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Cell membrane cloaked nanomedicines for bio-imaging and immunotherapy of cancer: Improved pharmacokinetics, cell internalization and anticancer efficacy

Hussain Z, Rahim MA, Jan N, Shah H, Rawas-Qalaji M, Khan S, et al.

J Control Release, 2021 07 10;335:130-157.
PMID: 34015400 DOI: 10.1016/j.jconrel.2021.05.018

Despite enormous advancements in the field of oncology, the innocuous and effectual treatment of various types of malignancies remained a colossal challenge. The conventional modalities such as chemotherapy, radiotherapy, and surgery have been remained the most viable options for cancer treatment, but lacking of target-specificity, optimum safety and efficacy, and pharmacokinetic disparities are their impliable shortcomings. Though, in recent decades, numerous encroachments in the field of onco-targeted drug delivery have been adapted but several limitations (i.e., short plasma half-life, early clearance by reticuloendothelial system, immunogenicity, inadequate internalization and localization into the onco-tissues, chemoresistance, and deficient therapeutic efficacy) associated with these onco-targeted delivery systems limits their clinical viability. To abolish the aforementioned inadequacies, a promising approach has been emerged in which stealthing of synthetic nanocarriers has been attained by cloaking them into the natural cell membranes. These biomimetic nanomedicines not only retain characteristics features of the synthetic nanocarriers but also inherit the cell-membrane intrinsic functionalities. In this review, we have summarized preparation methods, mechanism of cloaking, and pharmaceutical and therapeutic superiority of cell-membrane camouflaged nanomedicines in improving the bio-imaging and immunotherapy against various types of malignancies. These pliable adaptations have revolutionized the current drug delivery strategies by optimizing the plasma circulation time, improving the permeation into the cancerous microenvironment, escaping the immune evasion and rapid clearance from the systemic circulation, minimizing the immunogenicity, and enabling the cell-cell communication via cell membrane markers of biomimetic nanomedicines. Moreover, the preeminence of cell-membrane cloaked nanomedicines in improving the bio-imaging and theranostic applications, alone or in combination with phototherapy or radiotherapy, have also been pondered.
Fulltext Experimental and molecular modeling approach to optimize suitable polymers for fabrication of stable fluticasone nanoparticles with enhanced dissolution and antimicrobial activity

Ahmed S, Govender T, Khan I, Rehman NU, Ali W, Shah SMH, et al.

Drug Des Devel Ther, 2018;12:255-269.
PMID: 29440875 DOI: 10.2147/DDDT.S148912

Background and aim: The challenges with current antimicrobial drug therapy and resistance remain a significant global health threat. Nanodrug delivery systems are playing a crucial role in overcoming these challenges and open new avenues for effective antimicrobial therapy. While fluticasone (FLU), a poorly water-soluble corticosteroid, has been reported to have potential antimicrobial activity, approaches to optimize its dissolution profile and antimicrobial activity are lacking in the literature. This study aimed to combine an experimental study with molecular modeling to design stable FLU nanopolymeric particles with enhanced dissolution rates and antimicrobial activity.
Methods: Six different polymers were used to prepare FLU nanopolymeric particles: hydroxyl propyl methylcellulose (HPMC), poly (vinylpyrrolidone) (PVP), poly (vinyl alcohol) (PVA), ethyl cellulose (EC), Eudragit (EUD), and Pluronics®. A low-energy method, nanoprecipitation, was used to prepare the polymeric nanoparticles.
Results and conclusion: The combination of HPMC-PVP and EUD-PVP was found most effective to produce stable FLU nanoparticles, with particle sizes of 250 nm ±2.0 and 280 nm ±4.2 and polydispersity indices of 0.15 nm ±0.01 and 0.25 nm ±0.03, respectively. The molecular modeling studies endorsed the same results, showing highest polymer drug binding free energies for HPMC-PVP-FLU (-35.22 kcal/mol ±0.79) and EUD-PVP-FLU (-25.17 kcal/mol ±1.12). In addition, it was observed that Ethocel® favored a wrapping mechanism around the drug molecules rather than a linear conformation that was witnessed for other individual polymers. The stability studies conducted for 90 days demonstrated that HPMC-PVP-FLU nanoparticles stored at 2°C-8°C and 25°C were more stable. Crystallinity of the processed FLU nanoparticles was confirmed using differential scanning calorimetry, powder X-ray diffraction analysis and TEM. The Fourier transform infrared spectroscopy (FTIR) studies showed that there was no chemical interaction between the drug and chosen polymer system. The HPMC-PVP-FLU nanoparticles also showed enhanced dissolution rate (P<0.05) compared to the unprocessed counterpart. The in vitro antibacterial studies showed that HPMC-PVP-FLU nanoparticles displayed superior effect against gram-positive bacteria compared to the unprocessed FLU and positive control.
Integration of statistical and simulation analyses for ternary hybrid nanofluid over a moving surface with melting heat transfer

Rehman AU, Abbas Z, Hussain Z, Hasnain J, Asma M

Nanotechnology, 2024 Apr 09;35(26).
PMID: 38522098 DOI: 10.1088/1361-6528/ad373d

In industrial and engineering fields including lamination, melt-spinning, continuous casting, and fiber spinning, the flow caused by a continually moving surface is significant. Therefore, the problem of ternary hybrid nanofluid flow over a moving surface is studied. This study explores the stability and statistical analyses of the magnetohydrodynamics (MHD) forced flow of the ternary hybrid nanofluid with melting heat transfer phenomena. The impacts of viscous dissipation, Joule heating, and thermal radiation are also included in the flow. Different fluids including ternary hybrid nanofluid, hybrid nanofluids, and nanofluids with base fluid ethylene glycol (EG) are examined and compared, where magnetite (Fe3O4) and silica (SiO2) are taken as the magnetic nanomaterials while silver (Ag) is chosen as the nonmagnetic nanomaterial. The skin friction coefficient and the local Nusselt number are estimated through regression analysis. By employing similarity transformations, the governing partial differential equations are converted into non-linear ordinary differential equations. Then, the least square method is applied to solve the equations analytically. Dual solutions are established in a particular range of moving parameterλ. Due to this, a stability test is implemented to find the stable solution by using the bvp4c function in MATLAB software. It is found that the first solution is the stable one while the second is unstable. The use of ternary hybrid nanomaterials improves the heat transport rate. The increasing values of the Eckert number enlarge the heat passage. The fluid velocity and temperature profiles for nonmagnetic nanomaterials are higher than that of magnetic nanomaterials. The uniqueness and originality of this study stems from the fact that, to the best of the authors' knowledge, it is the first to use this combination technique.
Smart pH-responsive co-polymeric hydrogels for controlled delivery of capecitabine: Fabrication, Optimization and in vivo toxicology screening

Rehman U, Sarfraz RM, Mahmood A, Hussain Z, Thu HE, Zafar N, et al.

Curr Drug Deliv, 2021 Feb 11.
PMID: 33583374 DOI: 10.2174/1567201818666210212085912

BACKGROUND: Despite exhibiting promising anticancer potential, the clinical significance of capecitabine (a potent prodrug of 5-fluorouracil used for treatment of colorectal cancer) is limited owing to its acidic and enzymatic hydrolysis, lower absorption following the oral administration, poor bioavailability, short plasma half-life and poor patient compliance.
OBJECTIVES: The present study was aimed to fabricate the capecitabine as smart pH-responsive hydrogel network to efficiently facilitate its oral delivery while shielding its stability in the gastric media.
METHODS: The smart pH sensitive HP-β-CD/agarose-g-poly(MAA) hydrogel network was developed using an aqueous free radical polymerization technique. The developed hydrogels were characterized for drug-loading efficiency, structural and compositional features, thermal stability, swelling behaviour, morphology, physical form, and release kinetics. The pH-responsive behaviour of developed hydrogels was established by conducting the swelling and release behaviour at different pH values (1.2 and 7.4), demonstrating significantly higher swelling and release at pH 7.4 as compared with pH 1.2. The capecitabine-loaded hydrogels were also screened for acute oral toxicity in animals by analysing the body weight, water and food intake, dermal toxicity, ocular toxicity, biochemical analysis, and histological examination.
RESULTS: The characteristic evaluations revealed that capecitabine (anticancer agent) was successfully loaded into the hydrogel network. Capecitabine loading was ranged from 71.22% to 90.12%. An interesting feature of hydrogel was its pH-responsive behaviour which triggers release at basic pH (94.25%). Optimum swelling (95%) was seen at pH 7.4. Based upon regression coefficient R2 (0.96 - 0.99) best fit model was zero order. The extensive toxicity evaluations evidenced good safety profile with no signs of oral, dermal or ocular toxicities, as well as no variations in blood parameters and histology of vital organs.
CONCLUSION: Our findings conclusively evinced that the developed hydrogel exhibited excellent pharmaceutical and therapeutic potential and thus can be employed as pH-responsive system for controlled delivery of anticancer agents.
Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation

Zha GF, Zhang CP, Qin HL, Jantan I, Sher M, Amjad MW, et al.

Bioorg Med Chem, 2016 05 15;24(10):2352-9.
PMID: 27083471 DOI: 10.1016/j.bmc.2016.04.015

A series of new α,β-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ1-42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ1-42 aggregation. The compound 3o exhibited best AChE (IC50=0.037μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.
Synthesis and mechanistic studies of curcumin analog-based oximes as potential anticancer agents

Qin HL, Leng J, Youssif BG, Amjad MW, Raja MA, Hussain MA, et al.

Chem Biol Drug Des, 2017 Feb 10.
PMID: 28186369 DOI: 10.1111/cbdd.12964

The incidence of cancer can be decreased by chemoprevention using either natural or synthetic agents. Apart from synthetic compounds, numerous natural products have exhibited promising potential to inhibit carcinogenesis in vivo. In this study, α, β-unsaturated carbonyl-based anticancer compounds were used as starting materials to synthesize new oxime analogs. The findings from the antiproliferative assay using seven different human cancer cell lines provided a clear picture of structure-activity relationship. The oxime analogs namely 7a and 8a showed strong antiproliferative activity against the cell lines. The mechanistic effects of compounds on EGFR-TK kinases and tubulin polymerization and BRAF(V)(600E) were investigated. In addition, the efficacy of compounds in reversing the efflux-mediated resistance developed by cancer cells was also studied. The compounds 5a and 6a displayed potent activity on various targets such as BRAF(V)(600E) and EGFR-TK kinases and also exhibited strong antiproliferative activity against different cell lines hence showing potential of multifunctional anticancer agents.
Drug nanocarrier, the future of atopic diseases: Advanced drug delivery systems and smart management of disease

Shao M, Hussain Z, Thu HE, Khan S, Katas H, Ahmed TA, et al.

Colloids Surf B Biointerfaces, 2016 Nov 01;147:475-491.
PMID: 27592075 DOI: 10.1016/j.colsurfb.2016.08.027

Atopic dermatitis (AD) is a chronically relapsing skin inflammatory disorder characterized by perivascular infiltration of immunoglobulin-E (IgE), T-lymphocytes and mast cells. The key pathophysiological factors causing this disease are immunological disorders and the compromised epidermal barrier integrity. Pruritus, intense itching, psychological stress, deprived physical and mental performance and sleep disturbance are the hallmark features of this dermatological complication. Preventive interventions which include educational programs, avoidance of allergens, exclusive care towards skin, and the rational selection of therapeutic regimen play key roles in the treatment of dermatosis. In last two decades, it is evident from a plethora of studies that scientific focus is being driven from conventional therapies to the advanced nanocarrier-based regimen for an effective management of AD. These nanocarriers which include polymeric nanoparticles (NPs), hydrogel NPs, liposomes, ethosomes, solid lipid nanoparticles (SLNs) and nanoemulsion, provide efficient roles for the target specific delivery of the therapeutic payload. The success of these targeted therapies is due to their pharmaceutical versatility, longer retention time at the target site, avoiding off-target effects and preventing premature degradation of the incorporated drugs. The present review was therefore aimed to summarise convincing evidence for the therapeutic superiority of advanced nanocarrier-mediated strategies over the conventional therapies used in the treatment of AD.
Emerging Trends in Therapeutic Algorithm of Chronic Wound Healers: Recent Advances in Drug Delivery Systems, Concepts-to-Clinical Application and Future Prospects

Shao M, Hussain Z, Thu HE, Khan S, de Matas M, Silkstone V, et al.

Crit Rev Ther Drug Carrier Syst, 2017;34(5):387-452.
PMID: 29256838 DOI: 10.1615/CritRevTherDrugCarrierSyst.2017016957

Chronic wounds which include diabetic foot ulcer (DFU), pressure ulcer, and arterial or venous ulcers compel a significant burden to the patients, healthcare providers, and the healthcare system. Chronic wounds are characterized by an excessive persistent inflammatory phase, prolonged infection, and the failure of defense cells to respond to environmental stimuli. Unlike acute wounds, chronic nonhealing wounds pose a substantial challenge to conventional wound dressings, and the development of novel and advanced wound healing modalities is needed. Toward this end, numerous conventional wound-healing modalities have been evaluated in the management of nonhealing wounds, but a multifaceted approach is lacking. Therefore, this review aims to compile and explore the wide therapeutic algorithm of current and advanced wound healing approaches to the treatment of chronic wounds. The algorithm of chronic wound healing techniques includes conventional wound dressings; approaches based on autografts, allografts, and cultured epithelial autografts; and recent modalities based on natural, modified or synthetic polymers and biomaterials, processed mutually in the form of hydrogels, films, hydrocolloids, and foams. Moreover, this review also explores the promising potential of advanced drug delivery systems for the sustained delivery of growth factors, curcumin, aloe vera, hyaluronic acid, and other bioactive substances as well as stem cell therapy. The current review summarizes the convincing evidence for the clinical dominance of polymer-based chronic wound healing modalities as well as the latest and innovative therapeutic strategies for the treatment of chronic wounds.
Polymer-wrapped single-walled carbon nanotubes: a transformation toward better applications in healthcare

Chik MW, Hussain Z, Zulkefeli M, Tripathy M, Kumar S, Majeed ABA, et al.

Drug Deliv Transl Res, 2019 04;9(2):578-594.
PMID: 29594914 DOI: 10.1007/s13346-018-0505-9

Carbon nanotubes (CNTs) possess outstanding properties that could be useful in several technological, drug delivery, and diagnostic applications. However, their unique physical and chemical properties are hindered due to their poor solubility. This article review's the different ways and means of solubility enhancement of single-wall carbon nanotubes (SWNTs). The advantages of SWNTs over the multi-walled carbon nanotubes (MWNTs) and the method of non-covalent modification for solubility enhancement has been the key interest in this review. The review also highlights a few examples of dispersant design. The review includes some interesting utility of SWNTs being wrapped with polymer especially in biological media that could mediate proper drug delivery to target cells. Further, the use of wrapped SWNTs with phospholipids, nucleic acid, and amphiphillic polymers as biosensors is of research interest. The review aims at summarizing the developments relating to wrapped SWNTs to generate further research prospects in healthcare.
Comparative susceptibility studies of clinically isolated Pseudomonas aeruginosa, Escherichia coli and Klebsiella spp to cefoperazone and cefotaxime

Lee YH, Hussain ZA, Choong FP

J Hyg Epidemiol Microbiol Immunol, 1990;34(3):299-303.
PMID: 2125616

The in-vitro activity of cefotaxime and cefoperazone were compared using clinically isolated Escherichia coli, Klebsiella spp and Pseudomonas aeruginosa. Cefotaxime was found on a weight to weight basis, to be much more active than cefoperazone. All the three species studied show the presence of cefoperazone-resistant population which were sensitive to cefotaxime. The possible mechanisms of resistance to these antibiotics were discussed.
Nanomedicines as emerging platform for simultaneous delivery of cancer therapeutics: new developments in overcoming drug resistance and optimizing anticancer efficacy

Hussain Z, Arooj M, Malik A, Hussain F, Safdar H, Khan S, et al.

Artif Cells Nanomed Biotechnol, 2018;46(sup2):1015-1024.
PMID: 29873531 DOI: 10.1080/21691401.2018.1478420

Development and formulation of an efficient and safe therapeutic regimen for cancer theranostics are dynamically challenging. The use of mono-therapeutic cancer regimen is generally restricted to optimal clinical applications, on account of drug resistance and cancer heterogeneity. Combinatorial treatments can employ multi-therapeutics for synergistic anticancer efficacy whilst reducing the potency of individual moieties and diminishing the incidence of associated adverse effects. The combo-delivery of nanotherapeutics can optimize anti-tumor efficacy while reversing the incidence of drug resistance, aiming to homogenize pharmacological profile of drugs, enhance circulatory time, permit targeted drug accumulation, achieve multi-target dynamic approach, optimize target-specific drug binding and ensure sustained drug release at the target site. Numerous nanomedicines/nanotherapeutics have been developed by having dynamic physicochemical, pharmaceutical and pharmacological implications. These innovative delivery approaches have displayed specialized treatment effects, alone or in combination with conventional anticancer approaches (photodynamic therapy, radiotherapy and gene therapy), while reversing drug resistance and potential off-target effects. The current review presents a comprehensive overview of nanocarrier aided multi-drug therapies alongside recent advancements, future prospects, and the pivotal requirements for interdisciplinary research.
Nano-scaled materials may induce severe neurotoxicity upon chronic exposure to brain tissues: A critical appraisal and recent updates on predisposing factors, underlying mechanism, and future prospects

Hussain Z, Thu HE, Elsayed I, Abourehab MAS, Khan S, Sohail M, et al.

J Control Release, 2020 12 10;328:873-894.
PMID: 33137366 DOI: 10.1016/j.jconrel.2020.10.053

Owing to their tremendous potential, the inference of nano-scaled materials has revolutionized many fields including the medicine and health, particularly for development of various types of targeted drug delivery devices for early prognosis and successful treatment of various diseases, including the brain disorders. Owing to their unique characteristic features, a variety of nanomaterials (particularly, ultra-fine particles (UFPs) have shown tremendous success in achieving the prognostic and therapeutic goals for early prognosis and treatment of various brain maladies such as Alzheimer's disease, Parkinson's disease, brain lymphomas, and other ailments. However, serious attention is needful due to innumerable after-effects of the nanomaterials. Despite their immense contribution in optimizing the prognostic and therapeutic modalities, biological interaction of nanomaterials with various body tissues may produce severe nanotoxicity of different organs including the heart, liver, kidney, lungs, immune system, gastro-intestinal system, skin as well as nervous system. However, in this review, we have primarily focused on nanomaterials-induced neurotoxicity of the brain. Following their translocation into different regions of the brain, nanomaterials may induce neurotoxicity through multiple mechanisms including the oxidative stress, DNA damage, lysosomal dysfunction, inflammatory cascade, apoptosis, genotoxicity, and ultimately necrosis of neuronal cells. Our findings indicated that rigorous toxicological evaluations must be carried out prior to clinical translation of nanomaterials-based formulations to avoid serious neurotoxic complications, which may further lead to develop various neuro-degenerative disorders.
Fulltext Crystal structure of tetra-aqua-bis(3,5-di-amino-4H-1,2,4-triazol-1-ium)cobalt(II) bis-[bis-(pyridine-2,6-di-carboxyl-ato)cobaltate(II)] dihydrate

Johnson A, Mbonu J, Hussain Z, Loh WS, Fun HK

Acta Crystallogr E Crystallogr Commun, 2015 Jun 1;71(Pt 6):m139-40.
PMID: 26090171 DOI: 10.1107/S2056989015010014

The asymmetric unit of the title compound, [Co(C2H6N5)2(H2O)4][Co(C7H3NO4)2]2·2H2O, features 1.5 Co(II) ions (one anionic complex and one half cationic complex) and one water mol-ecule. In the cationic complex, the Co(II) atom is located on an inversion centre and is coordinated by two triazolium cations and four water mol-ecules, adopting an octa-hedral geometry where the N atoms of the two triazolium cations occupy the axial positions and the O atoms of the four water mol-ecules the equatorial positions. The two triazole ligands are parallel offset (with a distance of 1.38 Å between their planes). In the anionic complex, the Co(II) ion is six-coordinated by two N and four O atoms of the two pyridine-2,6-di-carboxyl-ate anions, exhibiting a slightly distorted octa-hedral coordination geometry in which the mean plane of the two pyridine-2,6-di-carboxyl-ate anions are almost perpendicular to each other, making a dihedral angle of 85.87 (2)°. In the crystal, mol-ecules are linked into a three-dimensional network via C-H⋯O, C-H⋯N, O-H⋯O and N-H⋯O hydrogen bonds.
Transferrin receptors-targeting nanocarriers for efficient targeted delivery and transcytosis of drugs into the brain tumors: a review of recent advancements and emerging trends

Choudhury H, Pandey M, Chin PX, Phang YL, Cheah JY, Ooi SC, et al.

Drug Deliv Transl Res, 2018 10;8(5):1545-1563.
PMID: 29916012 DOI: 10.1007/s13346-018-0552-2

Treatment of glioblastoma multiforme (GBM) is a predominant challenge in chemotherapy due to the existence of blood-brain barrier (BBB) which restricts delivery of chemotherapeutic agents to the brain together with the problem of drug penetration through hard parenchyma of the GBM. With the structural and mechanistic elucidation of the BBB under both physiological and pathological conditions, it is now viable to target central nervous system (CNS) disorders utilizing the presence of transferrin (Tf) receptors (TfRs). However, overexpression of these TfRs on the GBM cell surface can also help to avoid restrictions of GBM cells to deliver chemotherapeutic agents within the tumor. Therefore, targeting of TfR-mediated delivery could counteract drug delivery issues in GBM and create a delivery system that could cross the BBB effectively to utilize ligand-conjugated drug complexes through receptor-mediated transcytosis. Hence, approach towards successful delivery of antitumor agents to the gliomas has been making possible through targeting these overexpressed TfRs within the CNS and glioma cells. This review article presents a thorough analysis of current understanding on Tf-conjugated nanocarriers as efficient drug delivery system.
Fulltext Engineering of Naproxen Loaded Polymer Hybrid Enteric Microspheres for Modified Release Tablets: Development, Characterization, in silico Modelling and in vivo Evaluation

Hameed HA, Khan S, Shahid M, Ullah R, Bari A, Ali SS, et al.

Drug Des Devel Ther, 2020;14:27-41.
PMID: 32021089 DOI: 10.2147/DDDT.S232111

BACKGROUND: Naproxen (NP) is a non-steroidal anti-inflammatory drug with poor aqueous solubility and low oral bioavailability, which may lead to therapeutic failure. NP causes crucial GIT irritation, bleeding, and peptic and duodenal ulcers.
PURPOSE OF THE STUDY: This study aimed to engineer and characterize polymer hybrid enteric microspheres using an integrated (experimental and molecular modelling) approach with further development to solid dosage form with modified drug release kinetics and improved bioavailability.
MATERIALS AND METHODS: NP loaded polymer hybrid enteric microspheres (PHE-Ms) were fabricated by using a modified solvent evaporation technique coupled with molecular modelling (MM) approach. The PHE-Ms were characterized by particle size, distribution, morphology, crystallinity, EE, drug-polymer compatibility, and DSC. The optimized NP loaded PHE-Ms were further subjected to downstream procedures including tablet dosage form development, stability studies and comparative in vitro-in vivo evaluation.
RESULTS: The hydrophobic polymer EUD-L100 and hydrophilic polymer HPMC-E5 delayed and modified drug release at intestinal pH while imparting retardation of NP release at gastric pH to diminish the gastric side effects. The crystallinity of the NP loaded PHE-Ms was established through DSC and P (XRD). The particle size for the developed formulations of PEH-Ms (M1-M5) was in the range from 29.06 ±7.3-74.31 ± 17.7 μm with Span index values of 0.491-0.69, respectively. The produced NP hybrid microspheres demonstrated retarded drug release at pH 1.2 and improved dissolution at pH 6.8. The in vitro drug release patterns were fitted to various release kinetic models and the best-followed model was the Higuchi model with a release exponent "n" value > 0.5. Stability studies at different storage conditions confirmed stability of the NP loaded PHE-Ms based tablets (P<0.05). The molecular modelling (MM) study resulted in adequate binding energy of co-polymer complex SLS-Eudragit-HPMC-Naproxen (-3.9 kcal/mol). In contrast to the NP (unprocessed) and marketed formulations, a significant increase in the Cmax of PHE-MT1 (44.41±4.43) was observed.
CONCLUSION: The current study concludes that developing NP loaded PHE-Ms based tablets could effectively reduce GIT consequences with restored therapeutic effects. The modified release pattern could improve the dissolution rate and enhancement of oral bioavailability. The MM study strengthens the polymer-drug relationship in microspheres.
Phytotherapeutic potential of natural herbal medicines for the treatment of mild-to-severe atopic dermatitis: A review of human clinical studies

Hussain Z, Thu HE, Shuid AN, Kesharwani P, Khan S, Hussain F

Biomed Pharmacother, 2017 Sep;93:596-608.
PMID: 28686974 DOI: 10.1016/j.biopha.2017.06.087

For many decades, natural herbal medicines, polyherbal formulations and/or decoctions of plant-derived materials have widely been accepted as alternative complementary therapies for the treatment, cure or prevention of a wide range of acute and chronic skin diseases including chronic herpes, prurigo, acute and chronic wounds, psoriasis and atopic dermatitis (AD). This review was aimed to summarize and critically discuss about the therapeutic viability and clinical applicability of natural herbal medicines for the treatment of AD in human. The critical analysis of the literature revealed that oral (in the form of capsules, syrup or granules) and/or topical application (alone or in conjunction with wet-wrap dressing and/or acupuncture) of natural herbal medicines exhibit remarkable potential for the treatment of mild-to-severe AD in adults, children, infants and in the pregnant women. In this review, the clinical efficacy of various herbal formulations such as Chinese herbal therapies, Korean medicines, Iranian medicines, honey, natural herbal oils (coconut oil, olive oil and mineral oil), beeswax, dodder seeds and whey for the treatment of AD has been discussed. The clinical anti-AD efficacy of these complementary therapies has been observed in terms of down-regulation in Scoring Atopic Dermatitis (SCORAD) index, erythematic intensity, Children's Dermatology Life Quality Index (CDLQI), Dermatology Life Quality Index (DLQI), pruritus and itching frequency, transepidermal water loss (TEWL) and expression of AD-mediated chemokines. Conclusively, we recognized that natural herbal medicines demonstrate remarkable clinical efficacy when used alone or in conjunction with other complementary therapies for the treatment of AD in patients of all ages as well as pregnant women.
Recent Advances in Polymer-based Wound Dressings for the Treatment of Diabetic Foot Ulcer: An Overview of State-of-the-art

Hussain Z, Thu HE, Shuid AN, Katas H, Hussain F

Curr Drug Targets, 2018;19(5):527-550.
PMID: 28676002 DOI: 10.2174/1389450118666170704132523

BACKGROUND: Diabetic foot ulcers (DFUs) are the chronic, non-healing complications of diabetic mellitus which compels a significant burden to the patients and the healthcare system. Peripheral vascular disease, diabetic neuropathy, and abnormal cellular and cytokine/chemokine activity are among the prime players which exacerbate the severity and prevent wound repair. Unlike acute wounds, DFUs impose a substantial challenge to the conventional wound dressings and demand the development of novel and advanced wound healing modalities. In general, an ideal wound dressing should provide a moist wound environment, offer protection from secondary infections, eliminate wound exudate and stimulate tissue regeneration.
OBJECTIVE: To date, numerous conventional wound dressings are employed for the management of DFUs but there is a lack of absolute and versatile choice. The current review was therefore aimed to summarize and critically discuss the available evidences related to pharmaceutical and therapeutic viability of polymer-based dressings for the treatment of DFUs.
RESULTS: A versatile range of naturally-originated polymers including chitosan (CS), hyaluronic acid (HA), cellulose, alginate, dextran, collagen, gelatin, elastin, fibrin and silk fibroin have been utilized for the treatment of DFUs. These polymers have been used in the form of hydrogels, films, hydrocolloids, foams, membranes, scaffolds, microparticles, and nanoparticles. Moreover, the wound healing viability and clinical applicability of various mutually modified, semi-synthetic or synthetic polymers have also been critically discussed.
CONCLUSION: In summary, this review enlightens the most recent developments in polymer-based wound dressings with special emphasis on advanced polymeric biomaterials, innovative therapeutic strategies and delivery approaches for the treatment of DFUs.
Carbon nanotube scaffolds as emerging nanoplatform for myocardial tissue regeneration: A review of recent developments and therapeutic implications

Gorain B, Choudhury H, Pandey M, Kesharwani P, Abeer MM, Tekade RK, et al.

Biomed Pharmacother, 2018 Aug;104:496-508.
PMID: 29800914 DOI: 10.1016/j.biopha.2018.05.066

Myocardial infarction (cardiac tissue death) is among the most prevalent causes of death among the cardiac patients due to the inability of self-repair in cardiac tissues. Myocardial tissue engineering is regarded as one of the most realistic strategies for repairing damaged cardiac tissue. However, hindrance in transduction of electric signals across the cardiomyocytes due to insulating properties of polymeric materials worsens the clinical viability of myocardial tissue engineering. Aligned and conductive scaffolds based on Carbon nanotubes (CNT) have gained remarkable recognition due to their exceptional attributes which provide synthetic but viable microenvironment for regeneration of engineered cardiomyocytes. This review presents an overview and critical analysis of pharmaceutical implications and therapeutic feasibility of CNT based scaffolds in improving the cardiac tissue regeneration and functionality. The expository analysis of the available evidence revealed that inclusion of single- or multi-walled CNT into fibrous, polymeric, and elastomeric scaffolds results in significant improvement in electrical stimulation and signal transduction through cardiomyocytes. Moreover, incorporation of CNT in engineering scaffolds showed a greater potential of augmenting cardiomyocyte proliferation, differentiation, and maturation and has improved synchronous beating of cardiomyocytes. Despite promising ability of CNT in promoting functionality of cardiomyocytes, their presence in scaffolds resulted in substantial improvement in mechanical properties and structural integrity. Conclusively, this review provides new insight into the remarkable potential of CNT aligned scaffolds in improving the functionality of engineered cardiac tissue and signifies their feasibility in cardiac tissue regenerative medicines and stem cell therapy.
Nanomedicines for improved targetability to inflamed synovium for treatment of rheumatoid arthritis: Multi-functionalization as an emerging strategy to optimize therapeutic efficacy

Fang G, Zhang Q, Pang Y, Thu HE, Hussain Z

J Control Release, 2019 06 10;303:181-208.
PMID: 31015032 DOI: 10.1016/j.jconrel.2019.04.027

Owing to its intricate autoimmune pathophysiology and significant risks of progression to other rheumatic co-morbidities (i.e., osteoporosis and osteoarthritis), a plausible therapeutic regimen is mandatory for early-stage management of rheumatoid arthritis (RA). Nevertheless, the conventional therapeutic agents particularly the corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs) have shown grander success in the treatment of RA; however, long-term use of these agents is also associated with serious adverse events. To combat these issues and optimize therapeutic efficacy, nanotechnology-based interventions have been emerged as viable option. While, nanomedicines signposted superiority over the conventional pharmacological moieties; there are still many pharmacokinetic and pharmacodynamic challenges to nanomedicines following their intravenous or intra-articular administration. To circumvent these challenges, significant adaptations such as PEGylation, surface conjugation of targeting ligand(s), and site- responsive behavior (i.e., pH-, biochemical-, or thermal-responsiveness) have been implemented. Besides, multi-functionalization of nanomedicines has been emerging as an exceptional strategy to overcome pharmacokinetic challenges, improve targetability to inflamed synovium, maximise internalisation into the activated macrophages, and improved therapeutic outcomes for treatment of RA. Therefore, this review aims to conceptualize and recapitulate the substantial evidences regarding the pharmacokinetic and pharmacodynamic superiority of multi-functionalized nanomedicines over the naked nanomedicines for site-selective targeting to inflamed synovium and rational treatment of RA and other rheumatic co-morbidities. Pharmaceutical sustainability of the multi-functionalized nanomedicines for improved biocompatibility, profound interaction with the targeting tissue/cells/sub-cellular domain, and diminished systemic toxicity has also been pondered.
Design and development of novel hyaluronate-modified nanoparticles for combo-delivery of curcumin and alendronate: fabrication, characterization, and cellular and molecular evidences of enhanced bone regeneration

Dong J, Tao L, Abourehab MAS, Hussain Z

Int J Biol Macromol, 2018 Sep;116:1268-1281.
PMID: 29782984 DOI: 10.1016/j.ijbiomac.2018.05.116

Osteoporosis is a medical condition of fragile bones with an increased susceptibility to fracture. Despite having availability of a wide range of pharmacological agents, prevalence of osteoporosis is continuously escalating. Owing to excellent biomedical achievements of nanomedicines in the last few decades, we aimed combo-delivery of bone anti-resorptive agent, alendronate (ALN), and bone density enhancing drug, curcumin (CUR) in the form of polymeric nanoparticles. To further optimize the therapeutic efficacy, the prepared ALN/CUR nanoparticles (NPs) were decorated with hyaluronic acid (HA) which is a well-documented biomacromolecule having exceptional bone regenerating potential. The optimized nanoformulation was then evaluated for bone regeneration efficacy by assessing time-mannered modulation in the proliferation, differentiation, and mineralization of MC3T3-E1 cells, a pre-osteoblastic model. Moreover, the time-mannered expression of various bone-forming protein biomarkers such as bone morphogenetic protein, runt related transcription factor 2, and osteocalcin were assessed in the cell lysates. Results revealed that HA-ALN/CUR NPs provoke remarkable increase in the proliferation, differentiation, and mineralization in the ECM of MC3T3-E1 cells which ultimately leads to enhanced bone formation. This new strategy of employing simultaneous delivery of anti-resorptive and bone forming agents would open new horizons for scientists as an efficient alternative pharmacotherapy for the management of osteoporosis.

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