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This study was designed to enhance solubility of dexibuprofen, an NSAID drug used to treat moderate to severe pain, by fabricating first generation, carbonate type nanosponges of β-CD. Novel chain-growth polycondensation method was used for the first time for preparation of the β-CD nanosponges. The results exhibited 6.3-fold enhancement of dexibuprofen solubilization which is higher than previously reported β-CD formulations. The particle size of nanosponges was 275.1 ± 28.5 nm and suitable negative zeta potential indicated formation of stable nanosponges. The formation of a new polymeric network in nanosponges and interaction of dexibuprofen with nanosponges were confirmed by FTIR and DSC/TGA studies. PXRD analysis also revealed the decline in crystallinity of dexibuprofen due to its complexation with nanosponges which is desirable for complete solubilization of drugs. At pH 6.8, β-CD nanosponges exhibited swelling index of 3 whereas solubility was enhanced more than 3 times as compared to pure drug and 2 times as compared to dexibuprofen loaded β-CD complexes. In-vitro release studies exhibited 89% drug release within 30 min at pH 6.8 with β-CD nanosponges. Dexibuprofen release at pH 1.2 was remarkably slower yet β-CD nanosponges showed superior dissolution as compared to β-CD or pure drug. Acute oral toxicity studies in rats exhibited no sign of illness, mortality, adverse clinical signs and toxicologically relevant changes in hematology, clinical biochemistry and histological findings. Thus, β-CD nanosponges prepared by optimized condensation method may be superior to other nano-formulation of β-CD to improve oral administration of lipophilic drugs such as dexibuprofen.

Folic acid is often used for active targeting of tumor cells to enhance therapeutic outcomes. Here, folic acid was conjugated with chitosan and folate-conjugated chitosan-lipid hybrid nanoparticles were prepared by ionic gelation method using anionic lipid. These nanoparticles were in size range of 200 to 400 nm with spherical shape. In vitro drug release data suggested a sustained release of cisplatin. The therapeutic efficacy of the folate-conjugated hybrid nanoparticles was evaluated in SK-OV-3, A2780 and MCF-7 cancer cell lines. A significant increase in cytotoxicity was observed with folate targeted LPHNPs compared to non-targeted LPHNPs. Significantly enhanced cellular uptake and cell cycle arrest resulting from folate-targeted nanoparticles were confirmed using fluorescence microscopy and flow cytometry. The therapeutic efficacy and tumor penetration were further evaluated in 3D spheroid tumor models. These studies suggest that folate-conjugated lipid-chitosan nanoparticles could enhance therapeutic activity and may represent a promising platform for active targeting of tumor cells.

Synthesis of carbon dots (CDs) or carbon quantum dots (QCDs) from different carbon sources have attracted much attention due to their excellent potential to advance wide range of applications such as biosensing, bioimaging, photoscience and other biomedical usage. However, the interaction of CDs (without any complex surface functionalities) with different cell lines especially with respect to their surface charge still needs to be elaborated in certain phenomena i.e. cytotoxicity, cellular uptake and inflammatory profiling. In this study, two oppositely charged CDs were synthesized and compared for their surface charge dependent interaction with different cell lines. Positively charged CDs were synthesized by using bovine serum albumin (BSA) and negatively charged CDs were synthesized using citric acid (CA) by acidic hydrolysis and reflux methods, respectively. Using both CDs, a concentration dependent cytotoxicity was carried out on 3T3 fibroblast, MDA-MB-231 breast cancer and RAW 264.7 macrophage cell lines, while cellular uptake and inflammatory studies were conducted with RAW 264.7 macrophages cell line. Results showed that both BSA and CA-CDs were not cytotoxic up to 400 μg/mL. Flow-cytometry studies indicated that cellular uptake of negatively charged CA-CDs was quite higher (~6.25%) than that of positively charged BSA-CDs (~1.24%). On the other hand, positively charged BSA-CDs have significantly enhanced the inflammatory cytokines release by RAW 264.7 macrophages cells. A concentration dependent increase in tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) was observed when RAW 264.7 macrophages cells were treated with BSA-CDs. In comparison, CA-CDs did not show any effect on these cytokines release. Therefore, it was concluded that the interaction of CDs with different cells is dependent on their surface charge which can also control their cellular influx and release of inflammatory cytokines.

Despite of the remarkable cytotoxic and imaging potential of ultra-small metal nanoclusters, their toxicity-free and targeted delivery to cancerous cells remains a substantial challenge that hinders their clinical applications. In this study, a polymeric scaffold was first synthesized by grafting folic acid and thiol groups to chitosan (CS) for cancer cell targeting and improved gastric permeation. Furthermore, silver nanocluster (Ag NCs) were synthesized in situ, within CS scaffold by microwave irradiation and core-shell nanocapsules (NCPs) were prepared with hydrophobic docetaxel (DTX) in the core and Ag NCs embedded CS in the shell. A significant cytotoxicity synergism (~300 folds) was observed for DTX with co-delivery of Ag NCs against breast cancer MDA-MB-231 cells. Following oral administration, the DTX-Ag-NCPs increased bioavailability due to enhanced drug transport across gut (9 times), circulation half-life (~6.8 times) and mean residence time (~6.7 times), as compared to the control DTX suspension. Moreover, 14 days acute oral toxicity of the DTX-Ag-NCPs was performed in mice and evaluated for changes in blood biochemistry parameters, organ to body weight index and histopathology of liver and kidney tissues that revealed no significant evidence of toxicity suggesting the safety and efficiency of the DTX-Ag-NCPs as hybrid nanocarrier for biocompatible delivery of metal nanoclusters.

A simple and cost effective RPLC-UV bio-analytical method was developed and used for tenoxicam quantification on ODS Hypersil C-18 column using classical liquid-liquid extraction technique for sample preparation. Acetonitrile was used as precipitating agent for plasma proteins and supernatant was taken for injection without any further modification. The bio-analytical method depends upon isocratic elution using binary mixture of aqueous 0.1 M potassium dihydrogen phosphate and acetonitrile in 6 : 4 ratio. The pH of mobile phase was adjusted to 2.8 which favor tenoxicam to remain undissociated throughout the analysis. The optimized flow rate of 1.0 mL/min provided proper separation of peaks and column clean up within 5 min. The UV detection was achieved at 381 nm and 4.29 min. Reproducible calibration curve gave 0.325 μg/mL LOQ, linear dynamic range from 0.325 to 20 μg/mL and recovery from plasma was 98.5% with %CV 0.2314 achieved. After validation, the method was applied in pharmacokinetic study in healthy human volunteers (n = 8). The pharmacokinetic parameters were evaluated using kinetica version 4.1.1. The values of C. and area under curve for current study were 1.776 ± 0.003 pg/mL and 179.97 ± 0.0681 (mean ± SEM) pg x h/mL. The values of t, and volume of distribution for tenoxicam in current study were 74.103 0.167 h (mean ± SEM) and 11.962 ± 0.0677 L/kg (mean ± SEM), respectively. This method was simple, sensitive and successfully applied in pharmacokinetic studies. It can be extended to bioequivalence studies and evaluation of tenoxicam in different clinical situations.

Tuberculosis (TB) is an infectious disease that is communicable from one person to another. Pakistan stands forefront among few unfortunate countries that still have heavy burden of TB infection. Being a developing country, TB patients in Pakistan have to face different socio-economic constraints that upset life of the patients as well as their families. A cross sectional survey was conducted in three selected districts, Lodharan, Bahawalpur and Bahawalnagar during February 2011 to June 2011. From three hundred selected patients 210 were enrolled in study after receiving written consents. Data were collected though structured questionnaire and verbal interviews and statistically analyzed by using the univariate analysis. The survey results showed that the low educational status (p0.0012, CI 95%), unawareness of disease (88.7%), crowded population (p =0.0000, CI, 95%), poverty, high treatment cost and distant access to public health facilities were directly related to prevalence of TB. Different disease related constraints including poor attitude of family members, colleagues, society and even health care professionals (p = 0.0000, CI 95%) were also found to be major social factors leading to non-compliance and denial of TB treatment. Socio-economic constraints such as low literacy rate, unemployment, unawareness of disease, high treatment cost, poor attitude of family, society and health care professionals were directly related to noncompliance and should be given high priority consideration for achieving better TB management and mitigation.

Titanium-based materials do not fulfill all of the requirements of orthopedic implants due to a mismatch in mechanical properties with bone which are prone to change during the course of bone growth. Biofunctional biomaterials are a new class of materials that show bioactivity and adaptability at any stage of bone growth.Different biofunctional biomaterials have evolved over time that can enhance calcium phosphate (CaP) precipitation, stimulate osteogenic differentiation, and can control osteoblast gene expression. These materials include metals or metal alloys, ceramics, polymers and biocomposites. Similarly, naturally-inspired nanomaterials and nanometer surface featured modified materials can enhance bone growth if created to match bone's unique micro to nano hierarchical structure. Nanoscale manipulation of existing biomaterials can incorporate antimicrobial properties which is desirable to prevent infection and failure of orthopedic devices.Recent research trends in biofunctional biomaterials have focused to, first, understand the bone growth mechanism and, then, mimic natural bone architecture using biomaterials. Therefore, an enhanced understanding of material properties and tissue engineering principles will lead the way forward designing biofunctional biomaterials. In the future, the role of biofunctional biomaterials and orthopedic sensors will be more pronounced in terms of musculoskeletal disease prevention, diagnosis, and treatment.

Mubashar Rehman,1–3 Ayesha Ihsan,2 Asadullah Madni,1 Sadia Zafar Bajwa,2 Di Shi,3 Thomas J Webster,3,4 Waheed S Khan2 1Department of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Punjab, Pakistan; 2Nanobiotech Group, National Institute of Biotechnology and Genetic Engineering, Faisalabad, Punjab, Pakistan; 3Department of Chemical Engineering, Northeastern University, Boston, MA, USA; 4Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia Abstract: Thermoresponsive drug delivery systems are designed for the controlled and targeted release of therapeutic payload. These systems exploit hyperthermic tempera­tures (>39°C), which may be applied by some external means or due to an encountered symptom in inflammatory diseases such as cancer and arthritis. The objective of this paper was to provide some solid evidence in support of the hypothesis that solid lipid nanoparticles (SLNs) can be used for thermoresponsive targeting by undergoing solid–liquid phase transition at their melting point (MP). Thermoresponsive lipid mixtures were prepared by mixing solid and liquid natural fatty acids, and their MP was measured by differential scanning calorimetry (DSC). SLNs (MP 39°C) containing 5-fluorouracil (5-FU) were synthesized by hot melt encapsulation method, and were found to have spherical shape (transmission electron microscopy studies), desirable size (90% drug was released at 39°C after 5hours, suggesting that the SLNs show thermoresponsive drug release, thus confirming our hypothesis. Drug release from SLNs at 39°C was similar to oleic acid and linoleic acid nanoemulsions used in this study, which further confirmed that thermoresponsive drug release is due to solid–liquid phase transition. Next, a differential pulse voltammetry-based electrochemical chemical detection method was developed for quick and real-time analysis of 5-FU release, which also confirmed thermoresponsive drug release behavior of SLNs. Blank SLNs were found to be biocompatible with human gingival fibroblast cells, although 5-FU-loaded SLNs showed some cytotoxicity after 24hours. 5-FU-loaded SLNs showed thermoresponsive cytotoxicity to breast cancer cells (MDA-MB-231) as cytotoxicity was higher at 39°C (cell viability 72%–78%) compared to 37°C (cell viability >90%) within 1hour. In conclusion, this study presents SLNs as a safe, simple, and effective platform for thermoresponsive targeting. Keywords: temperature sensitive, breast cancer, 5-fluorouracil, nanostructured lipid carriers, emulsions, fatty acids

Thermoresponsive targeting is used to deliver therapeutic agents at hyperthermic conditions (39–45 °C). However, available thermoresponsive drug delivery systems (TDDS), including liposomes, have a complex method of preparation involving toxic solvents and reagents. The objective of this in vitro study was to prepare and characterize thermoresponsive lipid nanoparticles (TLN) for treating glioblastoma, the most aggressive brain tumor whose treatment is limited by a low blood brain barrier (BBB) permeability of drugs. Thermoresponsive lipids were prepared by mixing liquid and solid fatty acids (0.1 : 1 to 2 : 1 ratio) and lipid mixtures exhibiting a solid–liquid phase transition at 39 °C were identified by plotting melting point against liquid contents. TLN were prepared by a hot melt encapsulation method using mono- or double-surfactant systems. TLN showed desirable size (

In this study, polymeric blend microparticles are prepared with tunable drug releasing behavior, imparted by using poly(e-caprolactone) (PCL) as hydrophobic and hydroxypropyl methylcellulose (HPMC) as hydrophilic biodegradable polymeric constituents. Microparticles were prepared by simple oil in water emulsion-solvent evaporation method and evaluated for their sustained release profile by using nifedipine (half-life is about 2 h) as model drug. Hydrophilic PCL is added to optimize the drug release in simulated aqueous body fluid. Polyvinyl alcohol (PVA), used as emulsifier, was found to improve shape while HPMC increased surface smoothness of microparticles. High encapsulation efficiency was achieved, controllable by HPMC concentration. In vitro dissolution studies in acidic and neutral pH showed sustained release profile for all formulations. Synthesized microparticles, provided control over hydrophobic drug release by changing the proportion of HPMC and PCL in formulation at both acidic and intestinal pH.

The current study aimed to develop novel pH independent microparticles loaded with ropinirole (ROP) for sustained drug release. Eudragit RS 100 was used as release retardant and microparticles were fabricated by oil-in-oil emulsion solvent evaporation method. A three-factor three-level Box-Behnken design using Design-Expert software was employed to optimize formulation variables. Ropinirole loaded microparticles were evaluated with respect to morphology, particle size, encapsulation efficiency, and in vitro release profile. Optical microscopy and SEM micrographs indicated spherical shape with smooth surface and well-defined boundary. The particle size was in the range of 98.86 to 236.29 μm, being significantly increased with increasing polymer concentration. Higher polymer load also increased the thickness of internal polymer network, which led to reduced drug loss and higher entrapment efficiency (89%). The cumulative in vitro release was found to be in the range of 54.96 to 99.36% during the release studies (12 h) following zero order release kinetics and non-Fickian diffusion pattern. The developed microparticles have the potential to sustain the release of ropinirole, which may lead to a reduction in its adverse effects and improved management of Parkinson’s disease.

Nanotechnology has opened a new horizon of research in various fields including applied physics, chemistry, electronics, optics, robotics, biotechnology and medicine. In the biomedical field, nanomaterials have shown remarkable potential as theranostic agents. Materials which are considered inert are often used in nanomedicine owning to their nontoxic profile. At nanoscale, these inert materials have shown unique properties that differ from bulk and dissolved counterparts. In the case of metals, this unique behavior not only imparts paramount advantages but also confers toxicity due to their unwanted interaction with different cellular processes. In the literature, the toxicity of nanoparticles made from inert materials has been investigated and many of these have revealed toxic potential under specific conditions. The surge to understand underlying mechanism of toxicity has increased and different means have been employed to overcome toxicity problems associated with these agents. In this review, we have focused nanoparticles of three inert metallic materials i.e. gold, silver and iron as these are regarded as biologically inert in the bulk and dissolved form. These materials have gained wider research interest and studies indicating the toxicity of these materials are also emerging. Oxidative stress, physical binding and interference with intracellular signaling are the major role player in nanotoxicity and their predominance is highly dependent upon size, surface coating and administered dose of nanoparticles. Current strategies to overcome toxicity have also been reviewed in the light of recent literature. The authors also suggested that uniform testing standards and well-designed studies are needed to evaluate nanotoxicity of these materials that are otherwise considered as inert. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

We report the synthesis and evaluation of lecithin-gold hybrid nanocarriers for the oral delivery of drugs with improved pharmacokinetics, Au-drug interactive bioactivity and controlled drug releasing behavior at physiological pH inside human body. For this purpose, diacerein, a hydrophobic anti-arthritic drug, was loaded in lecithin NPs (LD NPs), which were further coated by Au NPs either by in-situ production of Au NPs on LD NPs or by employing pre-synthesized Au NPs. All LDAu NPs were found to release drug selectively at the physiological pH of 7.4 and showed 2.5 times increase in the oral bioavailability of diacerein. Pharmacological efficacy was significantly improved i.e., greater than the additive effect of diacerein and Au NPs alone. LDAu NPs started suppressing inflammation at first phase, whereas LD NPs showed activity in the second phase of inflammation. These results indicate the interaction of Au NPs with prostaglandins and histaminic mediators of first phase of carrageenan induced inflammation. Acute toxicity study showed no hepatic damage but the renal toxicity parameters were close to the upper safety limits. Toxicity parameters were dependent on surface engineering of LDAu NPs. Apart from enhancing the oral bioavailability of hydrophobic drugs and improving their anti-inflammatory activity, these hybrid nanocarriers may have potential applications in gold-based photothermal therapy and the tracing of inflammation at atherosclerotic and arthritic site.

Mubashar Rehman,1 Asadullah Madni,1 Ayesha Ihsan,2 Waheed Samraiz Khan,2 Muhammad Imran Khan,1 Muhammad Ahmad Mahmood,1 Muhammad Ashfaq,1 Sadia Zafar Bajwa,2 Imran Shakir31Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia University of Bahawalpur, Pakistan; 2Nanobiotechnology Group, Industrial Biotechnology Division, National Institute of Biotechnology and Genetic Engineering, Faisalabad, Pakistan; 3Sustainable Energy Technologies (SET) centre, College of Engineering, King Saud University, Riyadh, Saudi ArabiaAbstract: Binary fatty acid mixture-based solid lipid nanoparticles (SLNs) were prepared for delivery of diacerein, a novel disease-modifying osteoarthritis drug, with and without simultaneously loaded gold nanoparticles (GNPs). In order to optimize SLNs for temperature-responsive release, lipid mixtures were prepared using different ratios of solid (stearic acid or lauric acid) and liquid (oleic acid) fatty acids. SLNs were prepared by microemulsification (53 nm), hot melt encapsulation (10.4 nm), and a solvent emulsification-evaporation technique (7.8 nm). The physicochemical characteristics of SLNs were studied by Zetasizer, Fourier transform infrared, and X-ray diffraction analysis. High encapsulation of diacerein was achieved with diacerein-loaded and simultaneously GNP-diacerein-loaded SLNs. In vitro dissolution studies revealed a sustained release pattern for diacerein over 72 hours for diacerein-loaded SLNs and 12 hours for GNP-diacerein-loaded SLNs. An increase in diacerein payload increased the release time of diacerein while GNPs decreased it. In addition, rapid release of diacerein over 4 hours was observed at 40°C (melting point of optimized fatty acid mixture), demonstrating that these binary SLNs could be used for thermoresponsive drug delivery. Kinetic modeling indicated that drug release followed zero order and Higuchi diffusion models (R2>0.9), while the Korsmeyer-Peppas model predicted a diffusion release mechanism (n

Liposomes are lipid based vesicular systems that offer novel platform for versatile drug delivery to target cell. Liposomes were first reported by Bangham and his co-workers in 1964 (1). Since then, liposomes have undergone extensive research with the prime aim to optimize encapsulation, stability, circulation time and target specific drug delivery. Manipulation of a liposome’s lipid bilayer and surface decoration with selective ligands has transformed conventional liposomes into adaptable and multifunctional liposomes. Development of liposomes with target specificity provide the prospect of safe and effective therapy for challenging clinical applications. Bioresponsive liposomes offer the opportunity to release payload in response to tissue specific microenvironment. Incorporation of novel natural and synthetic materials has extended their application from stable formulations to controlled release targeted drug delivery systems. Integration and optimization of multiple features into one system revolutionized research in the field of cancer, gene therapy, immunotherapy and infectious diseases. After 50 years since the first publication, this review is aimed to highlight next generation of liposomes, their preparation methods and progress in clinical applications. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.