  
Luc Pijnenburg ◽  
Silvia Irusta ◽  
Erico Himawan ◽  
Gracia Mendoza ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Regeneration ◽  
Subchondral Bone ◽  
Therapeutic Potential ◽  
Sodium Hyaluronate ◽  
Vinyl Pyrrolidone ◽  
Regenerative Ability ◽  
Poly Vinyl Pyrrolidone

The treatment of osteochondral defects remains a challenge. Four scaffolds were produced using Food and Drug Administration (FDA)-approved polymers to investigate their therapeutic potential for the regeneration of the osteochondral unit. Polycaprolactone (PCL) and poly(vinyl-pyrrolidone) (PVP) scaffolds were made by electrohydrodynamic techniques. Hydroxyapatite (HAp) and/or sodium hyaluronate (HA) can be then loaded to PCL nanofibers and/or PVP particles. The purpose of adding hydroxyapatite and sodium hyaluronate into PCL/PVP scaffolds is to increase the regenerative ability for subchondral bone and joint cartilage, respectively. Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) were seeded on these biomaterials. The biocompatibility of these biomaterials in vitro and in vivo, as well as their potential to support MSC differentiation under specific chondrogenic or osteogenic conditions, were evaluated. We show here that hBM-MSCs could proliferate and differentiate both in vitro and in vivo on these biomaterials. In addition, the PCL-HAp could effectively increase the mineralization and induce the differentiation of MSCs into osteoblasts in an osteogenic condition. These results indicate that PCL-HAp biomaterials combined with MSCs could be a beneficial candidate for subchondral bone regeneration.

scholarly journals The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3088
Author(s):  
Mariana Matias ◽  
Jacinta O. Pinho ◽  
Maria João Penetra ◽  
Gonçalo Campos ◽  
Catarina Pinto Reis ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Drug Evaluation ◽  
Three Dimensional ◽  
Experimental Models ◽  
In Vivo Studies ◽  
Murine Models ◽  
In Vivo Experiments ◽  
Novel Therapeutic Strategies

Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.

scholarly journals Anti-Inflammatory Potential of Daturaolone from Datura innoxia Mill.: In Silico, In Vitro and In Vivo Studies

2021 ◽  
Vol 14 (12) ◽  
pp. 1248
Author(s):  
Muhammad Waleed Baig ◽  
Humaira Fatima ◽  
Nosheen Akhtar ◽  
Hidayat Hussain ◽  
Mohammad K. Okla ◽  
...  
Keyword(s):  
In Silico ◽  
Therapeutic Potential ◽  
In Vivo Studies ◽  
Metabolic Reaction ◽  
Datura Innoxia ◽  
In Vivo Models ◽  
Immobility Time ◽  
Anti Inflammatory

Exploration of leads with therapeutic potential in inflammatory disorders is worth pursuing. In line with this, the isolated natural compound daturaolone from Datura innoxia Mill. was evaluated for its anti-inflammatory potential using in silico, in vitro and in vivo models. Daturaolone follows Lipinski’s drug-likeliness rule with a score of 0.33. Absorption, distribution, metabolism, excretion and toxicity prediction show strong plasma protein binding; gastrointestinal absorption (Caco-2 cells permeability = 34.6 nm/s); no blood–brain barrier penetration; CYP1A2, CYP2C19 and CYP3A4 metabolism; a major metabolic reaction, being aliphatic hydroxylation; no hERG inhibition; and non-carcinogenicity. Predicted molecular targets were mainly inflammatory mediators. Molecular docking depicted H-bonding interaction with nuclear factor kappa beta subunit (NF-κB), cyclooxygenase-2, 5-lipoxygenase, phospholipase A2, serotonin transporter, dopamine receptor D1 and 5-hydroxy tryptamine. Its cytotoxicity (IC50) value in normal lymphocytes was >20 µg/mL as compared to cancer cells (Huh7.5; 17.32 ± 1.43 µg/mL). Daturaolone significantly inhibited NF-κB and nitric oxide production with IC50 values of 1.2 ± 0.8 and 4.51 ± 0.92 µg/mL, respectively. It significantly reduced inflammatory paw edema (81.73 ± 3.16%), heat-induced pain (89.47 ± 9.01% antinociception) and stress-induced depression (68 ± 9.22 s immobility time in tail suspension test). This work suggests a possible anti-inflammatory role of daturaolone; however, detailed mechanistic studies are still necessary to corroborate and extrapolate the findings.

Polyphenols in Food: Cancer Prevention and Apoptosis Induction

2018 ◽  
Vol 25 (36) ◽  
pp. 4740-4757 ◽  
Author(s):  
Ashita Sharma ◽  
Mandeep Kaur ◽  
Jatinder Kaur Katnoria ◽  
Avinash Kaur Nagpal
Keyword(s):  
Cancer Prevention ◽  
Defense Mechanism ◽  
Antioxidant Property ◽  
The Body ◽  
Water Soluble ◽  
Stress Factors ◽  
In Vivo Studies ◽  
Hydroxyl Groups

Polyphenols are a group of water-soluble organic compounds, mainly of natural origin. The compounds having about 5-7 aromatic rings and more than 12 phenolic hydroxyl groups are classified as polyphenols. These are the antioxidants which protect the body from oxidative damage. In plants, they are the secondary metabolites produced as a defense mechanism against stress factors. Antioxidant property of polyphenols is suggested to provide protection against many diseases associated with reactive oxygen species (ROS), including cancer. Various studies carried out across the world have suggested that polyphenols can inhibit the tumor generation, induce apoptosis in cancer cells and interfere in progression of tumors. This group of wonder compounds is present in surplus in natural plants and food products. Intake of polyphenols through diet can scavenge ROS and thus can help in cancer prevention. The plant derived products can also be used along with conventional chemotherapy to enhance the chemopreventive effects. The present review focuses on various in vitro and in vivo studies carried out to assess the anti-carcinogenic potential of polyphenols present in our food. Also, the pathways involved in cancer chemopreventive effects of various subclasses (flavonoids, lignans, stilbenes and phenolic acids) of polyphenols are discussed.

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