Assistant Professor + Postdoc fellow, Misr University for Science and Technology + Harvard Medical School
Combing Phosphodiesterase Inhibitor and Connective Tissue Stimulating Drugs in Nanofibrous Scaffold
According to several attempts to accelerate both wound healing and bone healing, it was observed that both healing process have several common healing features as inflammation, angiogenesis, epithetlization, collagen deposition and remodeling, Topical application of drugs shows promising bone healing activity e.g. phenytoin and sildenafil. However, no available product in the market loaded with any these drugs. Therefore, we propose to fabricate a highly porous electrospun nanofibrous scafold loaded with the two drugs with different healing mechanisms for bone healing to augment bone fracture healing.
The scaffold would be fabricated in the form of a two-layer sandwich structure, where each layer loaded with different drug. The first layer is composed of Phenytoin-loaded PLLA based nanofibers that could deliver the required dose in a well-controlled and sustained manner. The second layer is composed of Sildenafil-loaded PLLA based nanofibers that could deliver the required dose in a well-controlled and sustained manner. The two layers were prepared successfully through electrospinning technique after tailoring different parameters to produce highly porous scaffold in order to facilitate oxygen and nutrient diffusion for cell. Scanning electron microscope revealed that diameter of both PLLA based nanofibers layers were around ranged between 180 ± 20 nm to 290 ± 25 nm. Physicochemical characterization showed that PLLA based nanofibers showed swelling maximum after 6. In addition, biodegedability test showed that the nanofibers were capable of losing more than 25% of their weights in 14 days. Finally in vitro drug release profile showed that the nanofibers could deliver Phenytoin and sildenafil in a well-controlled manner along more than 20 days. Hence, the fabricated drug-loaded implantable scaffold could be a promising solution in complicated bone fracture/defects through targeting different phases in healing process.
Abstract: Smart materials are those materials that are responsive to chemical (organic molecules, chemical agents or specific agents), biochemical (protein, enzymes, growth factors, substrates or ligands), physical (electric field, magnetic field, temperature, pH, ionic strength or radiation) or mechanical (pressure or mechanical stress) signals. These responsive materials interact with the stimuli by changing their properties or conformational structures in a predictable manner. Recently, smart (stimuli-responsive) polymers have been utilized in various applications such as drug delivery and targeting, diagnostics, tissue engineering, and regenerative medicine. Particularly, they have been used as a platform to synthesize stimuli-responsive systems that could deliver therapeutics to a specific site for a specific period with minimal adverse effects. For instance, stimuli-responsive polymers-based systems have been recently reported to deliver different bioactive molecules such as carbohydrates (hyaluronic acid and heparin), chemotherapeutic agents (doxorubicin, paclitaxel, vincristine and fluorouracil), small organic molecules (anti-inflammatory drugs, anti-coagulants and steroids), nucleic acids (DNA, mRNA and siRNA), and proteins (antibodies, enzymes, growth factors and hormones). Proteins are considered to be life engines since they play many fundamental roles inside the human body in catalyzing biochemical reactions, forming cellular structures, and transporting molecules. Over the last decades, protein therapeutics played a fundamental role in treatment of various chronic diseases such as metabolic disorders e.g. diabetes, cancer as well as some autoimmune diseases. For instance insulin has been used in treatment of diabetes. However, being a protein in nature, insulin delivery is limited by its instability, short half-life, and easy denaturation when administered orally. In addition, traditional administration of insulin via injection does not meet patients' compliance over prolonged periods. To overcome these challenges, much research efforts have been devoted to design and develop convenient smart controlled nanosystems for protein therapeutics and insulin delivery. This review article highlights the most recent work done for developing smart responsive systems for the controlled delivery of therapeutic proteins and insulin.
Pub.: 06 Jun '17, Pinned: 28 Sep '17
Abstract: The aim of this study was to develop different vesicular systems for sertaconazole nitrate and evaluate the ability of targeting deep skin layers to treat dermal fungal infection. Therefore, different phospholipid based nanovesicles, namely liposomes, glycerosomes, transferosmes and ethosomes were prepared and in-vitro evaluated for morphology, entrapment efficiency, vesicle size and zeta potential value, followed by ex-vivo evaluation through skin penetration and permeation. The selected vesicular formula was incorporated into gel base system and assessed by ex-vivo permeation visualization study using confocal laser scanning microscopy (CLSM). In-vivo study was performed to compare antifungal efficacy of STZL loaded vesicular gel with commercial cream (Dermofix(®)). All nanovesicles were unilamller and almost spherical in shape. Entrapment efficiency, vesicle size and zeta potential were dependent upon vesicle composition. Vesicular formulae promoted drug permeation compared to commercial cream where transferosomal system containing 3% soyphospholipid (SPC) and 0.15% sodium deoxychloate (SDC) exhibited highest flux (645μg/cm(2)/hr). The CLSM images confirmed the penetration of the developed probe-loaded tansferosomal system to viable epidermis layers with fluorescence intensity greater than unencapsulated probe. The in-vivo study revealed significant prevention effect in immunecompromised rat model. Furthermore, the antifungal activity with lowest histopathological changes was significantly observed in the developed STZL-loaded transferosomal gel compared to commercial cream using immunecompromised rat model with fungal skin infection.
Pub.: 20 May '17, Pinned: 28 Sep '17
Abstract: This study aimed to coat lipid-based nanocarriers with chitosan to encapsulate nutraceuticals, minimize opsonization, and facilitate passive-targeting. Phase one was concerned with standardization according to the World Health Organization. Qualitative analysis using liquid chromatography-high-resolution mass spectrometry (LC-HRMS/MS) investigated the active constituents, especially reported cytotoxic agents. Cinnamaldehyde and rosmarinic acid were selected to be quantified using high-performance liquid chromatography. Phase two was aimed to encapsulate both extracts in solid lipid nanoparticles (core) and chitosan (shell) to gain the advantages of both materials properties. The developed experimental model suggested an optimum formulation with 2% lipid, 2.3% surfactant, and 0.4% chitosan to achieve a particle size of 254.77 nm, polydispersity index of 0.28, zeta potential of +15.26, and entrapment efficiency percentage of 77.3% and 69.1% for cinnamon and oregano, respectively. Phase three was focused on the evaluation of cytotoxic activity unencapsulated/encapsulated cinnamon and oregano extracts with/without 5-fluorouracil on HCT-116 cells. This study confirmed the success of the suggested combination with 5-fluorouracil for treating human colon carcinoma with a low dose leading to decreasing side effects and allowing uninterrupted therapy.
Pub.: 17 Aug '17, Pinned: 28 Sep '17
Abstract: Phenytoin (Ph), an antiepileptic drug, was reported to exhibit high wound healing activity. However, its limited solubility, bioavailability and inefficient distribution during topical administration limit its use. Therefore, this study aims to develop new single-dose electrospun nanoparticles-in-nanofibers (NPs-in-NFs) wound dressings that allow a well-controlled release of Ph. These NPs-in-NFs systems are based on enhanced chitosan (CS)/ polyethylene oxide (PEO) electrospun NFs incorporating optimized Ph-loaded nanocarriers. Firstly, a study was conducted to investigate Ph loading efficiency into polymeric nanocarriers with different natures; pluronic nanomicelles and poly(lactic-co-glycolic) acid (PLGA) NPs. The drug release profile form the nanocarriers was further optimized via lecithin coating. Secondly, different electrospinning parameters were manipulated to fabricate beads-free homogeneous NFs with optimized polymer ratios. Plain and Ph-loaded nanocarriers were characterized using FTIR, DSC, TGA, DLS and SEM. Both entrapment efficiency of Ph (EE%) and its release profile in PBS (pH 5.5), simulating wound environment were studied. Biodegradability, swelling, vapor permeability and porosity of the developed Ph-loaded NPs-in-NFs wound dressings were investigated. Morphology of the NPs-in-NFs was also studied using SEM and CLSM. Besides, the release profiles of Ph from the optimized NPs-in-NFs were assessed. The newly developed wound dressings were evaluated in-vitro for their cytotoxicity using human fibroblasts and in-vivo using a wound healing mice model. Nanocarriers with particle size of 100 to 180 nm were successfully prepared. All nanocarriers attained high drug entrapment efficiency exceeding 94%, and showed promising sustained release profiles compared to free Ph. Results also demonstrated that NFs incorporating the optimized lecithin-coated Ph-loaded PLGA NPs could be the most promising candidate for efficient wound healing. These NPs-in-NFs systems conferred a well-controlled and sustained release of Ph over 9 days. Moreover, they showed the best re-epithelization and healing quality during the in vivo study with minimal inflammatory and necrotic cells formation.
Pub.: 25 May '16, Pinned: 28 Sep '17
Abstract: This study reports a promising approach to enhance the oral delivery of propolis, improve its aqueous solubility and bioavailability, and allow its controlled release as well as enhancing its anticancer activity. Propolis was standardized then its solubility was improved via formulation into optimized solid dispersion (SD) matrices, and its release was controlled through incorporation into nanoparticles (NPs) of optimized composition followed by further inclusion into chitosan (Cs) microparticles. The anticancer activity of the newly developed propolis-loaded nano-in-microparticles (NIMs) was evaluated against human liver cancer (HepG2) and human colorectal cancer (HCT 116) cells. The prepared SDs, NPs and NIMs were characterized using SEM, TEM, DLS, FTIR, DSC and UV-Visible spectrophotometry. The therapeutic efficiency of formulated propolis was bio-assessed via cytotoxicity measurements, mitochondrial dysfunction, apoptosis-induced cell death and cell cycle arrest. The results demonstrated a considerable enhancement in propolis solubility with a controlled release profile in different GIT environments. In-vitro cytotoxicity studies showed that the propolis-loaded NIMs induce more cytotoxic effect on HepG2 cells than HCT-116 cells and mediated three-fold higher therapeutic efficiency than free propolis. The apoptosis assay indicated that the propolis-loaded NIMs induce apoptosis of HepG2 cells and significantly decrease their number in the proliferative G0/G1, S and G2/M phases.
Pub.: 07 Jul '16, Pinned: 28 Sep '17