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Farzana Parveen,1– 3 Asadullah Madni,2 Vladimir P Torchilin,1 Mubashar Rehman,4 Talha Jamshaid,2 Nina Filipczak,1 Nadia Rai,2,5 Muhammad Muzamil Khan,2,3 Muhammad Imran Khan6 1Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, 02115, USA; 2Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Punjab, 63100, Pakistan; 3Primary and Secondary Healthcare Department, Government of Punjab, Lahore, 54000, Pakistan; 4Department of Pharmacy, Quaid-i-Azam University, Islamabad, 45320, Pakistan; 5Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA, 92618, USA; 6Riphah Institute of Pharmaceutical Sciences, Riphah International University Lahore Campus, Lahore, 54000, PakistanCorrespondence: Asadullah Madni, Department of Pharmaceutics, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Punjab, 63100, Pakistan, Tel +92 62 925 5243, Fax +92 62 925 5565, Email asadpharmacist@hotmail.comBackground: Most of the traditional nanocarriers of cancer therapeutic moieties present dose-related toxicities due to the uptake of chemotherapeutic agents in normal body cells. The severe life-threatening effects of systemic chemotherapy are well documented. Doxorubicin, DOX is the most effective antineoplastic agent but with the least specific action that is responsible for severe cardiotoxicity and myelosuppression that necessitates careful monitoring while administering. Stimuli-sensitive/intelligent drug delivery systems, specifically those utilizing temperature as an external stimulus to activate the release of encapsulated drugs, have become a subject of recent research. Thus, it would be ideal to have a nanocarrier comprising safe excipients and controllable drug release capacity to deliver the drug at a particular site to minimize unwanted and toxic effects of chemotherapeutics. We have developed a simple temperature-responsive nanocarrier based on eutectic mixture of fatty acids. This study aimed to develop, physicochemically characterize and investigate the biological safety of eutectic mixture of fatty acids as a novel construct for temperature-responsive drug release potential.Methods: We have developed phase change material, PCM, based on a series of eutectic mixtures of fatty acids due to their unique and attractive physicochemical characteristics such as safety, stability, cost-effectiveness, and ease of availability. The reversible solid-liquid phase transition of PCM is responsible to hold firm or actively release the encapsulated drug. The eutectic mixtures of fatty acids (stearic acid and myristic acid) along with liquid lipid (oleic acid) were prepared to exhibit a tunable thermoresponsive platform. Doxorubicin-loaded lipid nanocarriers were successfully developed with combined hot melt encapsulation (HME) and sonication method and characterized to achieve enhanced permeability and retention (EPR) effect-based solid tumor targeting in response to exogenous temperature stimulus. The cytotoxicity against melanoma cell lines and in vivo safety studies in albino rats was also carried out.Results: Doxorubicin-loaded lipid nanocarriers have a narrow size distribution (94.59– 219.3 nm), and a PDI (0.160– 0.479) as demonstrated by photon correlation microscopy and excellent colloidal stability (Z.P value: − 22.7 to − 32.0) was developed. Transmission electron microscopy revealed their spherical morphology and characteristics of a monodispersed system. A biphasic drug release pattern with a triggered drug release at 41°C and 43°C and a sustained drug release was observed at 37°C. The thermoresponsive cytotoxic potential was demonstrated in B16F10 cancer cell lines. Hemolysis assay and acute toxicity studies with drug-free and doxorubicin lipid nanocarrier formulations provided evidence for their non-toxic nature.Conclusion: We have successfully developed a temperature-responsive tunable platform with excellent biocompatibility and intelligent drug release potential. The formulation components being from natural sources present superior characteristics in terms of cost, compatibility with normal body cells, and adaptability to preparation methods. The reported preparation method is adapted to avoid complex chemical processes and the use of organic solvents. The lipid nanocarriers with tunable thermoresponsive characteristics are promising biocompatible drug delivery systems for improved localized delivery of chemotherapeutic agents.Graphical Abstract: Keywords: nanostructured lipid carriers, lipid nanocarriers, thermoresponsive, eutectic mixtures, fatty acids, phase change materials, doxorubicin, acute toxicity studies, hemolysis assay

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.

Rehman M, Ihsan A, Madni A, et al. Int J Nanomedicine. 2017;12:8325–8336. The authors have advised Figure 3 on page 8332 is incorrect. An error was made in the labelling of the images with some FLOM samples incorrectly labelled as FLOD samples. The authors inadvertently selected a mislabelled FLOM sample to represent the FLOD sample without realising both the FLOM and FLOD images were the same. The correct Figure 3 is shown below. Figure 3 TEM images of (A) FLOM, (B) FLOD, (C) FLLM and (D) FLLD. Abbreviations: TEM, transmission electron microscopy; FLOM, 5-FU-loaded lauric acid and oleic acid nanoparticles prepared with mono-surfactant system; FLOD, 5-FU-loaded lauric acid and oleic acid nanoparticles prepared with double-surfactant system; FLLM, 5-FU-loaded lauric acid and linoleic acid nanoparticles prepared with mono-surfactant system; FLLD, 5-FU-loaded lauric acid and linoleic acid nanoparticles prepared with double-surfactant system; 5-FU, 5-fluorouracil. The authors apologize for this error and advise that this does not affect the results of the paper. Read the original article

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

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