Exploration on the adsorption mechanism of aminopyrimidines and quinazoline compounds on graphene oxide: Hydrophobicity and structure-controlled release process

In this study, graphene oxide was synthesized using the Hummers method, and stable and homogeneous graphene oxide aqueous solutions were obtained through mechanical stirring and ultrasonic stripping. In conjunction with our previous studies, graphene oxide-loaded insoluble compound delivery systems were prepared to verify the in vivo release profiles of the graphene oxide delivery system. Several insoluble compounds including imatinib, nilotinib, erlotinib, gefitinib, and afatinib were selected for loading and in vitro graphene oxide release assays to study the non-covalent adsorption mechanisms. Computer simulations were employed for validation processes. For in vivo release assays, the T1/2 values of the poorly water soluble groups were 1.104 ± 0.18 h and the Cmax was 2.600 ± 2.06 mg/L. In previous assays, compounds with high water solubility supported by graphene oxide were released and detected in vivo. The solubility of the compound and its binding force with the carrier played a crucial role in release. The results of graphene oxide loading experiments showed that the maximum loading and entrapment efficiencies of the insoluble model compounds with similar aromatic rings were comparable. Under basic conditions, the in vitro release rates and maximum release levels of amino pyrimidine were elevated. In contrast, quinazoline release declined. Combined with computer simulations, π–π stacking was identified as the dominant mechanism for adsorption onto graphene oxide. Both hydrogen bonding and cation-π bonds played an auxiliary reinforcing role, and the two were regarded as antagonistic.

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Considerable Improvement of Ursolic Acid Water Solubility by Its Encapsulation in Dendrimer Nanoparticles: Design, Synthesis and Physicochemical Characterization

Nanomaterials ◽

10.3390/nano11092196 ◽

2021 ◽

Vol 11 (9) ◽

pp. 2196 ◽

Cited By ~ 1

Author(s):

Silvana Alfei ◽

Anna Maria Schito ◽

Guendalina Zuccari

Keyword(s):

Ursolic Acid ◽

Water Solubility ◽

Drug Loading ◽

Physicochemical Characterization ◽

Systemic Toxicity ◽

Water Soluble ◽

Design Synthesis ◽

Pentacyclic Triterpenoid

Ursolic acid (UA) is a pentacyclic triterpenoid found in many medicinal plants and aromas endowed with numerous in vitro pharmacological activities, including antibacterial effects. Unfortunately, UA is poorly administered in vivo, due to its water insolubility, low bioavailability, and residual systemic toxicity, thus making urgent the development of water-soluble UA formulations. Dendrimers are nonpareil macromolecules possessing highly controlled size, shape, and architecture. In dendrimers with cationic surface, the contemporary presence of inner cavities and of hydrophilic peripheral functions, allows to encapsulate hydrophobic non-water-soluble drugs as UA, to enhance their water-solubility and stability, and to promote their protracted release, thus decreasing their systemic toxicity. In this paper, aiming at developing a new UA-based antibacterial agent administrable in vivo, we reported the physical entrapment of UA in a biodegradable not cytotoxic cationic dendrimer (G4K). UA-loaded dendrimer nanoparticles (UA-G4K) were obtained, which showed a drug loading (DL%) much higher than those previously reported, a protracted release profile governed by diffusion mechanisms, and no cytotoxicity. Also, UA-G4K was characterized by principal components analysis (PCA)-processed FTIR spectroscopy, by NMR and elemental analyses, and by dynamic light scattering experiments (DLS). The water solubility of UA-G4K was found to be 1868-fold times higher than that of pristine UA, thus making its clinical application feasible.

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Development and Characterization of the Neuroregenerative Xanthohumol C/Hydroxypropyl-β-cyclodextrin Complex Suitable for Parenteral Administration

Planta Medica ◽

10.1055/a-1013-1276 ◽

2019 ◽

Vol 85 (16) ◽

pp. 1233-1241

Author(s):

Michael Kirchinger ◽

Lara Bieler ◽

Julia Tevini ◽

Michael Vogl ◽

Elisabeth Haschke-Becher ◽

...

Keyword(s):

Water Solubility ◽

Pharmaceutical Research ◽

Water Soluble ◽

Complexing Agents ◽

Cyclodextrin Complex ◽

Scanning Calorimetry ◽

In Vivo Experiments ◽

Strong Candidate

AbstractThe chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-β-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-β-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-β-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i. p. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i. v., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i. p. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-β-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.

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Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

Molecules ◽

10.3390/molecules25112560 ◽

2020 ◽

Vol 25 (11) ◽

pp. 2560 ◽

Cited By ~ 1

Author(s):

Gökçe Şeker Karatoprak ◽

Esra Küpeli Akkol ◽

Yasin Genç ◽

Hilal Bardakcı ◽

Çiğdem Yücel ◽

...

Keyword(s):

South African ◽

Water Solubility ◽

The Body ◽

Water Soluble ◽

In Vivo Studies ◽

Lead Compounds ◽

Combretastatin A4 ◽

Potential Applications

Combretastatins are a class of closely related stilbenes (combretastatins A), dihydrostilbenes (combretastatins B), phenanthrenes (combretastatins C) and macrocyclic lactones (combretastatins D) found in the bark of Combretum caffrum (Eckl. & Zeyh.) Kuntze, commonly known as the South African bush willow. Some of the compounds in this series have been shown to be among the most potent antitubulin agents known. Due to their structural simplicity many analogs have also been synthesized. Combretastatin A4 phosphate is the most frequently tested compounds in preclinical and clinical trials. It is a water-soluble prodrug that the body can rapidly metabolize to combretastatin A4, which exhibits anti-tumor properties. In addition, in vitro and in vivo studies on combretastatins have determined that these compounds also have antioxidant, anti-inflammatory and antimicrobial effects. Nano-based formulations of natural or synthetic active agents such as combretastatin A4 phosphate exhibit several clear advantages, including improved low water solubility, prolonged circulation, drug targeting properties, enhanced efficiency, as well as fewer side effects. In this review, a synopsis of the recent literature exploring the combretastatins, their potential effects and nanoformulations as lead compounds in clinical applications is provided.

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Synthesis of New Water Soluble β-Cyclodextrin@Curcumin Conjugates and In Vitro Safety Evaluation in Primary Cultures of Rat Cortical Neurons

International Journal of Molecular Sciences ◽

10.3390/ijms22063255 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3255

Author(s):

Amina Ben Mihoub ◽

Samir Acherar ◽

Céline Frochot ◽

Catherine Malaplate ◽

Frances T. Yen ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Cortical Neurons ◽

Water Solubility ◽

Photophysical Properties ◽

Primary Cultures ◽

Average Diameter ◽

Water Soluble ◽

Cell Toxicity

Self-aggregation of Curcumin (Cur) in aqueous biological environment decreases its bioavailability and in vivo therapeutic efficacy, which hampers its clinical use as candidate for reducing risk of neurodegenerative diseases. Here, we focused on the design of new Cur- β-Cyclodextrin nanoconjugates to improve the solubility and reduce cell toxicity of Cur. In this study, we described the synthesis, structural characterization, photophysical properties and neuron cell toxicity of two new water soluble β-CD/Cur nanoconjugates as new strategy for reducing risks of neurodegenerative diseases. Cur was coupled to one or two β-CD molecules via triazole rings using CuAAC click chemistry strategy to yield β-CD@Cur and (β-CD)2@Cur nanoconjugates, respectively. The synthesized nanoconjugates were found to be able to self-assemble in aqueous condition and form nano-aggregates of an average diameter size of around 35 and 120 nm for β-CD@Cur and (β-CD)2@Cur, respectively. The photophysical properties, water solubility and cell toxicity on rat embryonic cortical neurons of the designed nanoconjugates were investigated and compared to that of Cur alone. The findings revealed that both new nanoconjugates displayed better water solubility and in vitro biocompatibility than Cur alone, thus making it possible to envisage their use as future nano-systems for the prevention or risk reduction of neurodegenerative diseases.

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Water Soluble Cyclophosphamide Adducts of Rhodium(II) Keto-Gluconate and Glucuronate. Synthesis, Characterization and In Vitro Cytostatic Assays

Metal-Based Drugs ◽

10.1155/mbd.1999.19 ◽

1999 ◽

Vol 6 (1) ◽

pp. 19-24 ◽

Cited By ~ 7

Author(s):

Eric de Souza Gil ◽

Maria Inês de Almeida Gonçalves ◽

Elizabeth Igne Ferreira ◽

Szulin Ber Zyngier ◽

Renato Najjar

Keyword(s):

Water Solubility ◽

High Water ◽

Water Soluble ◽

Biological Assays ◽

Visible Spectra ◽

Uv Visible ◽

K 562 Cells ◽

Sugar Derivatives ◽

High Water Solubility

The synthesis, characterization and biological assays of two new rhodium carboxylate sugar derivatives and respective cyclosphosphamide adducts are described. The compounds, characterized by C13 and H1 NMR , infrared and UV-visible spectra, presented high water solubility and hydration grades were confirmed given the concordance between thermal and CHN analyses. The adducts were active in vitro against K-562 cells.

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Antifungal Activity of Novel Formulations Based on Terpenoid Prodrugs against C. albicans in a Mouse Model

Pharmaceutics ◽

10.3390/pharmaceutics13050633 ◽

2021 ◽

Vol 13 (5) ◽

pp. 633

Author(s):

Suvidha Menon ◽

Xiuyi Liang ◽

Richa Vartak ◽

Ketankumar Patel ◽

Antonio Di Stefano ◽

...

Keyword(s):

Antifungal Activity ◽

Mouse Model ◽

Water Solubility ◽

Water Soluble ◽

Water Soluble Drugs ◽

Resistant Strains ◽

Antimicrobial And Antifungal Activity ◽

In Vitro Data

Carvacrol (CAR), a phenolic monoterpenoid, has been extensively investigated for its antimicrobial and antifungal activity. As a result of its poor physicochemical properties, water soluble carvacrol prodrugs (WSCPs) with improved water solubility were previously synthesized and found to possess antimicrobial activity. Here, three novel CAR analogs, WSCP1, WSCP2, and WSCP3, were tested against fluconazole (FLU)-sensitive and -resistant strains where they showed greater antifungal activity than CAR against C. albicans. The probable mechanism by which the CAR prodrugs exert the antifungal activity was studied. Results from medium acidification assays demonstrated that the CAR and its synthetically designed prodrugs inhibit the yeast plasma membrane H+-ATPase (Pma1p), an essential target in fungi. In other words, in vitro data indicated that CAR analogs can prove to be a better alternative to CAR considering their improved water solubility. In addition, CAR and WSCP1 were developed into intravaginal formulations and administered at test doses of 50 mg/kg in a mouse model of vulvovaginal candidiasis (VVC). Whereas the CAR and WSCP1 formulations both exhibited antifungal efficacy in the mouse model of VVC, the WSCP1 formulation was superior to CAR, showing a remarkable decrease in infection by ~120-fold compared to the control (infected, untreated animals). Taken together, a synthetically designed prodrug of CAR, namely WSCP1, proved to be a possible solution for poorly water-soluble drugs, an inhibitor of an essential yeast pump in vitro and an effective and promising antifungal agent in vivo.

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Efficacy of a novel potent and high water-soluble selective PARP inhibitor CVL218 in glioma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13539 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13539-e13539

Author(s):

Steve Shen ◽

Zehong Miao ◽

Chunhao Yang‘

Keyword(s):

Cell Growth ◽

Therapeutic Potential ◽

Parp Inhibitor ◽

Glioma Cells ◽

High Water ◽

Water Soluble ◽

Pharmacokinetic Studies ◽

Idh Mutations

e13539 Background: Glioma is the most common, deadly, and difficult-to-treat intracranial tumor. Up to 70% of gliomas are found to carry isocitrate dehydrogenase (IDH) mutations, which induce a homologous recombination defect (HRD) that renders glioma cells sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi). However, 4 launched PARPi have limitation for IDH-mutant glioma because of low concentration level in brain. CVL218 is a novel potent and high water-soluble selective PARP-1/2 inhibitor. Pharmacokinetic studies in rats showed that CVL218 can easily across the BBB, has 10 times higher concentration in brain than in the plasma, indicating its therapeutic potential in glioma. Here, we examined its effect on glioma in vitro and in vivo. Methods: BT142 mut/- glioma cells with a homozygous IDH1 R132H mutation were exploited. Chemotherapeutic agent temozolomide (TMZ), PARPi Olaparib and Niraparib, were used as controls. The inhibition of BT142 cell growth by compounds in vitro was measured by MTT assay. Female NOD/SCID mice with orthotopic xenografts of BT142 glioma cells were used to evaluate the antitumor efficacy of compounds in vivo. Medium survival time (MST) was compared using the Kaplan-Meier method and logrank test. Results: CVL218 inhibited the BT142 cell growth in vitro with an IC50 of 2.07 ± 0.62 μM, better than Olaparib and Niraparib. Orthotopic xenograft glioma mice model study showed that CVL218 group significantly extended the MST to 98.0 days ( p= 0.0206), while MST of TMZ treated group is 85.0 days. Conclusions: CVL218 inhibits IDH1-mutant BT142 glioma cell growth in vitro and in vivo. The present findings suggest that CVL218 is a potential agent which could be useful as a treatment for IDH-mutant glioma. We will start its phase I clinical study for glioma soon.

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Fenofibrate Solid Dispersion for Improving Oral Bioavailability: Preparation, and Characterization and in vivo Evaluation

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2020.13.5.7 ◽

2020 ◽

Vol 13 (5) ◽

pp. 5102-5109

Author(s):

Venu Madhav K ◽

Somnath De ◽

Chandra Shekar Bonagiri ◽

Sridhar Babu Gummadi

Keyword(s):

Oral Bioavailability ◽

Oral Delivery ◽

Solid Dispersions ◽

In Vitro Release ◽

Aqueous Solubility ◽

Water Soluble ◽

Scanning Calorimetry ◽

In Vivo Evaluation

Fenofibrate (FN) is used in the treatment of hypercholesterolemia. It shows poor dissolution and poor oral bioavailability after oral administration due to high liphophilicity and low aqueous solubility. Hence, solid dispersions (SDs) of FN (FN-SDs) were develop that might enhance the dissolution and subsequently oral bioavailability. FN-SDs were prepared by solvent casting method using different carriers (PEG 4000, PEG 6000, β cyclodextrin and HP β cyclodextrin) in different proportions (0.25%, 0.5%, 0.75% and 1% w/v). FN-SDs were evaluated solubility, assay and in vitro release studies for the optimization of SD formulation. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis was performed for crystalline and morphology analysis, respectively. Further, optimized FN-SD formulation evaluated for pharmacokinetic performance in Wistar rats, in vivo in comparison with FN suspension. From the results, FN-SD3 and FN-SD6 have showed 102.9 ±1.3% and 105.5±3.1% drug release, respectively in 2 h. DSC and PXRD studies revealed that conversion of crystalline to amorphous nature of FN from FT-SD formulation. SEM studies revealed the change in the orientation of FN when incorporated in SDs. The oral bioavailability FN-SD3 and FN-SD6 formulations exhibited 2.5-folds and 3.1-folds improvement when compared to FN suspension as control. Overall, SD of FN could be considered as an alternative dosage form for the enhancement of oral delivery of poorly water-soluble FN.

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Chemosensitizing Activity of Histone Deacetylases Inhibitory Cyclic Hydroxamic Acids for Combination Chemotherapy of Lymphatic Leukemia

Current Cancer Drug Targets ◽

10.2174/1568009617666170623104030 ◽

2018 ◽

Vol 18 (4) ◽

pp. 365-371 ◽

Cited By ~ 2

Author(s):

Denis V. Mishchenko ◽

Margarita E. Neganova ◽

Elena N. Klimanova ◽

Tatyana E. Sashenkova ◽

Sergey G. Klochkov ◽

...

Keyword(s):

Lipid Peroxidation ◽

Acute Toxicity ◽

Histone Deacetylases ◽

Hydroxamic Acids ◽

Water Soluble ◽

Male Rat ◽

Hybrid Male ◽

Cyclic Hydroxamic Acids

Background: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. Objective: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. Method: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. Results: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. Conclusion: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.

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