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Muhammad Ahmad Mahmood,1,2 Asadullah Madni,1 Mubashar Rehman,3 Muhammad Abdur Rahim,1 Abdul Jabar1 1Department of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan; 2Drug Testing Laboratory, Bahawalpur 63100, Pakistan; 3Faculty of Pharmacy, University of Central Punjab, Lahore 54000, PakistanCorrespondence: Asadullah MadniDepartment of Pharmacy, The Islamia University of Bahawalpur, Khawaja Fareed Campus, Railway Road, Bahawalpur, Punjab, PakistanTel +92 62 925 5243Fax +92 62 925 5565Email asadpharmacist@hotmail.comIntroduction: Polymeric nanoparticles are potential carriers for the efficient delivery of hydrophilic and hydrophobic drugs due to their multifaceted applications. Docetaxel is relatively less hydrophobic and twice as potent as paclitaxel. Like other taxane chemotherapeutic agents, docetaxel is not well tolerated and shows toxicity in the patients. Nanoencapsulation of potent chemotherapeutic agents has been shown to improve tolerability and therapeutic outcome. Therefore, the present study was designed to fabricate chitosan and sodium tripolyphosphate (STPP) based on ionically cross-linked nanoparticles for sustained release of docetaxel.Methods: Nanoparticles were prepared by the ionic-gelation method by dropwise addition of the STPP solution into the chitosan solution in different ratios. CNPs were characterized for post-formulation parameters like size, zeta potential, scanning electron microscope (SEM), FTIR, DSC/TGA, pXRD, and in-vitro drug release, as well as for acute oral toxicity studies in Wistar rats.Results and discussion: The optimized docetaxel loaded polymeric nanoparticles were in the size range (172.6nm–479.65 nm), and zeta potential (30.45–35.95 mV) required to achieve enhanced permeation and retention effect. In addition, scanning electron microscopy revealed rough and porous surface, whereas, FTIR revealed the compatible polymeric nanoparticles. Likewise, the thermal stability was ensured through DSC and TG analysis, and powder X-ray diffraction analysis exhibited solid-state stability of the docetaxel loaded nanoparticles. The in-vitro drug release evaluation in phosphate buffer saline (pH 7.4) showed sustained release pattern, i.e. 51.57–69.93% within 24 hrs. The data were fitted to different release kinetic models which showed Fickian diffusion as a predominant release mechanism (R2= 0.9734–0.9786, n= 0.264–0.340). Acceptable tolerability was exhibited by acute oral toxicity in rabbits and no abnormality was noted in growth, behavior, blood biochemistry or histology and function of vital organs.Conclusion: Ionically cross-linked chitosan nanoparticles are non-toxic and biocompatible drug delivery systems for sustained release of chemotherapeutic agents, such as docetaxel.Keywords: tripolyphosphate, ionic gelation, sustained release, targeting, biocompatible, biodegradable

Background: Lipid polymer hybrid nanoparticles (LPHNPs) for the controlled delivery of hydrophilic doxorubicin hydrochloride (DOX.HCl) and lipophilic DOX base have been fabricated by the single step modified nanoprecipitation method. Materials and methods: Poly (D, L-lactide-co-glicolide) (PLGA), lecithin, and 1,2-distearoyl-Sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000 (DSPE-PEG 2000) were selected as structural components. Results: The mean particle size was 173-208 nm, with an encapsulation efficiency of 17.8±1.9 to 43.8±4.4% and 40.3±0.6 to 59. 8±1.4% for DOX.HCl and DOX base, respectively. The drug release profile was in the range 33-57% in 24 hours and followed the Higuchi model (R2=0.9867-0.9450) and Fickian diffusion (n

The oral delivery of cancer chemotherapeutic drugs is challenging due to low bioavailability, gastrointestinal side effects, first-pass metabolism and P-glycoprotein efflux pumps. Thus, chemotherapeutic drugs, including Docetaxel, are administered via an intravenous route, which poses many disadvantages of its own. Recent advances in pharmaceutical research have focused on designing new and efficient drug delivery systems for site-specific targeting, thus leading to improved bioavailability and pharmacokinetics. A decent number of studies have been reported for the safe and effective oral delivery of Docetaxel. These nanocarriers, including liposomes, polymeric nanoparticles, metallic nanoparticles, hybrid nanoparticles, dendrimers and so on, have shown promising results in research papers and clinical trials. The present article comprehensively reviews the research efforts made so far in designing various advancements in the oral delivery of Docetaxel. Different strategies to improve oral bioavailability, prevent first-pass metabolism and inhibition of efflux pumping leading to improved pharmacokinetics and anticancer activity are discussed. The final portion of this review article presents key issues such as safety of nanomaterials, regulatory approval and future trends in nanomedicine research.

Graphene, the mother of all carbon materials, has unlocked a new era of biomedical nanomaterials due to its exceptional biocompatibility, physicochemical and mechanical properties. It is a single atom thick, nanosized, two-dimensional structure and provides high surface area with adjustable surface chemistry to form hybrids. The present article provides a comprehensive review of ever-expanding application of graphene nanomaterials with different inorganic and organic materials in drug delivery and theranostics. Methods of preparation of nanomaterials are elaborated and biological and physicochemical characteristics of biomedical relevance are also discussed. Graphene form nanomaterials with metallic nanoparticles offer multiscale application. First, graphene act as a platform to attach nanoparticles and provide excellent mechanical strength. Second, graphene improves efficacy of metallic nanoparticles in diagnostic, biosensing, therapeutic and drug delivery application. Graphene-based polymeric nanocomposites find wider application in drug delivery with flexibility to incorporate hydrophilic, hydrophobic, sensitive and macromolecules. In addition, grapheme quantum dots and graphene hybrids with inorganic nanocrystal and carbon nanotubes hybrids have shown interesting properties for diagnosis and therapy. Finally, we have pointed out research trends that may be more common in future for graphene-based nanomaterials.

Proniosomes (PN) are the dry water-soluble carrier systems that may enhance the oral bioavailability, stability, and topical permeability of therapeutic agents. The low solubility and low oral bioavailability due to extensive first pass metabolism make Pentazocine as an ideal candidate for oral and topical sustained release delivery. The present study was aimed to formulate the PNs by quick slurry method that are converted to niosomes (liquid dispersion) by hydration, and subsequently formulated to semisolid niosomal gel. The PNs were found in spherical shape in the SEM and stable in the physicochemical and thermal analysis (FTIR, TGA, and XRD). The quick slurry method produced high recovery (> 80% yield) and better flow properties (θ = 28.1–37.4°). After hydration, the niosomes exhibited desirable entrapment efficiency (44.45–76.23%), size (4.98–21.3 μm), and zeta potential (− 9.81 to − 21.53 mV). The in vitro drug release (T100%) was extended to more than three half-lives (2–4 h) and showed good fit to Fickian diffusion indicated by Korsmeyer-Peppas model (n = 0.136–0.365 and R2 = 0.9747–0.9954). The permeation of niosomal gel was significantly enhanced across rabbit skin compared to the pure drug-derived gel. Therefore, the PNs are found promising candidates for oral as dissolution enhancement and sustained release for oral and topical delivery of pentazocine for the management of cancer pain.

Lipid-polymer hybrid nanoparticles (LPHNPs) are emerging platforms for drug delivery applications. In the present study, methotrexate loaded LPHNPs consisted of PLGA and Lipoid S100 were fabricated by employing a single-step modified nanoprecipitation method combined with self-assembly. A three factor, three level Box Behnken design using Design-Expert® software was employed to access the influence of three independent variables on the particle size, drug entrapment and percent drug release. The optimized formulation was selected through numeric optimization approach. The results were supported with the ANOVA analysis, regression equations and response surface plots. Transmission electron microscope images indicated the nanosized and spherical shape of the LPHNPs with fair size distribution. The nanoparticles ranged from 176 to 308nm, which increased with increased polymer concentration. The increase in polymer and lipid concentration also increased the drug entrapment efficiency. The in vitro drug release was in range 70.34-91.95% and the release mechanism follow the Higuchi model (R2=0.9888) and Fickian diffusion (n

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.

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.

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 (

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.