Muhammad Sohail

Novel pH responsive supramolecular hydrogels of chitosan hydrochloride and polyoxometalate: In-vitro, in-vivo and preliminary safety evaluation

In the current study, electrostatically-driven pH responsive, supramolecular hydrogels of the trilacunary Wells-Dawson-type 15-tungsto-2-phosphate polyanion (P2W15) and chitosan hydrochloride (ChCl) were prepared, using methacrylic acid as pH responsive agent using benzoyl peroxide (BPO) as initiator. The prepared hydrogels were characterized by FT-IR, SEM, XRD and thermal analyses (TGA-DSC). The swelling and pH based P2W15 release profile of the hydrogels showed maximum swellability and release at pH 7.4. Different mathematical models were applied, showing that P2W15 release followed supercase transport-II mechanism and zero-order kinetics. The cytotoxicity results showed that free and embedded P2W15 exhibited dose-dependent cytotoxicity against cancer cell lines (MCF-7; HeLa) with minimal effects on normal cells (Vero). The developed hydrogels were administered to the rabbits for determining the pharmacokinetic behavior of the polyanion. Moreover, the developed hydrogel system as well as polyanion concentration used were also checked for its oral tolerability and safety evaluation in rabbits. The histopathological studies, serum chemistry (except blood glucose level) and hematological investigations exhibited that administered hydrogel suspension at maximal tolerable dose (4000mg/kg body weight) and polyanion concentration used (20mg) were safe from in-vivo point of view. The developed hydrogels exhibited desirable qualities of a drug delivery system that can be used for the delivery of the embedded polyanion.

Novel gelatin-polyoxometalate based self-assembled pH responsive hydrogels: formulation and in vitro characterization

Abstract The purpose of the study was to develop physically cross-linked novel pH-responsive gelatin – Wells–Dawson-type polyoxometalate (POM)-based self-assembled hydrogels using acrylic acid as a pH-responsive monomer. Cross-linking was achieved through electrostatic interactions between the cationic polymer and anionic Wells–Dawson POM [P2W15O56]12−. Ammonium persulfate and sodium hydrogen sulfite were used as initiators. The hydrogels were yellowish in color and exhibited low mechanical strength. Swelling, drug release, and pH sensitivity studies were conducted at pH 1.2 and 7.4. pH-dependent swelling and release of [P2W15O56]12− from the prepared hydrogels were observed, with a maximum at pH 7.4. The hydrogels were characterized by thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy, and Fourier transform infrared spectroscopy for evaluation of the surface morphology, hydrogel confirmation, and thermal properties. The results obtained confirmed the development of a gelatin–POM-based self-assembled hydrogel. It can be concluded that as a result of successful physical cross linking, the prepared hydrogels possess desired characteristics of a drug delivery system and can hence be used for a controlled delivery of the encapsulated polyanions. .

Natural and synthetic polymer-based smart biomaterials for management of ulcerative colitis: a review of recent developments and future prospects

Ulcerative colitis (UC) is an inflammatory disease of the colon that severely affects the quality of life of patients and usually responds well to anti-inflammatory agents for symptomatic relief; however, many patients need colectomy, a surgical procedure to remove whole or part of the colon. Though various types of pharmacological agents have been employed for the management of UC, the lack of effectiveness is usually predisposed to various reasons including lack of target-specific delivery of drugs and insufficient drug accumulation at the target site. To overcome these glitches, many researchers have designed and characterized various types of versatile polymeric biomaterials to achieve target-specific delivery of drugs via oral route to optimize their targeting efficiency to the colon, to improve drug accumulation at the target site, as well as to ameliorate off-target effects of chemotherapy. Therefore, the aim of this review was to summarize and critically discuss the pharmaceutical significance and therapeutic feasibility of a wide range of natural and synthetic biomaterials for efficient drug targeting to colon and rationalized treatment of UC. Among various types of biomaterials, natural and synthetic polymer-based hydrogels have shown promising targeting potential due to their innate pH responsiveness, sustained and controlled release characteristics, and microbial degradation in the colon to release the encapsulated drug moieties. These characteristic features make natural and synthetic polymer-based hydrogels superior to conventional pharmacological strategies for the management of UC.

Nanomedicines as emerging platform for simultaneous delivery of cancer therapeutics: new developments in overcoming drug resistance and optimizing anticancer efficacy

Abstract 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.

Novel polymeric composites based on carboxymethyl chitosan and poly(acrylic acid): in vitro and in vivo evaluation

The purpose of the study was to develop a novel, efficient, stable, chemically crosslinked polymeric system that have pH responsive behaviour and can effectively release 5-FU in a controlled manner. Furthermore it can target colonic cancer minimizing the side effects of in vivo chemotherapy via 5-FU. Swelling and drug release studies were performed to evaluate its in vitro release behaviour. Hydrogels were also characterized by FTIR, SEM and DSC. In vitro cytocompatibility and cytotoxicity of the hydrogels were determined by MTT assay using HeLa cells. Developed hydrogels were then administered to rabbits orally to evaluate its pharmacokinetic behaviour in vivo. Maximum swelling, drug loading and release were observed at pH 7.4. Similarly maximum absorption was achieved at pH 7.4 in rabbits. It is concluded that CMC-co-poly(AA) have a great potential to be used for controlled drug delivery and colonic targeting for the delivery for various anticancer drugs.Graphical Abstract

Mercury contamination in deposited dust and its bioaccumulation patterns throughout Pakistan

Mercury (Hg) contamination of environment is a major threat to human health in developing countries like Pakistan. Human populations, particularly children, are continuously exposed to Hg contamination via dust particles due to the arid and semi-arid climate. However, a country wide Hg contamination data for dust particles is lacking for Pakistan and hence, human populations potentially at risk is largely unknown. We provide the first baseline data for total mercury (THg) contamination into dust particles and its bioaccumulation trends, using scalp human hair samples as biomarker, at 22 sites across five altitudinal zones of Pakistan. The human health risk of THg exposure via dust particles as well as the proportion of human population that are potentially at risk from Hg contamination were calculated. Our results indicated higher concentration of THg in dust particles and its bioaccumulation in the lower Indus-plain agricultural and industrial areas than the other areas of Pakistan. The highest THg contamination of dust particles (3000ppb) and its bioaccumulation (2480ppb) were observed for the Lahore district, while the highest proportion (>40%) of human population was identified to be potentially at risk from Hg contamination from these areas. In general, children were at higher risk of Hg exposure via dust particles than adults. Regression analysis identified the anthropogenic activities, such as industrial and hospital discharges, as the major source of Hg contamination of dust particles. Our results inform environmental management for Hg control and remediation as well as the disease mitigation on potential hotspots.

Dexibuprofen nanocrystals with improved therapeutic performance: fabrication, characterization, in silico modeling, and in vivo evaluation

Background The aim of this study was to prepare and evaluate the impact of polymers on fabricating stable dexibuprofen (Dexi) nanocrystals with enhanced therapeutic potential, using a low energy, anti-solvent precipitation method coupled with molecular modelling approach. Methods Dexi nanocrystals were prepared using antisolvent precipitation with syringe pump. Crystallinity of the processed Dexi particles was confirmed using differential scanning calorimetry and powdered X-ray diffraction and transmission electron microscopy. Dissolution of Dexi nanocrystals was compared with raw Dexi and marketed tablets. Molecular modelling study was coupled with experimental studies to rationalise the appropriate polymers for stable Dexi nanocrystals. Antinociceptive study was carried out using balb mice. Results Combinations of hydroxypropyl methylcellulose (HPMC)–polyvinyl pyrrolidone (PVP) and HPMC–Eudragit (EUD) were shown to be very effective in producing stable Dexi nanocrystals with particle sizes of 85.0±2.5 nm and 90±3.0 nm, and polydispersity of 0.179±0.01, 0.182±0.02, respectively. The stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C–8°C and 25°C were more stable than those at 40°C. The maximum recovery of Dexi nanocrystals was observed from the formulations using the combination of HPMC–PVP and HPMC–EUD, which equated to 98% and 94% of the nominal active drug content respectively. The saturation solubility of the Dexi nanocrystals was substantially increased to 270.0±3.5 μg/mL compared to the raw Dexi in water (51.0±2.0 μg/mL) and stabilizer solution (92.0±3.0 μg/mL). Enhanced dissolution rate (P<0.05) was observed for the Dexi nanocrystals compared to the unprocessed drug substance and marketed tablets. Dexi nanocrystals produced the analgesic effect at much lower doses (5 mg/kg) than that of control standard, diclofenac sodium (20 mg/kg) and Dexi counterparts (40 mg/kg). Conclusion HPMC-PVP and HPMC-EUD were found the best polymer combination to stabilise Dexi nanocrystals. The Dexi nanocrystals exhibited significant dissolution, solubility and analgesic effect compared to the raw Dexi and the control standard diclofenac sodium.

Hyaluronic acid, a promising skin rejuvenating biomedicine: A review of recent updates and pre-clinical and clinical investigations on cosmetic and nutricosmetic effects

Hyaluronic acid (HA) plays multifaceted role in regulating the various biological processes such as skin repairmen, diagnosis of cancer, wound healing, tissue regeneration, anti-inflammatory, and immunomodulation. Owing to its remarkable biomedical and tissue regeneration potential, HA has been numerously employed as one of the imperative components of the cosmetic and nutricosmetic products. The present review aims to summarize and critically appraise recent developments and clinical investigations on cosmetic and nutricosmetic efficacy of HA for skin rejuvenation. A thorough analysis of the literature revealed that HA based formulations (i.e., gels, creams, intra-dermal filler injections, dermal fillers, facial fillers, autologous fat gels, lotion, serum, and implants, etc.) exhibit remarkable anti-wrinkle, anti-nasolabial fold, anti-aging, space-filling, and face rejuvenating properties. This has been achieved via soft tissue augmentation, improved skin hydration, collagen and elastin stimulation, and face volume restoration. HA, alone or in combination with lidocaine and other co-agents, showed promising efficacy in skin tightness and elasticity, face rejuvenation, improving aesthetic scores, reducing the wrinkle scars, longevity, and tear trough rejuvenation. Our critical analysis evidenced that application/administration of HA exhibits outstanding nutricosmetic efficacy and thus is warranted to be used as a prime component of cosmetic products.

pH-responsive CAP-co-poly(methacrylic acid)-based hydrogel as an efficient platform for controlled gastrointestinal delivery: fabrication, characterization, in vitro and in vivo toxicity evaluation

AbstractCellulose acetate phthalate-based pH-responsive hydrogel was synthesized for fabrication of polymeric matrix tablets for gastro-protective delivery of loxoprofen sodium. Cellulose acetate phthalate (CAP) was cross-linked with methacrylic acid (MAA) using free radical polymerization technique. Fourier transform infrared (FTIR) spectra confirmed the formation of cross-linked structure of CAP-co-poly(methacrylic acid). Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) confirmed the thermal stability of polymeric networks, and scanning electron microscopy (SEM) and energy-dispersive X-ray spectrum (EDS) images unveiled that the prepared formulations were porous in nature and thus the developed formulations had shown better diffusibility. Swelling and in vitro drug release was performed at various pHs and maximum swelling and release was obtained at pHxa07.4, while swelling and release rate was very low at pHxa01.2 which confirmed the pH-responsive behavior of CAP-co-poly(MAA). CAP-co-poly(MAA) copolymer prevents the release of loxoprofen sodium into the stomach due to reduced swelling at gastric pH while showing significant swelling and drug release in the colon. Cytotoxicity studies revealed higher biocompatibility of fabricated hydrogel. Acute oral toxicity studies were performed for the evaluation and preliminary screening of safety profile of the developed hydrogels. Matrix tablets were evaluated for release behavior at simulated body pH. The investigations performed for analysis of hydrogels and fabricated matrix tablets indicated the controlled drug release and gastro-protective drug delivery of CAP-co-poly(MAA) hydrogels and pH-sensitive matrix tablets for targeted delivery of gastro-sensitive/irritative agents.n Graphical abstract

Facile synthesis of chitosan based-(AMPS-co-AA) semi-IPNs as a potential drug carrier: enzymatic degradation, cytotoxicity, and preliminary safety evaluation

OBJECTIVEnThe study describes the development of chitosan-based (AMPS-co-AA) semi-IPN hydrogels using free radical polymerization technique.nnnMETHODSnThe resulting hydrogels were characterized using Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC), X-Ray diffraction (XRD), and Scanning Electron Microscopy (SEM). The successful crosslinking of chitosan, 2- Acrylamido-2-Methylpropane Sulfonic Acid (AMPS), and Acrylic Acid (AA) was confirmed by FT IR. Unloaded and drug-loaded hydrogels exhibited higher thermal stability after crosslinking compared to the individual components. XRD confirmed the decrease in crystallinity after hydrogel formation and molecular dispersion of Oxaliplatin (OXP) in the polymeric network. SEM showed rough, vague and nebulous surface resulting from crosslinking and loading of OXP.nnnRESULTSnThe experimental results revealed that swelling and drug release were influenced by the pH of the medium being low at acidic pH and higher at basic pH. Increasing the concentration of chitosan and AA enhanced the swelling, drug loading and drug release while AMPS was found to act inversely.nnnCONCLUSIONnIt was confirmed that the hydrogels were degraded more by specific enzyme lysozyme as compared to the non-specific enzyme collagenase. In-vitro cytotoxicity suggested that the unloaded hydrogels were non-cytotoxic while crude drug and drug-loaded hydrogel exhibited dose-dependent cytotoxicity against HCT-116 and MCF-7. Results of acute oral toxicity on rabbits demonstrated that the hydrogels are non-toxic up to 3900 mg/kg after oral administration, as no toxicity or histopathological changes were observed in comparison to control rabbits. These pH-sensitive hydrogels appear to provide an ideal basis as a safe carrier for oral drug delivery.