scholarly journals Hydroxy-Propil-β-Cyclodextrin Inclusion Complexes of two Biphenylnicotinamide Derivatives: Formulation and Anti-Proliferative Activity Evaluation in Pancreatic Cancer Cell Models

2020 ◽  
Vol 21 (18) ◽  
pp. 6545
Author(s):  
Rosa Maria Iacobazzi ◽  
Annalisa Cutrignelli ◽  
Angela Stefanachi ◽  
Letizia Porcelli ◽  
Angela Assunta Lopedota ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Inclusion Complexes ◽  
Water Solubility ◽  
Aqueous Solubility ◽  
Ductal Adenocarcinoma ◽  
New Therapeutic Approaches ◽  
M Phase ◽  
High Antitumor Activity ◽  
Poor Outcomes

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with poor outcomes largely due to its unique microenvironment, which is responsible for the low response to drugs and drug-resistance phenomena. This clinical need led us to explore new therapeutic approaches for systemic PDAC treatment by the utilization of two newly synthesized biphenylnicotinamide derivatives, PTA73 and PTA34, with remarkable antitumor activity in an in vitro PDAC model. Given their poor water solubility, inclusion complexes of PTA34 and PTA73 in Hydroxy-Propil-β-Cyclodextrin (HP-β-CD) were prepared in solution and at the solid state. Complexation studies demonstrated that HP-β-CD is able to form stable host–guest inclusion complexes with PTA34 and PTA73, characterized by a 1:1 apparent formation constant of 503.9 M−1 and 369.2 M−1, respectively (also demonstrated by the Job plot), and by an increase in aqueous solubility of about 150 times (from 1.95 µg/mL to 292.5 µg/mL) and 106 times (from 7.16 µg/mL to 762.5 µg/mL), in the presence of 45% w/v of HP-β-CD, respectively. In vitro studies confirmed the high antitumor activity of the complexed PTA34 and PTA73 towards PDAC cells, the strong G2/M phase arrest followed by induction of apoptosis, and thus their eligibility for PDAC therapy.

Complexation with Hydroxypropyl-gama-Cyclodextrin of Birch Tree Extract Physico-chemical Characterisation of their Binary Products

2008 ◽  
Vol 59 (6) ◽  
Author(s):  
Codruta Soica ◽  
Cristina A. Dehelean ◽  
Valentin Ordodi ◽  
Diana Antal ◽  
Vicentiu Vlaia
Keyword(s):  
Inclusion Complexes ◽  
Water Solubility ◽  
In Vitro Dissolution ◽  
Molar Ratio ◽  
Bark Extract ◽  
Birch Bark ◽  
Preparation Methods ◽  
Birch Tree ◽  
Physico Chemical

Birch bark contains important pentacyclic triterpens that determine an anticancer, anti-inflammatory and antiviral activity. The compounds can be extracted by simple procedures with organic solvents. The major problem of this type of triterpens is their low water solubility which can be increased by physical procedures like cyclodextrin complexation. The aim of present study was to analyse the products between birch bark extract and hydroxypropyl-g -cyclodextrin. Hydroxypropyl-g -cyclodextrin (HPGCD) was used as a host to improve its solubility in water, via inclusion complex formation. In order to obtain the inclusion complexes, 1:2 molar ratio and two preparation methods (physical mixing, kneading) were used. The inclusion complexes were analyzed by in vitro dissolution tests, thermal analysis and X-ray diffraction.

scholarly journals Silver Nanocolloids Loaded with Betulinic Acid with Enhanced Antitumor Potential: Physicochemical Characterization and In Vitro Evaluation

Nanomaterials ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 152
Author(s):  
Iulia Pinzaru ◽  
Cristian Sarau ◽  
Dorina Coricovac ◽  
Iasmina Marcovici ◽  
Crinela Utescu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Betulinic Acid ◽  
Water Solubility ◽  
Physicochemical Characterization ◽  
A549 Cells ◽  
Drug Carriers ◽  
Biological Evaluation ◽  
Correlation Spectroscopy ◽  
Hydrodynamic Diameter

Betulinic acid (BA), a natural compound with various health benefits including selective antitumor activity, has a limited applicability in vivo due to its poor water solubility and bioavailability. Thus, this study focused on obtaining a BA nano-sized formulation with improved solubility and enhanced antitumor activity using silver nanocolloids (SilCo and PEG_SilCo) as drug carriers. The synthesis was performed using a chemical method and the physicochemical characterization was achieved applying UV-Vis absorption, transmission electron microscopy (TEM), Raman and photon correlation spectroscopy (PCS). The biological evaluation was conducted on two in vitro experimental models—hepatocellular carcinoma (HepG2) and lung cancer (A549) cell lines. The physicochemical characterization showed the following results: an average hydrodynamic diameter of 32 nm for SilCo_BA and 71 nm for PEG_SilCo_BA, a spherical shape, and a loading capacity of 54.1% for SilCo_BA and 61.9% for PEG_SilCo_BA, respectively. The in vitro assessment revealed a cell type- and time-dependent cytotoxic effect characterized by a decrease in cell viability as follows: (i) SilCo_BA (66.44%) < PEG_SilCo_BA (72.05%) < BA_DMSO (75.30%) in HepG2 cells, and (ii) SilCo_BA (75.28%) < PEG_SilCo_BA (86.80%) < BA_DMSO (87.99%) in A549 cells. The novel silver nanocolloids loaded with BA induced an augmented anticancer effect as compared to BA alone.

scholarly journals In VitroAntileukemic Activity ofXanthosoma sagittifolium(Taioba) Leaf Extract

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Marina L. C. Caxito ◽  
Rachell R. Correia ◽  
Anne Caroline C. Gomes ◽  
Graça Justo ◽  
Marsen G. P. Coelho ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Leaf Extract ◽  
Leukemia Cells ◽  
No Production ◽  
3T3 Fibroblasts ◽  
Griess Reaction ◽  
Xanthosoma Sagittifolium ◽  
M Phase ◽  
Nih 3T3

Xanthosoma sagittifoliumSchott is a herb of the Araceae family, popularly known as taioba, which is consumed as food in some regions of Brazil, Africa, and Asia. This species has already been evaluated for the antifungal activities. However, based on its potential antitumor activity, the present study further aimed to examine the antitumor, as well as chelation, activity ofX. sagittifoliumleaf extract. Results showed that hydroethanolic extract ofX. sagittifoliumleaves (HEXs-L) exhibits cytotoxic effects against the immortalized line of human T-lymphocytic (Jurkat) and myelogenous (K562) leukemia cells, but not nontumor RAW 264.7 macrophages or NIH/3T3 fibroblasts. HEXs-L inhibited 50.3% of Jurkat cell proliferation, reducing by 20% cells in G2/M phase, but increasing cells in sub-G1 phase, thereby inducing apoptosis by 54%. In addition, HEXs-L inhibited NO production by 59%, as determined by Griess reaction, and chelated 93.8% of free Fe(II), as demonstrated by ferrozine assay. Phytochemical studies were carried out by ESI-MS, identifying apigenin di-C-glycosides as major compounds. Overall, this work revealed that leaf extract ofXanthosoma sagittifoliumpresented chelating activity andin vitroantitumor activity, arresting cell cycle and inducing apoptosis of leukemia cells, thus providing evidence that taioba leaves may have practical application in cancer therapy.

scholarly journals Use of Cyclodextrins in Anticancer Photodynamic Therapy Treatment

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1936 ◽  
Author(s):  
Amina Ben Mihoub ◽  
Ludivine Larue ◽  
Albert Moussaron ◽  
Zahraa Youssef ◽  
Ludovic Colombeau ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Photodynamic Therapy ◽  
Molecular Oxygen ◽  
Inclusion Complexes ◽  
Water Solubility ◽  
Cellular Damage ◽  
Hybrid Nanoparticles ◽  
Binding Modes

Photodynamic therapy (PDT) is mainly used to destroy cancerous cells; it combines the action of three components: a photoactivatable molecule or photosensitizer (PS), the light of an appropriate wavelength, and naturally occurring molecular oxygen. After light excitation of the PS, the excited PS then reacts with molecular oxygen to produce reactive oxygen species (ROS), leading to cellular damage. One of the drawbacks of PSs is their lack of solubility in water and body tissue fluids, thereby causing low bioavailability, drug-delivery efficiency, therapeutic efficacy, and ROS production. To improve the water-solubility and/or drug delivery of PSs, using cyclodextrins (CDs) is an interesting strategy. This review describes the in vitro or/and in vivo use of natural and derived CDs to improve antitumoral PDT efficiency in aqueous media. To achieve these goals, three types of binding modes of PSs with CDs are developed: non-covalent CD–PS inclusion complexes, covalent CD–PS conjugates, and CD–PS nanoassemblies. This review is divided into three parts: (1) non-covalent CD-PS inclusion complexes, covalent CD–PS conjugates, and CD–PS nanoassemblies, (2) incorporating CD–PS systems into hybrid nanoparticles (NPs) using up-converting or other types of NPs, and (3) CDs with fullerenes as PSs.

scholarly journals Formulation and Characterization of Felodipine as an Oral Nanoemulsions

2021 ◽  
Vol 30 (1) ◽  
pp. 209-217
Author(s):  
Sumaya B. Hamed ◽  
Shaimaa N. Abd Alhammid
Keyword(s):  
Particle Size ◽  
Oleic Acid ◽  
Zeta Potential ◽  
Water Solubility ◽  
Tween 80 ◽  
Aqueous Solubility ◽  
Compatibility Study ◽  
Drug Content ◽  
Drug Molecules

            Felodipine is a calcium-channel blocker with low aqueous solubility and bioavailability. Lipid dosage forms are attractive delivery systems for such hydrophobic drug molecules. Nanoemulsion (NE) is one of the popular methods that has been used to solve the dispersibility problems of many drugs. Felodipine was formulated as a NE utilizing oleic acid as an oil phase, tween 80 and tween 60 as surfactants and ethanol as a co-surfactant. Eight formulas were prepared, and different tests were performed to ensure the stability of the NEs, such as particle size, polydispersity index, zeta potential, dilution test, drug content, viscosity and in-vitro drug release. Results of characterization showed that felodipine nanoemulsion (F3) with (oleic acid 10%) ,(Smix 60% of tween80 :ethanol in a ratio of 3:1), (DDW 30%) was selected as the best formula, since it has a particle size of (17.01)nm, low PDI (0.392), zeta potential (-22.34mV), good dilution without drug precipitation , higher percent of drug content (99.098%) with  acceptable viscosity , and complete release of the drug after (45 min.) with significantly higher (P<0.05)   dissolution  rate in comparison with the pure drug powder. The selected formula (F3) subjected to further investigations as drug and excipient compatibility study by Fourier transform infrared spectroscopy (FTIR) The outcomes of the (FTIR) explain that the distinctive peaks for felodipine were not affected by other components and displayed the same functional group's band with very slight shifting. This indicates that there was no interaction between felodipine and other NE components. Therefore, these excipients were found to be compatible with felodipine. In conclusion, the NE was found to be an efficient method to enhance the dispersibility and permeatioins of drugs that have poor water solubility (lipophilic drugs).

scholarly journals MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages

2019 ◽  
Author(s):  
Pietro Delfino ◽  
Christian Neander ◽  
Dea Filippini ◽  
Sabrina L. D’Agosto ◽  
Caterina Vicentini ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Map Kinase ◽  
Ductal Adenocarcinoma ◽  
Oncogenic Signaling ◽  
Kinase Activation ◽  
Immune Contexture ◽  
Inflammatory Macrophages

ABSTRACTThe RAF/MEK/ERK (MAP Kinase) pathway is the index oncogenic signaling towards which many compounds have been developed and tested for the treatment of KRAS-driven cancers, including pancreatic ductal adenocarcinoma (PDA). Here, we explored the immunological changes induced by targeted MEK1/2 inhibition (MEKi) using trametinib in preclinical mouse models of PDA. We evaluated the dynamic changes in the immune contexture of mouse PDA upon MEKi using a multidimensional approach (mRNA analyses, flow cytometry, and immunophenotyping). Effect of MEKi on the viability and metabolism of macrophages was investigated in vitro. We showed that transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA subtype (squamous/basal-like/quasimesenchymal), while short term MEKi treatment in mouse PDA induced subtype switching. Integrative mRNA expression and immunophenotypic analyses showed that MEKi reshapes the immune landscape of PDA by depleting rather than reprogramming macrophages, while augmenting infiltration by neutrophils. Depletion of macrophages is observed early in the course of in vivo treatment and is at least partially due to their higher sensitivity to MEKi. Tumor-associated macrophages were consistently reported to interfere with gemcitabine uptake by PDA cells. Here, our in vivo studies show a superior antitumor activity upon combination of MEKi and gemcitabine using a sequential rather than simultaneous dosing protocol. Our results show that MEK inhibition induces a dramatic remodeling of the tumor microenvironment of mouse PDA through depletion of macrophages, which substantially improves the antitumor activity of gemcitabine.

scholarly journals A N-propionylsulfonamide prodrug of K-5a2 provided improved aqueous solubility and hERG inhibition

2020 ◽  
Author(s):  
Xiaofang Zuo ◽  
Zhipeng Huo ◽  
Dongwei Kang ◽  
Tong Zhao ◽  
Erik De Clercq ◽  
...  
Keyword(s):  
Water Solubility ◽  
Parent Drug ◽  
Aqueous Solubility ◽  
Drug Candidate ◽  
Log P ◽  
Vitro Assay ◽  
Subacute Toxicity ◽  
Anti Hiv ◽  
Hiv 1

Abstract Background Having the potential disadvantages and safety risk of the use of anti-HIV-1 drug candidate K-5a2 in the longterm treatment of HIV patients in mind, we set out with the goal of finding a second-generation backup compound of K-5a2 with the appropriate anti-HIV potency, significantly reduced hERG activity, decreased induction of the CYP enzyme, and improved aqueous solubility. Herein, using a N-propionylsulfonamide prodrug strategy, we report the discovery of compound HM-1Methods In vitro assay of anti-HIV activities in TZM-bl and MT-4 cells, metabolic stability in HLM and human plasma, measurements of water solubility and Log P, assay procedures for hERG activity, acute and subacute toxicity experiment and cytochrome P450 inhibition assay were carried out for HM-1.Results HM-1 can be rapidly hydrolyzed to parent drug K-5a2 and exhibited high potency against HIV-1NL4 − 3 strain (EC50 = 7.99 nM) in TZM-bl cells, HIV-1IIIB strain (EC50 = 2.9 nM) and HIV-1Y181C strain (EC50 = 5.5 nM) in MT-4 cells. And it also showed a > 70-fold improvement in aqueous solubility and presented a low acute toxicity in mice (LD50 > 2 g•kg− 1); no obvious organ damage was detected in the assessment of subacute toxicity. Meanwhile, HM-1 also showed 50 times lower hERG inhibition (IC50 = 6.39 µM) than K-5a2 (IC50 = 0.13 µM).Conclusions It was HM-1 appeared to be free of most of the drawbacks associated with K-5a2 and has been selected for further development as an oral anti-HIV-infection agent.

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