Targeted delivery of liposomal Ribociclib to SLC7A5 transporters in breast cancer cells.

This study aimed to prepare SLC7A5 transporters targeted liposomes of Ribociclib (RB) by stear(o)yl conjugation of Phe, Asp, Glu amino acids to liposomes as targeting moieties. The liposomes were optimized for their formulations. Cell analysis on two cell lines of MCF-7 and NIH-3T3 were done including; cell viability test by MTT assay, cellular uptake, and cell cycle arrest by flow cytometry. The optimal liposomes showed the particle size of 123.6 ± 1.3 nm, drug loading efficiency and release efficiency of 83.87% ± 1.33% and 60.55% ± 0.46%, respectively. The RB loaded liposomes showed no hemolysis activity. Targeted liposomes increased cytotoxicity on MCF-7 cells more significantly than NIH-3T3 cells. Cell flow cytometry indicated that targeted liposomes uptake was superior to plain (non-targted) liposomes and free drug. Free drug and RB-loaded liposomes interrupted cell cycle in G1. However, amino acid-targeted liposomes arrested cells more than the free drug at this stage. Targeted liposomes reduced cell cycle with more interruption in the G2/M phase compared to the negative control.

Keratinocyte Exosomes for Topical Delivery of Tofacitinib in Treatment of Psoriasis: an In Vitro/ In Vivo Study in Animal Model of Psoriasis.

INTRODUCTION: Exosomes are extracellular vesicles in the range of 40-150 nm released from the cell membrane. Exosomes secreted by keratinocytes can communicate with other keratinocytes and immune cells with specific biomarkers at their surface, which may be effective on inflammation of psoriasis and its pathogenesis. OBJECTIVE: The present study aimed to formulate and study effectiveness of an exosomal delivery system of tofacitinib (TFC). METHODS: TFC was loaded by different methods in exosomes and then characterized for particle size, zeta potential, drug loading efficiency, and release efficiency. By comparing these parameters, the probe sonication method was chosen to load TFC into exosomes. The MTT assay was used to compare the cytotoxicity of the free drug with the TFC-loaded exosomes (TFC-Exo), and Real-time PCR was used to determine the expression levels of several genes involved in psoriasis expressed in the A-431 keratinocyte and their suppression after treatment. Animal model of psoriasis was induced in BALB/c mice by imiquimod and the efficacy of free TFC, and TFC-Exo were studies on macroscopic appearance and histopathological symptoms. RESULTS: Exosomes encapsulating TFC showed lower cytotoxicity in MTT assay, higher suppression the expression of TNF-a, IL-23, IL-6, and IL-15 genes in real-time PCR and better therapeutic effect on animal models compered to free TFC. CONCLUSIONS: This method of drug delivery for TFC may be effective on enhancing its therapeutic effects and reduction its side effects favorably in chronic administration.

Antibacterial and pH-sensitive methacrylate poly-L-Arginine/poly (ß-amino ester) polymer for soft tissue engineering.

During the last decade, pH-sensitive biomaterials containing antibacterial agents have grown exponentially in soft tissue engineering. The aim of this study is to synthesize a biodegradable pH sensitive and antibacterial hydrogel with adjustable mechanical and physical properties for soft tissue engineering. This biodegradable copolymer hydrogel was made of Poly-L-Arginine methacrylate (Poly-L-ArgMA) and different poly (ß- amino ester) (PßAE) polymers. PßAE was prepared with four different diacrylate/diamine monomers including; 1.1:1 (PßAE1), 1.5:1 (PßAE1.5), 2:1 (PßAE2), and 3:1 (PßAE3), which was UV cross-linked using dimethoxy phenyl-acetophenone agent. These PßAE were then used for preparation of Poly-L-ArgMA/PßAE polymers and revealed a tunable swelling ratio, depending on the pH conditions. Noticeably, the swelling ratio increased by 1.5 times when the pH decreased from 7.4 to 5.6 in the Poly-L-ArgMA/PßAE1.5 sample. Also, the controllable degradation rate and different mechanical properties were obtained, depending on the PßAE monomer ratio. Noticeably, the tensile strength of the PßAE hydrogel increased from 0.10 ± 0.04 MPa to 2.42 ± 0.3 MPa, when the acrylate/diamine monomer molar ratio increased from 1.1:1 to 3:1. In addition, Poly-L-ArgMA/PßAE samples significantly improved L929 cell viability, attachment and proliferation. Poly-L-ArgMA also enhanced the antibacterial activities of PßAE against both Escherichia coli (~5.1 times) and Staphylococcus aureus (~2.7 times). In summary, the antibacterial and pH-sensitive Poly-L-ArgMA/PßAE1.5 with suitable mechanical, degradation and biological properties could be an appropriate candidate for soft tissue engineering, specifically wound healing applications.

Preparation and characterization of hydroxyapatite nanoparticles doped with nickel, tin, and molybdate ions for their antimicrobial effects.

BACKGROUND: Hydroxyapatite (HAp) nanoparticles doped with some ions have shown anticancer and antibacterial properties and are of great interest for the development of new biomedical applications. Therefore, the present study aimed to investigate the preparation and in vitro characterization of HAp nanoparticles doped with (Ni2+), tin (Sn2+), molybdate (Mo3+) ions for prevention of infections specially in bone tissue engineering. METHODS: HAp and HAp nanocrystal powders doped with nickel (Ni2+), tin (Sn2+), molybdate ions (Mo3+) with concentrations of 500, 1000, and 2000 ppm were prepared by the sol-gel method using a combination of calcium nitrate and phosphorous pentoxide as chemical reagents. The nanoparticles were characterized by FT-IR, XRD, EDAX and SEM. Their antimicrobial effect was studied by disk diffusion method on two types of bacteria: Pseudomonas aeruginosa and Staphylococcus aureus. RESULTS: FT-IR and XRD tests confirmed the formation of HAp nanoparticles. SEM images showed the morphology and nanostructure of HAp and Ni@HAp. Ni@HAp showed significantly more antimicrobial effects than the other two ions on S. aureus. EDAX confirmed the presence of Ni2+ ions in the Ni@HAp structure and the element map also showed very good dispersion of elements in both HAp and Ni@HAp structures. CONCLUSIONS: HAp nanoparticles doped with nickel ions may be considered as a promising antibacterial treatment in bone tissue engineering and repairing of skeletal injuries contaminated with S. aureus.

In vivo assessment of bone repair by an injectable nanocomposite scaffold for local co-delivery of autologous platelet-rich plasma and calcitonin in a rat model.

BACKGROUND: Gellan gum is obtained from the bacterium Sphingomonas elodea and is a polysaccharide with carboxylic acid functional groups. The goal of this project was to investigate the osteoinductive effect of local administration of calcitonin through an injectable scaffold of gellan gum containing salmon calcitonin loaded in silsesquioxane nanoparticles, hydroxyapatite, and platelets rich plasma. METHODS: The femur of rats was defected by creating a 2 × 5 mm2 hole using an electric drill. The defect was filled with an injectable hydrogel scaffold composed of gellan gum enriched with salmon calcitonin loaded in silsesquioxane nanoparticles, hydroxyapatite, platelets rich plasma, and then the radiologic images were taken. Bone densitometry and the histologic studies were carried out by Hematoxylin & Eosin test. Biochemical analysis was done to measure the serum alkaline phosphatase (ALP), calcium, and calcitonin concentration. RESULTS: Healing of the bone defects and bone densitometry in the treated group by calcitonin-loaded scaffold was significantly higher (p < 0.05) and bone formation occupied 75% of the defect was greater than in other groups. Serum ALP and calcium levels in the scaffold-loaded calcitonin group were more than in the other groups (p < 0.05). The osteogenic marker genes also increased significantly (p < 0.05) with free calcitonin and the scaffold. CONCLUSIONS: Gellan gum-based scaffold loaded with calcitonin may be considered a promising local treatment to progress bone formation in repairing skeletal injuries.

Ocular delivery of sunitinib-loaded nanoparticles doped in tragacanthic acid hydrogel in treatment of diabetic retinopathy in rats.

OBJECTIVE: Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus. This study aimed to compare the effect of sunitinib-loaded poly (glycerol sebacate) (PGS)/gelatin nanoparticles doped in an injectable hydrogel with bevacizumab as a standard treatment of DR. METHODS: The shear-sensitive hydrogel was prepared based on tragacanthic acid (TA) cross-linked with sodium acetate. DR was induced in rats by streptozotocin (STZ), and the animals were injected intravitreally a single dose of 20 µL sunitinib solution in three different concentrations (12.5, 25, and 50 µg/mL), sunitinib-loaded nanoparticles in hydrogel (413 µg/mL) and bevacizumab solution (6.25 mg/mL). The efficacy of the treatments was studied by histological and immunohisitological tests, angiogenesis, and optical coherence tomography (OCT). Vascular endothelial growth factor (VEGF) concentration was measured in the retina. RESULTS: The results revealed that 20 µL of sunitinib with the concentration of 25 µg/mL was effective in DR without any disruption in the retina or any other side effects. This dose was considered the therapeutic dose for nanoparticles. Sunitinib loaded PGS/gelatin nanoparticles that were incorporated in the injectable hydrogel were as effective as bevacizumab in controlling DR. Although sunitinib solution reduced VEGF production and neovascularization in the retina compared to the negative control group, it was not as suitable as the nanoparticles. TA-based hydrogel showed no toxicity on the normal retina, and the angiography and histologic studies confirmed the VEGF results.' CONCLUSIONS: Sunitinib nanoparticles doped in TA hydrogel may be an appropriate substitution of bevacizumab in the treatment of DR.

pH-responsive glucosamine anchored polydopamine coated mesoporous silica nanoparticles for delivery of Anderson-type polyoxomolybdate in breast cancer.

AIM: This study aimed to develop novel pH-sensitive Glucosamine (Glu) targeted Polydopamine (PDA) coated mesoporous silica (SBA-15) nanoparticles (NPs) for selective delivery of anticancer Anderson-type manganese polyoxomolybdate (POMo) to breast cancer. METHODS: The POMo@SBA-PDA-Glu NPs were prepared via direct hydrothermal synthesis of SBA, POMo loading, in situ PDA post functionalization, and Glu anchoring; the chemical structures were fully studied by different characterisation methods. The anticancer activity was studied by MTT method and Annexin V-FITC apoptosis detection kit. RESULTS: The optimised NPs had a hydrodynamic size (HS) of 195 nm, a zeta potential (ZP) of -18.9 mV, a loading content percent (LC%) of 45%, and a pH-responsive release profile. The targeted NPs showed increased anticancer activity against breast cancer cell lines compared to the free POMo with the highest cellular uptake and apoptosis level in the MDA-MB-231 cells. CONCLUSIONS: POMo@SBA-PDA-Glu NPs could be a promising anticancer candidate for further studies.

Cationic Okra gum coated nanoliposomes as a pH-sensitive carrier for co-delivery of hesperetin and oxaliplatin in colorectal cancers.

Oxaliplatin (OXP) is the typical treatment for colorectal cancer. Combining chemotherapeutic drugs can reduce drug resistance and side effects. In the present study, the co-delivery of OXP with Hesperetin (HSP), a natural anti-cancer flavonoid, by nanoliposomes was studied against HT-29 colon cancer cells. Cationic Okra gum (COG) was synthesized to coat nanoliposomes. The successful synthesis of COG was confirmed by NMR spectroscopy. Liposomes were prepared by thin film hydration technique. Formulations containing 0.5, 1, and 2 mg·ml-1 COG, had particle sizes ranging from 145 to 175 nm and zeta potentials for uncoated and coated formulations changed between -29 and -0.403 mV. Coated liposomes released 98 and 66% of HSP and OXP, respectively during 24 h pH-dependently. Cationic Okra gum enhanced the physical stability of the liposomes for about 30 days. The composite liposomes containing OXP and HSP at final concentrations of 1.125 and 125 µM, respectively could generate significant cytotoxicity at 48 h in comparison to each drug alone. Extracted drug-target interactions from the STITCH database, showed that Catalase (CAT) is the common target between OXP and HSP drugs. Measurement of the CAT activity may be used as an indicator to investigate the mechanism of action of these drugs in subsequent experiments.

Biotin-Targeted Nanomicellar Formulation of an Anderson-Type Polyoxomolybdate: Synthesis and In Vitro Cytotoxicity Evaluations.

This study is aimed at developing a micellar carrier for an Anderson-type manganese polyoxomolybdate (TRIS-MnPOMo) to improve the potency and reduce the general toxicity. The biotin-targeted stearic acid-polyethylene glycol (SPB) polymeric conjugate was selected for the first time as a micelle-forming basis for the delivery of TRIS-MnPOMo to breast cancer cells. The cytotoxicity of TRIS-MnPOMo and its nanomicellar form (TRIS-MnPOMo@SPB) was evaluated against MCF-7, MDA-MB-231 (breast cancer cell lines), and HUVEC (normal cell line) in vitro using the MTT assay. The quantity of cellular uptake and apoptosis level were studied properly using standard methods. The hydrodynamic size, zeta potential, and polydispersity index of the prepared micelles were 140 nm, -15.6 mV, and 0.16, respectively. The critical micelle concentration was about 30 µg/mL, which supports the colloidal stability of the micellar dispersion. The entrapment efficiency was interestingly high (about 82%), and a pH-responsive release of TRIS-MnPOMo was successfully achieved. The micellar form showed better cytotoxicity than the free TRIS-MnPOMo on cancer cells without any significant heme and normal cell toxicity. Biotin-targeted nanomicelles internalized into the MDA-MB-231 cells interestingly better than nontargeted micelles and TRIS-MnPOMo, most probably via the endocytosis pathway. Furthermore, at the same concentration, micelles remarkably increased the level of induced apoptosis in MDA-MB-231 cells. In conclusion, TRIS-MnPOMo@SPB could profoundly improve potency, safety, and cellular uptake; these results are promising for further evaluations in vivo.

Production of doxorubicin-loaded PCL nanoparticles through a flow-focusing microfluidic device: encapsulation efficacy and drug release.

The present study shows a facile route for producing doxorubicin (DOX)-loaded polycaprolactone (PCL) nanoparticles using a microfluidic device with a flow-focusing platform in a single step. Indeed, the evaluation of the performance of the flow-focusing microfluidic device for the preparation of DOX-loaded PCL (DOX/PCL) nanoparticles with a uniform size distribution and high encapsulation efficiency (EE) by applying the liquid non-solvent precipitation process is very important. Accordingly, the physicochemical characteristics of the DOX/PCL nanoparticles such as their mean size, polydispersity index (PDI), and EE were investigated by studying different parameters such as the flow rate ratio (FRR) and DOX concentration. Also, the release study was carried out at two pH of 5.5 and 7.4. The mean size of DOX/PCL nanoparticles achieved was in the range of 120-320 nm with a PDI ≤ 0.29 and EE between 48% and 87%. Moreover, the release profile of DOX/PCL nanoparticles was sustained for 10 days (≤66%) at pH 7.4. This means that the production process can result in a high EE and low release of the DOX drug.

Co-delivery of rituximab targeted curcumin and imatinib nanostructured lipid carriers in non-Hodgkin lymphoma cells.

The aim of the present study was production of nanostructured lipid carriers (NLCs) of curcumin and imatinib for co-administration in non-Hodgkin lymphoma cells. NLCs were prepared and conjugated to rituximab to target CD20 receptors of lymphoma cell lines. Oleic acid or Labrafac and glyceryl monostearate or lecithin were used for production of NLCs. The antibody coupling efficiency to NLCs and their physical characteristics were studied. The cytotoxicity of NLCs on Jurkat T cells (CD20 receptor negative) and Ramos B cells (CD20 receptor positive) was studied by MTT assay. The cellular uptake was determined by fluorescent microscopy. The results indicated both curcumin and imatinib targeted NLCs had a significant cytotoxic effect much higher than the free drugs and non-targeted NLCs on Ramos cells. In both cell lines, the cytotoxicity of the co-administrated drugs was significantly higher than each drug alone. In Ramos cells the co-administration of curcumin (15 µg/ml)/imatinib (5 µg/ml) decreased the free curcumin IC50 from 8.3 ± 0.9 to 1.9 ± 0.2 µg/ml, and curcumin targeted NLCs from 6.7 ± 0.1 to 1.3 ± 0.2 µg/ml. In this case the IC50 of imatinib was reduced from 11.1 ± 0.7 to 2.3 ± 0.1 µg/ml and imatinib targeted NLCs from 4.3 ± 0.1 to 1.4 ± 0.0 µg/ml. The co-administration of ritoximab conjugated NLCs of curcumin and imatinib may enhance cytotoxicity of imatinib in treatment of non-Hodgkin lymphoma.

Boron phenyl alanine targeted chitosan-PNIPAAm core-shell thermo-responsive nanoparticles: boosting drug delivery to glioblastoma in BNCT.

Boron neutron capture therapy (BNCT) is one of the best treatment modalities for glioblastoma multiform that could selectively kill the tumor cells. To be successful in BNCT, it is crucial to have enough 10B in the tumor. l-boron phenylalanine (l-BPA) targeted thermo-responsive core-shell nanoparticles (NPs) of chitosan-poly(N-isopropylacrylamide) (PNIPAAm) were our idea for endocytosis via sialic acid receptors, and selective delivery of 10B to glial cells. Methotrexate (MTX) was chosen as a model drug for evaluating the efficacy of NPs in tumor cells, and BPA was selected for BNCT purposes. The polymeric conjugates were synthesized and the chemical structures were approved by spectroscopic methods (FTIR, 1H NMR, and 11B NMR). Cargos were loaded efficiently (>95%) in the prepared NPs, and the release profile of MTX and BPA was studied around the lower critical solution temperature (LCST; about 39 °C). The loaded drugs were released quantitatively at the LCST, while almost no drug was released at 37 °C. The prepared NPs did not show considerable hemolysis ratio (<2%) and were still safe when loaded BPA, on U87MG cells. The MTX loaded NPs showed lower IC50 (30.78 µg/mL) than the free MTX (37.03 µg/mL) in MTT assay, and targeted NPs had the lowest IC50s in U87MG cell lines (27.35 µg/mL). Targeted BPA@CSSU-PNI NPs were uptaken better than the non-targeted ones by U87MG cells, and CR-39 assay showed the boron content efficiency for further applications in BNCT. This study's results introduce novel targeted thermo-responsive NPs for treating glioblastoma using BNCT.

In vitro and in vivo evaluation of an ionic sensitive in situ gel containing nanotransfersomes for aripiprazole nasal delivery.

In the current study, a composite in-situ gel formulation containing aripiprazole (APZ) loaded transfersomes (TFS) was developed for the intranasal brain targeting of APZ. APZ loaded TFS were prepared by applying the film hydration method and optimized using an irregular factorial design. The prepared formulations were optimized based on different parameters including particle size, polydispersity index (PdI), zeta potential, encapsulation efficiency (EE) and release efficiency (RE). The optimized APZ-TFS were distributed in an ion-triggered deacetylated gellan gum solution (APZ-TFS-Gel) and evaluated in terms of pH, gelling time, rheological properties and in-vitro release study. The therapeutic efficacy of the best APZ-TFS-Gel was then tested in the mice model of schizophrenia induced by ketamine by evaluating various behavioral parameters. The optimized formulation showed the particle size of 72.12 ± 0.72 nm, the PdI of 0.19 ± 0.07, the zeta potential of -55.56 ± 1.9 mV, the EE of 97.06 ± 0.10%, and the RE of 70.84 ± 1.54%. The in-vivo results showed that compared with the other treatment groups, there was a considerable increase in swimming and climbing time and a decrease in locomotors activity and immobility time in the group receiving APZ-TFS-Gel. Thus, APZ-TFS-Gel was found to have desirable characteristics for therapeutic improvement.

Sustained-release of erythropoietin using a novel injectable thermosensitive hydrogel: in vitro studies, biological activity, and efficacy in rats.

In the current study erythropoietin (EPO) loaded trimethyl chitosan/tripolyphosphate nanoparticles-embedded in a thermosensitive hydrogel was prepared. The influence of the main experimental factors on the properties of EPO-loaded nanoparticles were evaluated using a two-factors central composite design and the optimized formulation was then freeze dried. Sodium dodecyl sulfate-page and circular dichroismspectroscopy were used to confirm the structural stability of EPO following encapsulation and freeze drying. Rheological properties, and the release rate of EPO from the hydrogel were examined. Mean particle size, zeta potential, and entrapment efficiency of the optimized EPO-loaded nanoparticles were confirmed 151.5 ± 16 nm, 11.5 ± 1.8 mV, and 78.5 ± 5.9%, respectively. The hydrogel containing nanoparticles existed as a solution at room temperature converted to a semisolid upon increasing the temperature to 35 ± 1.2 °C and demonstrated controlled release of EPO for more than 10 days. The stability of EPO in the hydrogel system was further investigated using in vivo biological activity assay and the result revealed relative potency of 0.85 as calibrated with standard EPO. Finally, a single injection of the EPO-loaded nanoparticles-embedded in the hydrogel administered to Sprague-Dawley rats resulted in elevated reticulocytes for about 20 days compared to control group received blank hydrogel.

Calcitonin-loaded octamaleimic acid-silsesquioxane nanoparticles in hydrogel scaffold support osteoinductivity in bone regeneration.

Novel osteoinductive scaffolds fabricated using the benefits of tissue engineering techniques accompanied by utilizing drugs can accelerate bone regeneration. The purpose of this study was to load salmon calcitonin (sCT) in octamaleimic acid-silsesquioxane (OMA-POSS) nanoparticles and enrich the hydrogel scaffold based on hydroxyapatite, Gelrite® and platelet-rich plasma (PRP) for use in bone tissue engineering. The loading efficiency, release percentage, particle size and zeta potential of the nanoparticles were evaluated. The proliferation of seeded MG-63 osteoblast cells on the designed scaffold, its cytotoxicity and osteo-conductivity were studied by alkaline phosphatase measurement and Alizarin red staining. The expression of cellular osteogenic markers such as collagen 1 (COL1A1), osteocalcin (BGLAP) and osteopontin (SPP1) was examined using reverse transcription polymerase chain reaction. The results revealed that the particle size of the nanoparticles varied between 94.2 and 199.2 nm and their negative surface charge increased after drug conjugation. The osteoblast cell proliferation and calcium granule production in the optimum formulation were significantly higher in comparison with the control group (p < 0.05). Osteogenic markers increased significantly after a specific number of days of cell culture compared to the control group (p < 0.05). The results also showed the potential of the designed scaffold in bone tissue engineering.

Boron phenyl alanine targeted ionic liquid decorated chitosan nanoparticles for mitoxantrone delivery to glioma cell line.

Nanotechnology has revolutionized drug delivery in cancer treatment. In this study, novel efficient pH-responsive boron phenylalanine (BPA) targeted nanoparticles (NPs) based on ionic liquid modified chitosan have been introduced for selective mitoxantrone (MTO) delivery to the U87MG glioma cells. Urocanic acid (UA) and imidazolium (Im) based ionic liquids were used for structural modification simultaneously. The NPs were prepared by ionic gelation and fully characterized; the pH-responding and swelling index of NPs were studied carefully. The drug release was studied at a pH of 5.5 in comparison to the neutral state. Also, the cytotoxicity of loaded NPs was evaluated on U87MG glial cells, and cellular uptake was studied. The NPs were smaller than 250 nm, with a spherical pattern and acceptable uniformity with a zeta potential around +20 mV. The loading efficacy was about 85%, and most of the loaded MTO released at a pH of 5.5 after 48 h with a swelling-controlled mechanism. The NPs showed a relatively lower IC50 than the free MTO, and the BPA-targeted NPs have lower IC50 and better cellular uptake than non-targeted NPs in U87MG cells. More studies on this promising formula are on the way, and the results will be published soon.

A review of network-based approaches to drug repositioning.

Experimental drug development is time-consuming, expensive and limited to a relatively small number of targets. However, recent studies show that repositioning of existing drugs can function more efficiently than de novo experimental drug development to minimize costs and risks. Previous studies have proven that network analysis is a versatile platform for this purpose, as the biological networks are used to model interactions between many different biological concepts. The present study is an attempt to review network-based methods in predicting drug targets for drug repositioning. For each method, the preferred type of data set is described, and their advantages and limitations are discussed. For each method, we seek to provide a brief description, as well as an evaluation based on its performance metrics.We conclude that integrating distinct and complementary data should be used because each type of data set reveals a unique aspect of information about an organism. We also suggest that applying a standard set of evaluation metrics and data sets would be essential in this fast-growing research domain.

Preparation and characterization of polypills containing aspirin and simvastatin using 3D printing technology for the prevention of cardiovascular diseases.

Three-dimensional (3D) printing has become a promising manufacturing technique for pharmaceutical products. Fused deposition modeling (FDM) is the most affordable printing technology. But this technique has two major drawbacks: limited drug-loading capacity and the stability of thermolabile drugs. So, other techniques such as melt casting could be associated with FDM to overcome these limitations. In the melt casting method, the drug is mixed with a molten polymer and is poured in the mold and allowed to solidify. The present study for the first time describes the preparation of a multi-compartment polypill permits the physical separation of incompatible drugs by combination of FDM and melt casting techniques. A two-compartment polypill was made using FDM by Eudragit® L100-55 and simultaneously its compartments were filled by aspirin and simvastatin containing molten PEG 6000. Simultaneous usage of FDM and melt casting techniques could increase the drug-loading capacity of 3D-printed polypills. The low temperatures used in melt casting and the absence of solvent in this method would warrant the integrity of polypills, the complete separation of incompatible drugs, and their stability. The prepared polypills showed good uniformity in drug content which confirms the precision of FDM and melt casting techniques. Drug interaction was investigated before and after the accelerated stability test using DSC, which showed that 3D-printed polypills successfully preserved drugs from the interaction. For the first time, this study demonstrates the feasibility of the combination of FDM and melt casting techniques as an innovative platform for CVD polypills production.

Preparation and evaluation of inhalable dry powder containing glucosamine-conjugated gefitinib SLNs for lung cancer therapy.

Gefitinib as an epidermal growth factor receptor tyrosine kinase inhibitor has strong potential in lung cancer therapy. However, a major challenge of using gefitinib is its toxicities. In the present study, we developed a dry powder inhaler dosage form containing gefitinib loaded glucosamine targeted solid lipid nanopaticles (Gef-G-SLNs) to locally transfer anticancer agent to the lung tumor. The Gef-G-SLNs were prepared by emulsion-solvent diffusion and evaporation method and optimized with irregular factorial design. The optimized nanoformulation was tested for action against A549 cells. Mannitol or lactose based dry powders were obtained from Gef-G-SLNs after spray drying and characterized using Anderson Cascade Impactor. The optimized formulation had drug loading of 33.29%, encapsulation efficiency of 97.31 ± 0.23%, zeta potential of -15.53 ± 0.47 mV, particle size of 187.23 ± 14.08 nm, polydispersity index of 0.28 ± 0.02 and release efficiency of 35.46 ± 2.25%. The Gef-G-SLNs showed superior anticancer effect compared to free gefitinib. The increased cellular uptake of G-SLNs in A549 cells was demonstrated compared with non-targeted SLNs using flow cytometry and fluorescence microscopy. The produced mannitol based microparticles showed suitable aerodynamic properties with an acceptable mass median aerodynamic diameter of 4.48 µm and fine particle fraction of 44.41%. Therefore, it can be concluded that this formulation represents promising drug delivery to treatment of lung cancer.

RGD peptide grafted polybutylene adipate-co-terephthalate/gelatin electrospun nanofibers loaded with a matrix metalloproteinase inhibitor drug for alleviating of wounds: an in vitro/in vivo study.

The objective of the present study was the fabrication of a wound dressing membrane based on RGD modified polybutylene adipate-co-terephthalate (PBAT)/gelatin nanofibrous structures loaded with doxycycline (DOX). This type of nanofiber for wound healing has not been reported so far and is quite novel. PBAT and gelatin nanofibers were separately electrospun using double needles electrospinning setup. Electrospinning variables were optimized to obtain bead-free thin nanofibers. The amount of drug loaded and release were measured in different concentrations of DOX and PBAT. MMPs inhibition was studied by polyacrylamide gel-zymography. Then, surface of the nanofibers was modified with RGD peptide, and their antimicrobial effect was investigated on Staphylococcus aureus and Pseudomonas aeruginosa. Effect of developed nanofibrous membranes on L929 fibroblast cells proliferation, adhesion and closure of excised wounds in rat were also studied. PBAT/gelatin nanofibrous structures with average fiber diameter of 75-529 nm were developed successfully. Drug release study revealed that about 65% of DOX was released from the optimized formulation (P17D1.6) after 20 h. The developed DOX loaded membrane inhibited the MMPs activity and showed no cytotoxicity. RGD surface-modified PBAT/gelatin nanofibers significantly improved the wound closure and histopathological results (re-epithelialization, collagen deposition, and angiogenesis) in rats compared to the control groups. Overall, RGD immobilized PBAT/gelatin nanofibrous membrane may have a potential application for wound healing.