Publications by authors named "Sanjay Tiwari"

69 Publications

Further SAR studies on natural template based neuroprotective molecules for the treatment of Alzheimer's disease.

Bioorg Med Chem 2021 Aug 28;46:116385. Epub 2021 Aug 28.

Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India. Electronic address:

In our earlier paper, we described ferulic acid (FA) template based novel series of multifunctional cholinesterase (ChE) inhibitors for the management of AD. This report has further extended the structure-activity relationship (SAR) studies of this series of molecules in a calibrated manner to improve upon the ChEs inhibition and antioxidant property to identify the novel potent multifunctional molecules. To investigate the effect of replacement of phenylpiperazine ring with benzylpiperazine, increase in the linker length between FA and substituted phenyl ring, and replacement of indole moiety with tryptamine on this molecular template, three series of novel molecules were developed. All synthesized compounds were tested for their acetyl and butyryl cholinestrases (AChE and BChE) inhibitory properties. Enzyme inhibition and PAS binding studies identified compound 13b as a lead molecule with potent inhibitor property towards AChE/BChE (AChE IC = 0.96 ± 0.14 µM, BChE IC = 1.23 ± 0.23 µM) compared to earlier identified lead molecule EJMC-G (AChE IC = 5.74 ± 0.13 μM, BChE IC = 14.05 ± 0.10 μM, respectively). Molecular docking and dynamics studies revealed that 13b fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Trp86, Ser125, Glu202, Trp 286, Phe295, Tyr 337 in AChE, and with Trp 82, Gly115, Tyr128, and Ser287 in BChE. The compound, 13b was found to be three times more potent antioxidant in a DPPH assay (IC = 20.25 ± 0.26 µM) over the earlier identified EJMC-B (IC = 61.98 ± 0.30 µM) and it also was able to chelate iron. Co-treatment of 13b with HO, significantly attenuated and reversed HO-induced toxicity in the SH-SY5Y cells. The parallel artificial membrane permeability assay-blood brain barrier (PAMPA-BBB) revealed that 13b could cross BBB efficiently. Finally, the in-vivo efficacy of 13b at dose of 10 mg/kg in scopolamine AD model has been demonstrated. The present study strongly suggests that the naturally inspired multifunctional molecule 13b may behave as a potential novel therapeutic agent for AD management.
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http://dx.doi.org/10.1016/j.bmc.2021.116385DOI Listing
August 2021

Therapeutic potential of nanoemulsions as feasible wagons for targeting Alzheimer's disease.

Drug Discov Today 2021 Jul 29. Epub 2021 Jul 29.

Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India. Electronic address:

Alzheimer's disease (AD) is an irreversible dementia state with characteristic clinical manifestations, including declining cognitive skills and loss of memory, which particularly affects the older population. Despite significant efforts in the field of nano-based drug delivery, there have been few successes achieved in the design of a rational drug therapy. Nanoemulsions (NEs) have potential for the delivery of AD therapeutics owing to their capability for brain drug delivery. Still, there is a long way to go before such therapeutics become a reality in the clinic. In this review, we highlight the preclinical assessment of NEs for AD and discuss the regulatory constraints to their clinical acceptance.
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http://dx.doi.org/10.1016/j.drudis.2021.07.020DOI Listing
July 2021

Recent advances in nanoparticles mediated photothermal therapy induced tumor regression.

Int J Pharm 2021 Sep 30;606:120848. Epub 2021 Jun 30.

Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India. Electronic address:

Photothermal therapy (PTT) is a minimally invasive procedure for treating cancer. The two significant prerequisites of PTT are the photothermal therapeutic agent (PTA) and near-infrared radiation (NIR). The PTA absorbs NIR, causing hyperthermia in the malignant cells. This increased temperature at the tumor microenvironment finally results in tumor cell damage. Nanoparticles play a crucial role in PTT, aiding in the passive and active targeting of the PTA to the tumor microenvironment. Through enhanced permeation and retention effect and surface-engineering, specific targeting could be achieved. This novel delivery tool provides the advantages of changing the shape, size, and surface attributes of the carriers containing PTAs, which might facilitate tumor regression significantly. Further, inclusion of surface engineering of nanoparticles is facilitated through ligating ligands specific to overexpressed receptors on the cancer cell surface. Thus, transforming nanoparticles grants the ability to combine different treatment strategies with PTT to enhance cancer treatment. This review emphasizes properties of PTAs, conjugated biomolecules of PTAs, and the combinatorial techniques for a better therapeutic effect of PTT using the nanoparticle platform.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120848DOI Listing
September 2021

Starvation Survival and Biofilm Formation under Subminimum Inhibitory Concentration of QAMs.

Biomed Res Int 2021 14;2021:8461245. Epub 2021 Jan 14.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cariology and Endodontics & Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.

Quaternary ammonium methacrylates (QAMs) are useful antimicrobial compounds against oral bacteria. Here, we investigated the effects of two QAMs, dimethylaminododecyl methacrylate (DMADDM) and dimethylaminohexadecyl methacrylate (DMAHDM), on biofilm formation, survival and development of tolerance by biofilm, and survival and development of tolerance against QAMs after prolonged starvation. (. ), (. ), (. ), and (. ) were used. Minimum inhibitory concentration (MIC) of QAMs against multispecies biofilm was determined. Biofilm formed under sub-MIC was observed by crystal violet staining and confocal laser scanning microscopy (CLSM). Metabolic activity was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactic acid production measurement. Development of tolerance was determined by MIC values before and after exposure to QAMs or after prolonged starvation. It was found that . and . could survive and form biofilm under sub-MIC of QAMs. Lactic acid production from biofilms formed under sub-MIC was significantly higher than control specimens ( < 0.05). The exposure to sub-MIC of QAMs promoted biofilm formation, and prolonged starvation or prolonged contact with sub-MIC helped bacteria develop tolerance against killing by QAMs.
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http://dx.doi.org/10.1155/2021/8461245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822668PMC
June 2021

Adsorption of P103 Nanoaggregates on Graphene Oxide Nanosheets: Role of Electrostatic Forces in Improving Nanosheet Dispersion.

Langmuir 2021 01 5;37(2):867-873. Epub 2021 Jan 5.

Maliba Pharmacy College, UKA Tarsadia University, Gopal-Vidyanagar Campus, Surat 394350, India.

Graphene oxide (GO) nanosheet suspension is not stable in physiological ionic fluids. To improve stability, surfactants such as Pluronic 103 (P103) have been tested. Going further, this work investigated whether conferring positive surface charge to the surfactant may improve the adsorption ability of P103 micelles on GO sheets. Positive charge on the surfactant was induced by adding dodecyltrimethylammonium bromide (DTAB, a cationic surfactant) in P103 micelles. Subsequent changes in aggregation parameters were investigated through dynamic light scattering and small-angle neutron scattering studies. DTAB incorporation was accompanied by a steady increase in the ζ potential and mixed micelle formation. At high surface charge density, the interaction between adjacent head groups was distorted, which led to dissociation of mixed micelles. Structural developments during the adsorption of mixed micelles on the sheet surface (mass fractal formation) were monitored in terms of changes in the scattering features of aggregates. These fractals emerged as a result of electrostatic interactions. Our observations point toward the existence of small-sized building blocks at low DTAB concentration (≤4 mM). With a superior adsorption, mixed micelles are expected to occupy the intersheet space and maintain a hydration layer. However, at a higher DTAB concentration (≥10 mM), micelles dissociate to produce DTAB-rich unimers and P103-rich loose aggregates. At this point, sheets tend to aggregate in the solvent, regardless of fractal formation.
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http://dx.doi.org/10.1021/acs.langmuir.0c03206DOI Listing
January 2021

Self-Association in EO-BO-EO Triblock Copolymers as a Nanocarrier Template for Sustainable Release of Anticancer Drugs.

J Phys Chem B 2020 12 11;124(51):11750-11761. Epub 2020 Dec 11.

Department of Chemistry, Veer Narmad South Gujarat University (VNSGU), Udhana-Magdalla Road, Surat 395 007, Gujarat, India.

Ethylene oxide (EO)-butylene oxide (BO)-ethylene oxide (EO)-based triblock copolymers with varying hydrophilic-hydrophobic ratios in arrangement, generally referred to as EBE, were scrutinized in an aqueous environment. Various self-associative (micellization) physicochemical properties of these EBEs were examined at different temperatures unified with a quantum chemical study. The salting-out effect on 5%w/v EBE was examined by observing their aqueous solution behavior where the clear transparent solution/turbidity suggested the probable presence of spherical or ellipsoidal micelles, which was confirmed from the scattering outline. The hydrodynamic radius () of the formed micellar geometry as a function of temperature and electrolyte (2 M NaCl) was inspected from dynamic light scattering and further supported by small-angle neutron scattering, where the -range prototype and scattering parameters were evaluated by the best fitting of the structure factor. Furthermore, these micelles were employed as potential nanocarriers for anticancer (curcumin and quercetin) drugs, where its release profile at a particular time interval was estimated using UV-vis spectroscopy. Different kinetic models were employed to fit the release profile data that enabled this study to act as an ideal platform for drug delivery. Also, the plausible interactions between EO-BO-EO blocks and the anticancer drugs were inferred from the evaluated computational descriptors.
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http://dx.doi.org/10.1021/acs.jpcb.0c09386DOI Listing
December 2020

Nanocarriers based on vitamin E-TPGS: Design principle and molecular insights into improving the efficacy of anticancer drugs.

Int J Pharm 2021 Jan 16;592:120045. Epub 2020 Nov 16.

Maliba Pharmacy College, UKA Tarsadia University, Gopal-Vidyanagar Campus, Surat 394350, Gujarat, India. Electronic address:

α-Tocopheryl polyethylene glycol succinate (vitamin E-TPGS or TPGS) is a nonionic amphiphile synthesized by the esterification of vitamin E succinate. It has been categorized as a safe excipient by US-FDA and EMA. Like other polyethylene glycol (PEG) condensates, TPGS spontaneously forms kinetically stable core-shell micelles (diameter 12-15 nm) and exhibits interesting properties as solubilizing agent, emulsifier, dispersant and gelling agent. Its aggregation behavior can be tuned in association with other amphiphiles and organic additives. These properties have been exploited for developing a variety of vesicular, semisolid and multi-particulate drug formulations. It improves the bioavailability of drugs through permeation enhancement and down-regulation of P-glycoproteins. Multimodal therapeutic platforms have been explored following its chemical modification with recognizable and stimuli-responsive groups. Research in the past two decades has revealed its specific role in mediating the re-sensitization of multi-drug resistant cancer cells. This review describes the physicochemical and biological properties of TPGS relevant to drug delivery applications. We have emphasized on the role of TPGS in improving the bioavailability and targetability of anticancer drugs.
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http://dx.doi.org/10.1016/j.ijpharm.2020.120045DOI Listing
January 2021

Synthesis, Colloidal Characterization and Targetability of Phenylboronic Acid Functionalized α-Tocopheryl Polyethylene Glycol Succinate in Cancer Cells.

Polymers (Basel) 2020 Oct 1;12(10). Epub 2020 Oct 1.

Department of Chemistry, Veer Narmad South Gujarat University, Surat 395007, India.

This study reports targetable micelles developed after covalent functionalization of α-tocopheryl polyethylene glycol succinate (TPGS) with amino phenylboronic acid (APBA). Nuclear magnetic resonance (NMR) and infrared (IR) spectroscopic results showed successful attachment of APBA to the hydrophilic segment of TPGS. Dynamic light scattering and small-angle neutron scattering studies revealed that the conjugate self-assembled in water to produce spherical core-shell micelles (14-20 nm) which remained stable against temperature (ca. 25-45 °C) and pH changes. The micelles could solubilize a high payload of paclitaxel (PLX) without exhibiting changes in the average size. However, at the saturation solubility, drug molecules migrated from the core to the shell region and engaged with APBA groups via π-π stacking interaction. Confocal microscopy and cell sorting analyses verified the effective translocation ability of TPGS-APBA micelles in sialic acid (SA) expressing MDA-MB-453 cells. At equivalent PLX dose, TPGS-APBA micelles showed about a twofold improvement in apoptotic death among the cells exposed for 2 h. Our findings indicate that the attachment of APBA can be a potential strategy for improving the intra-cellular localization of carriers among cancer cells expressing SA residues.
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http://dx.doi.org/10.3390/polym12102258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600591PMC
October 2020

Recent advances in targeted nanomedicine as promising antitumor therapeutics.

Drug Discov Today 2020 12 1;25(12):2227-2244. Epub 2020 Oct 1.

Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan, 333031, India. Electronic address:

A tumor serves as a major avenue in drug development owing to its complexity. Conventional therapies against tumors possess limitations such as suboptimal therapeutic efficacy and extreme side effects. These display poor pharmacokinetics and lack specific targeting, with non-specific distribution resulting in systemic toxicity. Therefore, nanocarriers targeted against cancers are increasingly being explored. Nanomedicine aids in maintaining a balance between efficacy and toxicity by specifically accumulating in tumors. Nanotherapeutics possess advantages such as increased solubility of chemotherapeutics, encapsulation of multiple drugs and improved biodistribution, and can ensure tumor-directed drug delivery and release via the approaches of passive targeting and active targeting. This review aims to offer a general overview of the current advances in tumor-targeting nanocarriers for clinical and diagnostic use.
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http://dx.doi.org/10.1016/j.drudis.2020.09.031DOI Listing
December 2020

Influence of surface oxygen clusters upon molecular stacking of paclitaxel over graphene oxide sheets.

Mater Sci Eng C Mater Biol Appl 2020 Nov 23;116:111232. Epub 2020 Jun 23.

UKA Tarsadia University, Maliba Pharmacy College, Gopal-Vidyanagar Campus, Surat 394350, India. Electronic address:

Aqueous dispersibility of graphene oxide (GO) sheets can be improved through enrichment of oxygen content (oxidation). However, the resulting 'oxygen clusters' are accompanied with numerous point defects, depletive to π-π stacking behavior of sheets. In this work, we have investigated the properties of sheets oxidized with 2, 4, 6, 8, 10 and 12 weight equivalents of KMnO. Sheets were characterized by spectroscopic, X-ray diffraction (XRD) and electron microscopic techniques. Paclitaxel (PLX) was used as a model drug to analyze the changes in the loading efficiency at different levels of oxidation. Density of oxygen clusters increased as we shifted across increasing proportion of KMnO. This was accompanied with increased inter-layer spacing, disruption of pure graphitic domains and changes in hybridization of carbon atoms (sp to sp). However, these defects exhibited the tendency of saturation at a finite proportion of KMnO. Oxygen groups negatively affected the loading efficiency of sheets for PLX. Improvement in the loading efficiency of reduced GO (rGO) sheets clarified the predominant role of π-π interactions at the surface. Our study reveals that high oxidation may offset the loading potential of highly aqueous dispersible GO sheets. Therefore, the extent of oxidation must be tuned taking into account the availability of H-bond forming groups in the drug molecule.
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http://dx.doi.org/10.1016/j.msec.2020.111232DOI Listing
November 2020

Targeting anticancer drugs with pluronic aggregates: Recent updates.

Int J Pharm 2020 Aug 16;586:119544. Epub 2020 Jun 16.

Chemistry Department, Veer Narmad South Gujarat University, Surat 395007, Gujarat, India. Electronic address:

Pluronics are triblock (PEO-b-PPO-b-PEO) copolymers, commercially available in a range of amphiphilicity. Usually, pluronics self-assemble in aqueous solution to form core-shell micelles, but their aggregation behavior is remarkably influenced by the molecular characteristics, solution temperature, and presence of additives. Accompanying transitions result into formation of rigid structures, such as liquid crystals and viscoelastic gels. Certain pluronics have been approved by United States Food and Drug Administration (US-FDA) and European Medicines Agency (EMA) for usage as injectable pharmaceutical excipients. While these carriers have been explored in drug delivery since long, advancements in polymer synthesis have now shifted the focus toward pluronic-based targeted and stimulti-responsive nanomedicines. Majority of these attempts lean over chemical modification of the hydrophilic block in order to enable distinctive identification and elimination of cancerous cells. This review presents the physicochemical and design aspects of pluronic micelles relevant from the standpoint of targeted drug delivery to cancer cells. Using up-to-date literature reports, we have discussed how therapeutic outcomes can be amplified by facilitating the translocation of carriers from tumor interstitium to specific cytosolic targets.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119544DOI Listing
August 2020

Graphene nanosheets as reinforcement and cell-instructive material in soft tissue scaffolds.

Adv Colloid Interface Sci 2020 Jul 23;281:102167. Epub 2020 Apr 23.

Chemistry Department, Veer Narmad South Gujarat University, Surat, Gujarat 395007, India.

Mechanical strength of polymeric scaffolds deteriorates quickly in the physiological mileu. This can be minimized by reinforcing the polymeric matrix with graphene, a planar two-dimensional material with unique physicochemical and biological properties. Association between the sheet and polymer chains offers a range of porosity commensurate with tissue requirements. Besides, studies suggest that corrugated structure of graphene offers desirable bio-mechanical cues for tissue regeneration. This review covers three important aspects of graphene-polymer composites, (a) the opportunity on reinforcing the polymer matrix with graphene, (b) challenges associated with limited aqueous processability of graphene, and (c) physiological signaling in the presence of graphene. Among numerous graphene materials, our discussion is limited to graphene oxide (GO) and reduced graphene oxide (rGO) nanosheets. Challenges associated with limited dispersity of hydrophobic sheets within the polymeric matrix have been discussed at molecular level.
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http://dx.doi.org/10.1016/j.cis.2020.102167DOI Listing
July 2020

Colloidal stability of graphene oxide nanosheets in association with triblock copolymers: A neutron scattering analysis.

Mater Sci Eng C Mater Biol Appl 2020 Apr 16;109:110559. Epub 2019 Dec 16.

Uka Tarsadia University, Maliba Pharmacy College, Gopal-Vidyanagar Campus, Surat 394350, India. Electronic address:

This study investigates stabilization of graphene oxide (GO) nanosheets in polyethylene oxide-polypropylene oxide (PEO-PPO) block copolymers (P103, P123 and F127). Changes in micellization of copolymers upon GO addition were monitored using dynamic light (DLS) and small angle neutron scattering (SANS). Structural developments at sheet surface were studied with two possibilities; (i) adsorption of PPO block over hydrophobic basal plane allowing the engagement of hydrophilic PEO with aqueous bulk, and (ii) adsorption of micelles mediated via carboxylated groups. Insignificant changes in micellar parameters for P123 and P127 were indicative of their inferior interaction with GO. On the other hand, P103 micelles exhibited high affinity for sheets, noticeable as emergence of mass fractals and more than two-fold enhancement in micelle number density. The latter allowed coverage of entire surface with P103 micelles. Existence of mass fractals was verified by extracting the form and structure factors from the fitted SANS data. Spectroscopic and thermogravimetric analyses illustrated non-covalent adsorption of copolymer aggregates. It was interesting to note that the dispersion remained stable against protein and electrolyte addition. A comprehensive understanding on colloidal stability can be valuable for drug delivery applications of GO sheets.
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http://dx.doi.org/10.1016/j.msec.2019.110559DOI Listing
April 2020

Dasatinib prevents skeletal metastasis of osteotropic MDA-MB-231 cells in a xenograft mouse model.

Arch Gynecol Obstet 2020 06 14;301(6):1493-1502. Epub 2020 Mar 14.

Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Arnold-Heller-Straße 3, 24105, Kiel, Germany.

Purpose: Bone metastasis in breast cancer has been linked to activity of c-Src kinase, one of the extensively explored tyrosine kinases in cell biology. The impact of TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptors has just recently been integrated into this conception.

Methods: An osteotropic clone of MDA-MB-231 cells simulated a model for bone metastasis of triple-negative breast cancer (TNBC). The effects of Dasatinib, a clinically established inhibitor of Src kinases family and Abl were evaluated in vitro and in vivo. In vivo effects of Dasatinib treatment on the occurrence of skeletal metastases were tested in a xenograft mouse model after intra-cardiac injection of osteotropic MDA-MB-231-cells. Ex vivo analyses of the bone sections confirmed intraosseous growth of metastases and allowed determination of osteoclastic activity.

Results: Treatment of osteotropic MDA-MB-231 cells with Dasatinib inhibited proliferation rates in vitro. A shift in TRAIL-receptor expression towards an induction of oncogenic TRAIL-R2 was observed. In vivo, 15 of 30 mice received an intra-peritoneal treatment with Dasatinib. These mice showed significantly less skeletal metastases in bioluminescence scans. Moreover, a pronounced increase in bone volume was observed in the treatment group, as detected by µ-Computed Tomography. Dasatinib treatment also led to a greater increase in bone density in tibiae without metastatic affection, which was accompanied by reduced recruitment of osteoclasts.

Conclusion: Our observations support the concept of utilizing Dasatinib in targeting early-stage bone metastatic TNBC and sustaining bone health.
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http://dx.doi.org/10.1007/s00404-020-05496-4DOI Listing
June 2020

Effect of cosurfactant addition on phase behavior and microstructure of a water dilutable microemulsion.

Colloids Surf B Biointerfaces 2020 Feb 17;186:110736. Epub 2019 Dec 17.

Uka Tarsadia University, Maliba Pharmacy College, Gopal-Vidyanagar Campus, Surat, 394350, India. Electronic address:

This study reports a detailed characterization of a nonionic microemulsion (μE) composed of n-butylacetate/α-tocopheryl polyethylene glycol succinate (TPGS)/alcohol/water. Two approaches of expanding the monophasic area were explored; (i) addition of Pluronic® 123 (P123) in aqueous phase, and (ii) use of short chain alcohol (CHOH; n = 2-4) as cosurfactant. Pseudo-ternary phase diagrams were constructed using water titration method. Characterizations were performed using dynamic light scattering (DLS), differential scanning calorimetry (DSC), small angle neutron scattering (SANS) and electron microscopic techniques. DSC and SANS results showed gradual structural transformation from water-in-oil to oil-in-water system. The optimized formulation (oil/S/water - 19/40/41) showed average hydrodynamic diameter of 22 nm, consistent with electron microscopic observations. Ethanol (EtOH), with its high fluidity and smaller headgroup area, offered maximum expansion in the phase boundary. Surfactant unimers, derived from EtOH-driven de-micellization, reinforced the interface and solubilized the incoming oil molecules. Oil incorporation was accompanied with improved loading of carbamazepine, a hydrophobic drug. Except marginal swelling, no significant microstructural changes were noticed during water dilution (≈90%) and salt addition (0.9% NaCl) in the optimized μE formulation. A linear increase in oil incorporation was noticed upon adding propylene glycol as a cosolvent.
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http://dx.doi.org/10.1016/j.colsurfb.2019.110736DOI Listing
February 2020

Dispersed graphene materials of biomedical interest and their toxicological consequences.

Adv Colloid Interface Sci 2020 Jan 21;275:102051. Epub 2019 Oct 21.

Maliba Pharmacy College, UKA Tarsadia University, Gopal-Vidyanagar Campus, Surat 394350, Gujarat, India. Electronic address:

Graphene is one-atom thick nanocarbon displaying a unique honeycomb structure and extensive conjugation. In addition to high surface area to mass ratio, it displays unique optical, thermal, electronic and mechanical properties. Atomic scale tunability of graphene has attracted immense research interest with a prospective utility in electronics, desalination, energy sectors, and beyond. Its intrinsic opto-thermal properties are appealing from the standpoint of multimodal drug delivery, imaging and biosensing applications. Hydrophobic basal plane of sheets can be efficiently loaded with aromatic molecules via non-specific forces. With intense biomedical interest, methods are evolving to produce defect-free and dispersion stable sheets. This review summarizes advancements in synthetic approaches and strategies of stabilizing graphene derivatives in aqueous medium. We have described the interaction of colloidal graphene with cellular and sub-cellular components, and subsequent physiological signaling. Finally, a systematic discussion is provided covering toxicological challenges and possible solutions on utilizing graphene formulations for high-end biomedical applications.
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http://dx.doi.org/10.1016/j.cis.2019.102051DOI Listing
January 2020

Understanding the Pharmaceutical Aspects of Dendrimers for the Delivery of Anticancer Drugs.

Curr Drug Targets 2020 ;21(6):528-540

Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER GUWAHATI), Ministry of Chemicals & Fertilizers, Govt. of India, NH 37, NITS Mirza, Kamrup- 781125, Guwahati (Assam), India.

Dendrimers are emerging class of nanoparticles used in targeted drug delivery systems. These are radially symmetric molecules with well-defined, homogeneous, and monodisperse structures. Due to the nano size, they can easily cross the biological membrane and increase bioavailability. The surface functionalization facilitates targeting of the particular site of action, assists the high drug loading and improves the therapeutic efficiency of the drug. These properties make dendrimers advantageous over conventional drug delivery systems. This article explains the features of dendrimers along with their method of synthesis, such as divergent growth method, convergent growth method, double exponential and mixed method, hyper-core and branched method. Dendrimers are effectively used in anticancer delivery and can be targeted at the site of tumor either by active or passive targeting. There are three mechanisms by which drugs interact with dendrimers, and they are physical encapsulation, electrostatic interaction, chemical conjugation of drug molecules. Drug releases from dendrimer either by in vivo cleavage of the covalent bond between drugdendrimer complexes or by physical changes or stimulus like pH, temperature, etc.
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http://dx.doi.org/10.2174/1389450120666191031092259DOI Listing
February 2021

Slow degrading hyaluronic acid hydrogel reinforced with cationized graphene nanosheets.

Int J Biol Macromol 2019 Dec 30;141:232-239. Epub 2019 Aug 30.

Uka Tarsadia University, Maliba Pharmacy College, Gopal-Vidyanagar Campus, Surat 394350, India. Electronic address:

Graphene possesses a large surface area and offers high loading capacity for aromatic compounds. However, the load is quickly released in the absence of rate limiting diffusion barrier. In this study, we have explored the electrostatic interaction between polyanionic hyaluronic acid (HA) and cationized reduced graphene oxide (rGO) as a means to develop a reinforced hydrogel matrix. We tested if; (i) degradation kinetics of HA matrix can be modulated in the presence of cationized nanosheets, and (ii) reinforced hydrogel can offer controlled release of paclitaxel (PLX) stacked over the sheets. Successful synthesis, cationization and drug loading on graphene sheets were demonstrated using Raman and FT-IR spectroscopy. Reinforcement was confirmed through electron microscopy, neutron scattering and texture profile analyses. While incorporation of sheets enhanced the resistance of HA hydrogel against enzymatic digestion, a significant improvement in the biocompatibility of cationized rGO was obtained through this association. Reinforced gel offered sustained release of PLX up to 104 h which can further be extended by tuning its architecture.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.08.243DOI Listing
December 2019

Solubilization of Carbamazepine in TPGS Micelles: Effect of Temperature and Electrolyte Addition.

AAPS PharmSciTech 2019 May 28;20(5):203. Epub 2019 May 28.

Maliba Pharmacy College, UKA Tarsadia University, Gopal-Vidyanagar Campus, Surat, Gujarat, 394350, India.

D-α-Tocopheryl polyethylene glycol succinate (TPGS), a polyethylene glycol condensate, is a biologically important nonionic amphiphile. In this study, we report on aqueous solution behavior of TPGS with a focus on its clouding, surface activity, micellar characteristics, and solubilization capacity for a model hydrophobic drug, carbamazepine (CBZ). Micelles were characterized by dynamic light and small-angle neutron scattering studies as a function of temperature, salt addition, and CBZ solubilization. TPGS showed a cloud point of 78°C and possessed good surface activity (as observed from surface tension reduction and adsorption parameters). The critical micelle concentration (CMC), obtained from surface tension and fluorescence studies, was 0.02 mM. Scattering studies showed formation of stable micelles (average diameter-12 nm), exhibiting no significant changes in size upon salt addition (up to 1 M NaCl), CBZ incorporation (up to 5 mM), and temperature increase (40°C). Micelles in 5 wt% TPGS showed about twentyfold enhancement in CBZ solubility. Considering the remarkable CBZ solubilization and its positioning in the core, we suggest that the formulation can be exploited as a sustained delivery vehicle.
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http://dx.doi.org/10.1208/s12249-019-1412-1DOI Listing
May 2019

Derivatization approaches and applications of pullulan.

Adv Colloid Interface Sci 2019 Jul 5;269:296-308. Epub 2019 May 5.

Chemistry Department, Veer Narmad South Gujarat University, Surat 395007, Gujarat, India.

Pullulan (PUL), a linear exo-polysaccharide, is useful in industries as diverse as food, cosmetics and pharmaceuticals. PUL presents many favorable characteristics, such as renewable origin, biocompatibility, stability, hydrophilic nature, and availability of reactive sites for chemical modification. With an inherent affinity to asialoglycoprotein receptors, PUL can be used for targeted drug delivery to the liver. Besides, these primary properties have been combined with modern synthetic approaches for developing multifunctional biomaterials. This is evident from numerous studies on approaches, such as hydrophobic modification, cross-linking, grafting and transformation as a polyelectrolyte. In this review, we have discussed up-to-date advances on chemical modifications and emerging applications of PUL in targeted theranostics and tissue engineering. Besides, we offer an overview of its applications in food, cosmetics and environment remediation.
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http://dx.doi.org/10.1016/j.cis.2019.04.014DOI Listing
July 2019

Polysaccharide Based Scaffolds for Soft Tissue Engineering Applications.

Polymers (Basel) 2018 Dec 20;11(1). Epub 2018 Dec 20.

Chemistry Department, Veer Narmad South Gujarat University, Surat 395007, Gujarat, India.

Soft tissue reconstructs require materials that form three-dimensional (3-D) structures supportive to cell proliferation and regenerative processes. Polysaccharides, due to their hydrophilicity, biocompatibility, biodegradability, abundance, and presence of derivatizable functional groups, are distinctive scaffold materials. Superior mechanical properties, physiological signaling, and tunable tissue response have been achieved through chemical modification of polysaccharides. Moreover, an appropriate formulation strategy enables spatial placement of the scaffold to a targeted site. With the advent of newer technologies, these preparations can be tailor-made for responding to alterations in temperature, pH, or other physiological stimuli. In this review, we discuss the developmental and biological aspects of scaffolds prepared from four polysaccharides, viz. alginic acid (ALG), chitosan (CHI), hyaluronic acid (HA), and dextran (DEX). Clinical studies on these scaffolds are also discussed.
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http://dx.doi.org/10.3390/polym11010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401776PMC
December 2018

Molecular interaction between bi-antennary phenylboronic acid and sialic acid using density functional theory and multi-time scale trajectories.

J Biomol Struct Dyn 2020 03 2;38(4):1242-1247. Epub 2019 Apr 2.

Department of Physics, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.

Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1596839DOI Listing
March 2020

Paclitaxel Encapsulation into Dual-Functionalized Multi-Walled Carbon Nanotubes.

AAPS PharmSciTech 2019 Jan 7;20(2):51. Epub 2019 Jan 7.

Maliba Pharmacy College, Uka Tarsadia University, Gopal-Vidyanagar Campus, Surat, 394350, India.

This work reports the synthesis of multi-walled carbon nanotubes (CNTs) from xylene/ferrocene using catalytic chemical vapor deposition technique. Following characterization using transmission electron microscopy (TEM), energy-dispersive X-ray (EDX), and Raman spectroscopy, CNT surface was dual-functionalized using ethylenediamine and phenylboronic acid groups. Average diameter of CNTs was calculated to be 16.5 nm. EDX spectra confirmed the existence of carbonaceous deposits on the tube's surface. Scattered electron diffraction and X-ray peak broadening calculations showed consistent inter-planer distance of the grown CNTs. Chemical functionalization, confirmed from FT-IR and Raman spectra, showed an enhanced dispersibility of CNTs in water. We describe the changes in the first- and second-order regions of the Raman spectra following the encapsulation of an anti-cancer drug, paclitaxel (PLX), into the free volume of functionalized CNTs. High PLX loading, achieved through its non-covalent π-π stacking within the CNT interior, is confirmed through the blue-shifted, softened G band in the Raman spectrum. While not addressed here, we will exploit this dual functionalization tactic to elaborate the relative role of attached moieties in the affinity interaction of CNTs with extra-cellular sialic acid, a biological target showing metastatic stage-dependent over-expression in colon cancer cells.
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http://dx.doi.org/10.1208/s12249-018-1218-6DOI Listing
January 2019

Functionalized graphene nanosheets with improved dispersion stability and superior paclitaxel loading capacity.

Colloids Surf B Biointerfaces 2019 Jan 9;173:421-428. Epub 2018 Oct 9.

Uka Tarsadia University, Maliba Pharmacy College, Gopal-Vidyanagar Campus, Surat, 394350, India. Electronic address:

This study reports our attempt of improving dispersibility of reduced graphene oxide (rGO) through differential functionalization of carboxyl moieties with ethylene diamine (EDA) and folic acid (FA) using carbodimide chemistry. Successful covalent linkage was demonstrated through FT-IR, Raman and energy dispersive X-ray spectroscopy. Functionalized nanosheets (GNs) produced a stable dispersion up to 0.1 wt% which remained unaffected against salt- and protein-induced aggregation. Hemolysis test showed negligible toxicity of GNs in murine erythrocytes up to 100 μg/ml. Non-covalent hydrophobic and п-п stacking interactions between GNs and paclitaxel (PLX) offered a superior loading (95.07%) capacity. The latter could substantially minimize the incidence of disruptive protein-carrier interactions and thus, inflate the biomedical potential of graphene materials. Besides, the attached FA groups can be exploited for target-selective delivery of PLX to folate receptor over-expressing tumor cells.
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http://dx.doi.org/10.1016/j.colsurfb.2018.10.016DOI Listing
January 2019

Modified hyaluronic acid based materials for biomedical applications.

Int J Biol Macromol 2019 Jan 12;121:556-571. Epub 2018 Oct 12.

Chemistry Department, Veer Narmad South Gujarat University, Surat 395007, Gujarat, India.

Hyaluronic acid (HA) is a high molecular weight, non-sulfated anionic polysaccharide from glycosamine glycan family. It is a versatile biomaterial that binds to specific cell receptor CD44 (frequently over-expressed on the tumor cell surface) and is useful in skin rejuvenation, drug delivery, tissue engineering and molecular imaging due to its biodegradable, non-toxic, biocompatible, non-immunogenic and non-inflammatory characteristics. It can be chemically modified by cross-linking, grafting, linking with hydrophobic substances and drugs, or through polyion complex formation with oppositely charged polysaccharides, proteins or surfactants. Its interpenetrating network produces self-assembled aggregates, nanoparticles and gels. The present review is aimed to provide recent updates on researches on HA, with an emphasis on different modification approaches. Various transformations in HA through covalent and non-covalent interactions and resulting applications in biomedical fields from the recent literature are described. Studies on stabilization of nanoparticles (NPs) and other colloidal carriers through layer-by-layer adsorption of HA are also highlighted. The article provides a greater visibility into the magnitude of HA application in the development of targeted drug vectors and implantable biomaterials.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.10.049DOI Listing
January 2019

Liver metastasis of pancreatic cancer: the hepatic microenvironment impacts differentiation and self-renewal capacity of pancreatic ductal epithelial cells.

Oncotarget 2018 Aug 3;9(60):31771-31786. Epub 2018 Aug 3.

Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel (CAU) and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at advanced stages with the liver as the main site of metastases. The hepatic microenvironment has been shown to determine outgrowth of liver metastases. Cancer stem cells (CSCs) are essential for initiation and maintenance of tumors and acquisition of CSC-properties has been linked to Epithelial-Mesenchymal-Transition. Thus, this study aimed at elucidating whether and how the hepatic microenvironment impacts stemness and differentiation of disseminated pancreatic ductal epithelial cells (PDECs). Culture of premalignant H6c7-kras and malignant Panc1 PDECs together with hepatocytes and hepatic stellate cells (HSC) promoted self-renewal capacity of both PDEC lines. This was indicated by higher colony formation compared to cells cocultured with hepatocytes and hepatic myofibroblasts. Different Panc1 colony types derived from an HSC-enriched coculture were expanded and characterized revealing that holoclones exhibited an enhanced colony formation ability, elevated and exclusive expression of the CSC-marker Nestin and a more pronounced mesenchymal phenotype compared to paraclones. Moreover, Panc1 holoclone cells showed an increased tumorigenic potential leading to formation of undifferentiated tumors in 7/10 animals, while inoculation of paraclone cells only led to formation of tumors in 2/10 animals being smaller in number and size. Holoclone tumors were characterized by elevated expression of mesenchymal markers, complete loss of E-cadherin expression and high expression of Nestin. Finally, Etanercept-mediated TNF-α blocking partly reversed the mesenchymal CSC-phenotype of Panc1 holoclone cells. Overall, these data provide evidence that the hepatic microenvironment determines stemness and differentiation of PDECs, thereby substantially contributing to liver metastases of PDAC.
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http://dx.doi.org/10.18632/oncotarget.25884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114965PMC
August 2018

Bioadhesive polymeric film-based integrative platform for the unidirectional carbamazepine release from a volatile microemulsion.

Colloids Surf B Biointerfaces 2018 Oct 5;170:683-691. Epub 2018 Jul 5.

UKA Tarsadia University, Maliba Pharmacy College, Gopal-Vidyanagar Campus, Surat, 394350, Gujarat, India. Electronic address:

Carbamazepine (CBZ) shows inconsistent absorption primarily due to its poor dissolution rate. In this study, we describe a bioadhesive polymeric film, embedded with microemulsion (ME), as a tool to enable improved CBZ dissolution and achieve sustained release. The ME was formulated using pseudo-ternary components; water, oil (n-butyl acetate), surfactant (tocopheryl polyethylene glycol 1000 succinate, TPGS) and cosurfactant (1,4-butanediol). The region at surfactant to co-surfactant ratio of 1:1 was characterized using dynamic light scattering, small angle neutron scattering and differential scanning calorimetry. Scattering studies showed that size distribution did not change upon water addition and temperature. Optimized ME composition containing CBZ was embedded into bioadhesive films composed with a backing layer. We successfully demonstrate the confinement of CBZ-ME into the film matrix and thereupon, the achievement of unidirectional sustained drug release up to 8 h. Our further investigations are directed over testing the system for localized drug delivery applications.
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http://dx.doi.org/10.1016/j.colsurfb.2018.07.009DOI Listing
October 2018

Mannosylated Constructs as a Platform for Cell-Specific Delivery of Bioactive Agents.

Authors:
Sanjay Tiwari

Crit Rev Ther Drug Carrier Syst 2018 ;35(2):157-194

UKA Tarsadia University, Maliba Pharmacy College, Gopal-Vidyanagar Campus, Surat, Gujarat 394350, India.

Dictating the transport of drug carriers and augmenting the drug concentration at the desired anatomical site with high selectivity are worthwhile pursuits of current pharmaceutical research. Such approaches to drug targeting have been classified into passive and active strategies. As discussed in this article, active targeting promises greater selectivity because it exploits the incorporation of appropriate ligands, which are recognized by the target cells. Ligands, such as folate, peptides, transferrin, antibodies and their fragments, sugar, and sugar-mimetics, etc., with affinity to the molecules typical to or enriched in target tissues, have been investigated in this context. Mannose receptors (MRs) are abundantly expressed on a variety of cells, such as antigen-presenting cells, dendritic cells, and macrophages. Mannose receptors have lectin recognition domains that exhibit a high binding affinity for mannose. As a result, specific recognition of mannose-functionalized constructs has extensively been explored in the cell-specific targeting of drugs, vaccines, and other bioactive agents. This review outlines and discusses the key aspects of synthesis of mannosylated constructs, their mode of cellular uptake and application to targeted delivery of bioactive agents.
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http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.2018020313DOI Listing
September 2018

Density functional theory based probe of the affinity interaction of saccharide ligands with extra-cellular sialic acid residues.

J Biomol Struct Dyn 2019 Apr 10;37(6):1545-1554. Epub 2018 May 10.

a Department of Physics, Faculty of Science , The Maharaja Sayajirao University of Baroda , Vadodara - 390 002 , India.

Changes in glycosylation pattern leads to malignant transformations among the cells. In combination with upregulated actions of sialyltransferases, it ultimately leads to differential expression of sialic acid (SA) at cell surface. Given its negative charge and localization to extracellular domain, SA has been exploited for the development of targeted theranostics using approaches, such as, cationization and appending recognition saccharides on carrier surface. In this study, we have performed quantum mechanical calculations based on density functional theory (DFT) to study the interaction of saccharides with extracellular SA. Gradient-corrected DFT with the three parameter function (B3) was utilized for the calculation of Lee-Yang-Parr (LYP) correlation function. Atomic charge, vibrational frequencies and energy of the optimized structures were calculated through B3LYP. Our calculations demonstrate a stronger galactose-sialic acid interaction at tumour-relevant low pH and hyperthermic condition. These results support the application of pH responsive delivery vehicles and targeted hyperthermic chemotherapy for eradicating solid tumour deposits. These studies, conducted a priori, can guide the formulation scientists over appropriate choice of ligands and their applications in the design of 'smart' theranostic tools.
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http://dx.doi.org/10.1080/07391102.2018.1461690DOI Listing
April 2019

The hepatic microenvironment essentially determines tumor cell dormancy and metastatic outgrowth of pancreatic ductal adenocarcinoma.

Oncoimmunology 2017;7(1):e1368603. Epub 2017 Oct 26.

Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel (CAU) and University Medical Center Schleswig-Holstein (UKSH) Campus Kiel, Kiel, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed when liver metastases already emerged. This study elucidated the impact of hepatic stromal cells on growth behavior of premalignant and malignant pancreatic ductal epithelial cells (PDECs). Liver sections of tumor-bearing KPC mice comprised micrometastases displaying low proliferation located in an unobtrusive hepatic microenvironment whereas macrometastases containing more proliferating cells were surrounded by hepatic myofibroblasts (HMFs). In an age-related syngeneic PDAC mouse model livers with signs of age-related inflammation exhibited significantly more proliferating disseminated tumor cells (DTCs) and micrometastases despite comparable primary tumor growth and DTC numbers. Hepatic stellate cells (HSC), representing a physiologic liver stroma, promoted an IL-8 mediated quiescence-associated phenotype (QAP) of PDECs in coculture. QAP included flattened cell morphology, Ki67-negativity and reduced proliferation, elevated senescence-associated β galactosidase activity and diminished p-Erk/p-p38-ratio. In contrast, proliferation of PDECs was enhanced by VEGF in the presence of HMF. Switching the micromilieu from HSC to HMF or blocking VEGF reversed QAP in PDECs. This study demonstrates how HSCs induce and maintain a reversible QAP in disseminated PDAC cells, while inflammatory HMFs foster QAP reversal and metastatic outgrowth. Overall, the importance of the hepatic microenvironment in induction and reversal of dormancy during PDAC metastasis is emphasized.
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http://dx.doi.org/10.1080/2162402X.2017.1368603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739558PMC
October 2017
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