How do lipid-based drug delivery systems affect the pharmacokinetic and tissue distribution of amiodarone? A comparative study of liposomes, solid lipid nanoparticles, and nanoemulsions.

Objectives: Lipid-based drug delivery systems (DDS) can improve the pharmacokinetic (PK) parameters of some drugs. Especially those with a high volume of distribution (Vd) leading to off-target accumulation and toxicity. Amiodarone as an anti-arrhythmic agent induces hypothyroidism and liver disorders limiting its clinical indication. Materials and Methods: In the present study, amiodarone PK parameters and biodistribution after IV administration of four nano-formulations to rats were compared. The formulations were liposomes, solid lipid nanoparticles (SLN), PEGylated SLN (PEG-SLN), and nanoemulsions (NE). All formulations were optimized. Results: The nanoparticles were spherical with a diameter of 100-200 nm and sustained in vitro drug release in buffer pH 7.4. The best-fitted model for the plasma concentration-time profile was two-compartmental. In vivo studies indicated the most changes in PKs induced after liposome, SLN, and NE administration, respectively. The area under the curve (AUC) and maximum plasma concentration (Cmax) of liposomes, SLN, and NE were 22.5, 2.6, 2.46 times, and 916, 58, and 26 times higher than that of amiodarone solution, respectively (P-value<0.05). The heart-to-liver ratio of amiodarone was higher for nano-formulations compared to drug solution except for liposomes. Conclusion: Lipid-based particles can improve the PK parameters of amiodarone and its distribution in different tissues.

Enhanced intracellular accumulation and cytotoxicity of bortezomib against liver cancer cells using N-stearyl lactobionamide surface modified solid lipid nanoparticles.

Asialoglycoprotein receptors (ASGPRs) are highly expressed on hepatocytes and have been used for liver-targeted delivery and hepatocellular carcinoma (HCC) therapy. However, targeted delivery of bortezomib (BTZ) to HCC has not been reported. In this study, N-stearyl lactobionamide (N-SALB) with galactose (Gal) moiety was synthesized as a targeting agent and its structure was confirmed by FT-IR and NMR analyses. N-SALB surface-modified solid lipid nanoparticles (SLNs) loaded with BTZ (Gal-SLNs/BTZ) were developed to target BTZ delivery into HCC cancer cells. The Gal-SLNs/BTZ had an average particle size of 116.3 nm, polydispersity index (PDI) of 0.210, and zeta potential of -13.8 mV. TEM analysis showed their nanometer-sized spherical morphology. The encapsulation efficiency (EE) and drug loading (DL) capacity were 84.5 % and 1.16 %, respectively. Release studies showed that BTZ loaded inside the SLNs was slowly released over a period of 72 h at pH 7.4. Flow cytometry analysis showed significantly higher intracellular uptake of N-SALB-targeted nanoparticles than non-targeted nanoparticles in HepG2 cells. All lipid formulations showed good biocompatibility in the cytotoxicity study using MTT assay. Concentration-dependent cytotoxicity was observed for all formulations, with N-SALB-targeted nanoparticles demonstrating more cytotoxicity against HepG2 cells. The highest percentage of apoptosis was obtained for N-SALB-targeted nanoparticles compared to non-targeted nanoparticles (42.2 % and 8.70 %, respectively). Finally, biodistribution studies in HepG2 bearing nude mice showed that the accumulation of targeted nanoparticles in the tumor was significantly higher than non-targeted nanoparticles.

An update review of smart nanotherapeutics and liver cancer: opportunities and challenges.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, typically diagnosed in advanced stages. Chemotherapy is necessary for treating advanced liver cancer; however, several challenges affect its effectiveness. These challenges include low specificity, high dosage requirements, high systemic toxicity and severe side effects, which significantly limit the efficacy of chemotherapy. These limitations can hinder the treatment of HCC. This review focuses on the prevalence of HCC, different types of liver cancer and the staging of the disease, along with available treatment methods. Additionally, explores recent and relevant studies on smart drug- and gene-delivery systems specifically designed for HCC. These systems include targeted endogenous and exogenous stimuli-responsive platforms.

Liver cancer is the third leading cause of cancer deaths in the world that is usually diagnosed in the last stages. Chemotherapy is commonly used to treat advanced liver cancer, but it faces several challenges that reduce its effectiveness. These challenges include low specificity (not targeting cancer cells specifically), high dosage requirements and side effects that can affect anywhere in the body. As a result, the efficacy of chemotherapy is significantly limited, making it difficult to treat liver cancer. This review discusses the prevalence of liver cancer, different types of liver cancer and how the disease is staged. It also explores various treatment methods available for liver cancer. Furthermore, the article explores recent and relevant studies on smart drug- and gene-delivery systems that are specifically designed to target liver cancer. These systems include platforms that respond to targeted and internal or external stimuli. They aim to improve the effectiveness of treatment for liver cancer.

Investigating the Effect of Basic Amino Acids and Glucosamine on the Solubility of Ibuprofen and Piroxicam.

Purpose: Poor aqueous solubility hampers the development of several compounds as pharmacological agents. Hence, preparing novel formulations with augmented absorption is a challenge in pharmaceutical industries. In this paper, we have examined the effect of basic amino acids including arginine (ARG), lysine (LYS), and glucosamine (GlucN) on the solubility of ibuprofen (IBU) and piroxicam (PXM) as drugs with limited solubility. We have also studied the effect of the dissolution media with the pH values 1.2 to 7.4. Methods: The saturation shake-flask method was used for solubility studies in the presence of amino acids. Briefly, buffer solutions containing different concentrations of amino acids were prepared. Then, an excess amount of each drug with these buffers was shaken to reach equilibrium. After 48 hours, the upper phase was separated, and solubility was calculated by reading their UV-Vis absorbance. Results: The results illustrated that amino acids increased solubility of both drugs with different ratios, which were pH and concentration-dependent. Solubility improved as the amount of amino acids went up, and this upward pattern was more robust with ARG than LYS. The presence of GlucN in citrate buffer significantly enhanced IBU solubility. The solubility of PXM in accompany of GlucN in water did not change significantly while in citrate buffer solubility enhanced specially at pH 6. Conclusion: Overall, GlucN in citrate buffer and ARG in phosphate buffer could be introduced as the most suitable media for IBU and PXM solubility improvement, respectively.

Intratumoural Delivery of mRNA Loaded on a Cationic Hyper-Branched Cyclodextrin-Based Polymer Induced an Anti-Tumour Immunological Response in Melanoma.

mRNA technology has demonstrated potential for use as an effective cancer immunotherapy. However, inefficient in vivo mRNA delivery and the requirements for immune co-stimulation present major hurdles to achieving anti-tumour therapeutic efficacy. Therefore, we used a cationic hyper-branched cyclodextrin-based polymer to increase mRNA delivery in both in vitro and in vivo melanoma cancer. We found that the transfection efficacy of the mRNA-EGFP-loaded Ppoly system was significantly higher than that of lipofectamine and free mRNA in both 2D and 3D melanoma cancer cells; also, this delivery system did not show cytotoxicity. In addition, the biodistribution results revealed time-dependent and significantly higher mEGFP expression in complexes with Ppoly compared to free mRNA. We then checked the anti-tumour effect of intratumourally injected free mRNA-OVA, a foreign antigen, and loaded Ppoly; the results showed a considerable decrease in both tumour size and weight in the group treated with OVA-mRNA in loaded Ppoly compared to other formulations with an efficient adaptive immune response by dramatically increasing most leukocyte subtypes and OVA-specific CD8+ T cells in both the spleen and tumour tissues. Collectively, our findings suggest that the local delivery of cationic cyclodextrin-based polymer complexes containing foreign mRNA antigens might be a good and reliable concept for cancer immunotherapy.

Amphotericin B liposomal formulation: applicable preparation methods, challenges, and tips.

OBJECTIVE: This study was intended to explore and evaluate the appropriate methods for preparation of Amphotericin B (AmB) liposomes with acceptable characteristics. SIGNIFICANCE: This project provides pre-formulations for industrial manufacturing of liposomal AmB which confers improved properties, besides reduced toxicity compared with the plain drug. METHODS: At first, Solubility screening tests were performed, and in the following, three liposome preparation methods including ethanol injection, solvent evaporation, and solvent-free method were examined. In the following, the physicochemical characteristics of the prepared liposomes as well as size, size distribution, zeta potential (ZP), morphology, drug loading, loading capacity, physicochemical stability, and drug-lipid interaction studies were investigated. HPLC was applied for analyzing AmB. RESULTS: In all three methods, liposomes with acceptable characteristics were obtained. The size range of liposomes was 150.3 to 263.9 nm and polydispersity index ≤0.32. In morphologic evaluations, the liposomes have appeared as spherical and separate vesicles. A physical loading of AmB without specific interaction between components was achieved. The lyophilized powder in the solvent-free method was physicochemically stable for 6 months without changes in appearance; the remaining drug after 6-month storage at 25 °C and 60% RH, accounts for 91.5 ± 0.5% compared with the initial drug loaded in liposomes, and degradation pattern follows a linear order. CONCLUSION: As a result, AmB-loaded liposomes were prepared in three applicable methods. The solvent-free method can be considered the most economical and environmental-friendly.

Oral supplementation of solvent-free kynurenic acid/cyclodextrin nanosponges complexes increased its bioavailability.

Many nutraceuticals present problems due to their poor water solubility or stability, which prevents the final bioactivity achievement. For that reason, the oral administration of KYNA complexed with HPß-CD and ßNS-CDI nanosponges was evaluated in mice. The solvent-free technology was used to prepare the complexes in a complete comparison between kneading in ball milling and classical inclusion complex preparation. The solvent-free ones showed higher strength and efficiency with ball milling, considerably reducing time. A 50 mg KYNA/kg/day dosage was orally administered in formulations showing a higher bioavailability when the nutraceutical was complexed with ßNS-CDI compared to HPß-CD and free KYNA, respectively. Several antioxidant statuses demonstrated a higher global antioxidant level perfectly related to bioavailability. Finally, the formulation of KYNA reduced the temporal oxidative stress damage in the kidney and liver, making ßNS-CDI the best formulation. These results suggest an important future application of cyclodextrin-based nanosponges for the oral delivery of nutraceuticals and their stabilization.

Hyper-Branched Cyclodextrin-Based Polymers as Anticoagulant Agents: In Vitro and In Vivo Studies.

This study tested the anticoagulant effect of cyclodextrin (CD) hyper-branched-based polymers (HBCD-Pols). These polymers were synthesized and tested for their coagulant characteristics in vitro and in vivo. Due to their polymeric structure and anionic nature, the polymers can chelate Ca2+, reducing the free quantity in blood. HBCD-Pol increased the blood clotting time, PT, and aPTT 3.5 times over the control, showing a better effect than even ethylenediaminetetraacetic acid (EDTA), as occured with recalcification time as well. A titration of HBCD-Pol and EDTA showed exciting differences in the ability to complex Ca2+ between both materials. Before executing in vivo studies, a hemocompatibility study was carried out with less than 5% red blood cell hemolysis. The fibrinogen consumption and bleeding time were analyzed in vivo. The fibrinogen was considerably decreased in the presence of HBCD-Pol in a higher grade than EDTA, while the bleeding time was longer with HBCD-Pols. The results demonstrate that the anticoagulant effect of this HBCD-Pol opens novel therapy possibilities due to the possible transport of drugs in this carrier. This would give combinatorial effects and a potential novel anticoagulant therapy with HBCD-Pol per se.

Hyper-Branched Cationic Cyclodextrin Polymers for Improving Plasmid Transfection in 2D and 3D Spheroid Cells.

In this article, we used monolayer two dimensional (2D) and 3D multicellular spheroid models to improve our understanding of the gene delivery process of a new modified cationic hyper-branched cyclodextrin-based polymer (Ppoly)-loaded plasmid encoding Enhanced Green Fluorescent Protein (EGFP). A comparison between the cytotoxicity effect and transfection efficiency of the plasmid DNA (pDNA)-loaded Ppoly system in 2D and 3D spheroid cells determined that the transfection efficiency and cytotoxicity of Ppoly-pDNA nanocomplexes were lower in 3D spheroids than in 2D monolayer cells. Furthermore, histopathology visualization of Ppoly-pDNA complex cellular uptake in 3D spheroids demonstrated that Ppoly penetrated into the inner layers. This study indicated that the Ppoly, as a non-viral gene delivery system in complex with pDNA, is hemocompatible, non-toxic, high in encapsulation efficiency, and has good transfection efficiency in both 2D and 3D cell cultures compared to free pDNA and lipofectamine (as the control).

Advances in Aptamers-Based Applications in Breast Cancer: Drug Delivery, Therapeutics, and Diagnostics.

Aptamers are synthetic single-stranded oligonucleotides (such as RNA and DNA) evolved in vitro using Systematic Evolution of Ligands through Exponential enrichment (SELEX) techniques. Aptamers are evolved to have high affinity and specificity to targets; hence, they have a great potential for use in therapeutics as delivery agents and/or in treatment strategies. Aptamers can be chemically synthesized and modified in a cost-effective manner and are easy to hybridize to a variety of nano-particles and other agents which has paved a way for targeted therapy and diagnostics applications such as in breast tumors. In this review, we systematically explain different aptamer adoption approaches to therapeutic or diagnostic uses when addressing breast tumors. We summarize the current therapeutic techniques to address breast tumors including aptamer-base approaches. We discuss the next aptamer-based therapeutic and diagnostic approaches targeting breast tumors. Finally, we provide a perspective on the future of aptamer-based sensors for breast therapeutics and diagnostics. In this section, the therapeutic applications of aptamers will be discussed for the targeting therapy of breast cancer.

Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery.

INTRODUCTION: The argument around cancer therapy is an old one. Using chemotherapeutic drugs, as one of the most effective strategies in treatment of malignancies, is restricted by various issues that progress during therapy and avoid achieving clinical endpoints. Multidrug resistance (MDR), frequently mediated by ATP-binding cassette (ABC) transporters, is one of the most recognized obstacles in the success of pharmacological anticancer approaches. These transporters efflux diverse drugs to extracellular environment, causing MDR and responsiveness of tumor cells to chemotherapy diminishes. AREAS COVERED: Several strategies have been used to overcome MDR phenomenon. Succession in this field requires complete knowledge about features and mechanism of ABC transporters. In this review, conventional synthetic and natural inhibitors are discussed first and then novel approaches including RNA, monoclonal antibodies, nanobiotechnology, and structural modification techniques are represented. EXPERT OPINION: With increasing frequency of MDR in cancer cells, it is essential to develop new drugs to inhibit MDR. Using knowledge acquired about ABC transporter's structure, rational design of inhibitors is possible. Also, some herbal products have shown to be potential lead compounds in drug discovery for reversal of MDR.

Synthesis and preparation of vitamin A coupled butein-loaded solid lipid nanoparticles for liver fibrosis therapy in rats.

The development of a therapeutic system for hepatic fibrosis has become a research hotspot to date. Butein, a simple chalcone derivative, displays anti-fibrotic effects through different pathways. However, impurities, low solubility, and low concentration in the target tissue hinder therapy with herbal ingredients. Hepatic stellate cells (HSCs), the vitamin A (VA) storage cells, as the main contributors to liver fibrogenesis, are not readily accessible to drugs owing to their anatomical location. Targeted delivery of therapeutics to the activated HSCs is therefore critical for successful treatment. For these reasons, the current study aimed at increasing butein delivery to the liver. Hence, high purity butein was synthesized in three steps. A novel VA-Myrj52 ester conjugate was also synthesized using all-trans retinoic acid and a hydrophilic emulsifier (Myrj52) as a targeting agent. Next, butein was encapsulated inside the novel VA-modified solid lipid nanoparticles (VA-SLNs) and studied in vitro and in vivo. According to our evaluations, negatively charged SLNs with a mean diameter of 150 nm and entrapment efficacy of 75 % were successful in liver fibrosis amelioration. Intraperitoneal (i.p.) injection of VA-SLNs in fibrotic rats, for four weeks long, reduced serum AST and ALT by 58% (P, 0.001) and 72% (P, 0.05), respectively, concerning the CCl4 group. Additionally, histologic damage score decline and normalization of tissue oxidative stress markers collectively confirmed the efficacy of formulations in hepatic fibrosis and kidney damage amelioration.

Cyclodextrin-Based Nanosponges as Perse Antimicrobial Agents Increase the Activity of Natural Antimicrobial Peptide Nisin.

At present, antibiotic resistance is considered a real problem. Therefore, for decades scientists have been looking for novel strategies to treat bacterial infections. Nisin Z, an antimicrobial peptide (AMP), can be considered an option, but its usage is mainly limited by the poor stability and short duration of its antimicrobial activity. In this context, cyclodextrin (CD)-based nanosponges (NSs), synthesized using carbonyldiimidazole (CDI) and pyromellitic dianhydride (PMDA), were chosen for nisin Z loading. To determine the minimum inhibitory of nisin Z loaded on CD-NS formulations, agar well diffusion plates were used. Then, the bactericide concentrations of nisin Z loaded on CD-NS formulations were determined against Gram-positive (Staphylococcus aureus) and -negative (Escherichia coli) bacteria, using microdilution brain heart infusion (BHI) and tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). The minimum and bactericide inhibitory values of the nisin complex with NSs were potentially decreased against both bacteria, compared with the nisin-free sample, while the nisin complex with ß-CD showed lower antibacterial activity. The antimicrobial effect was also demonstrated by free NSs. Furthermore, the total viable counts (TVCs) antibacterial experiment indicated that the combination of nisin Z in both PMDA and CDI ß-CD-based NSs, especially CDI, can provide a better conservative effect on cooked chicken meat. Generally, the present study outcomes suggest that the cross-linked ß-CD-based NSs can present their own antimicrobial potency or serve as promising carriers to deliver and enhance the antibacterial action of nisin Z.

Stabilization and Anticancer Enhancing Activity of the Peptide Nisin by Cyclodextrin-Based Nanosponges against Colon and Breast Cancer Cells.

The great variability of cancer types demands novel drugs with broad spectrum, this is the case of Nisin, a polycyclic antibacterial peptide that recently has been considered for prevention of cancer cells growth. As an accepted food additive, this drug would be very useful for intestinal cancers, but the peptide nature would make easier its degradation by digestion procedures. For that reason, the aim of present study to investigate the protective effect of two different ß-cyclodextrin-based nanosponges (carbonyl diimidazole and pyromellitic dianhydride) and their anti-cancer enhancement effect of Nisin-Z encapsulated with against colon cancer cells (HT-29). To extend its possible use, a comparison with breast (MCF-7) cancer cell was carried out. The physicochemical properties, loading efficiency, and release kinetics of Nisin complex with nanosponges were studied. Then, tricin-SDS-PAGE electrophoresis was used to understand the effect of NSs on stability of Nisin-Z in the presence of gastric peptidase pepsin. In addition, the cytotoxicity and cell membrane damage of Nisin Z were evaluated by using the MTT and LDH assay, which was complemented via Annexin-V/ Propidium Iodide (PI) by using flowcytometry. CD-NS are able to complex Nisin-Z with an encapsulation efficiency around 90%. A protective effect of Nisin-Z complexed with CD-NSs was observed in presence of pepsin. An increase in the percentage of apoptotic cells was observed when the cancer cells were exposed to Nisin Z complexed with nanosponges. Interestingly, Nisin Z free and loaded on PMDA/CDI-NSs is more selectively toxic towards HT-29 cells than MCF-7 cancer cells. These results indicated that nanosponges might be good candidates to protect peptides and deliver drugs against intestinal cancers.

Comparison of three synthetic transferrin mimetic small peptides to promote the blood-brain barrier penetration of vincristine liposomes for improved glioma targeted therapy.

The existence of the blood-brain barrier (BBB) makes the clinical chemotherapy of glioma a formidable challenge, because it hinders the passage of different chemotherapeutics into the brain and reduces the overall therapeutic efficiency. Therefore, it is necessary to design a drug delivery system in way that would favor the transportation of anti-cancer agents across the BBB and increase their selective accumulation within the tumor cells without affecting the normal tissues. Transferrin receptor (TfR) that shows an elevated level of expression on the BBB and glioma cells emerges as a promising tool for brain targeted delivery and glioma therapy. However, only a limited number of studies have comparatively evaluated the functionally of TfR targeting ligands. Herein, a series of liposomal formulations modified with the most well-known TfR targeting peptides including T12 (also known as THR), B6, and T7 was developed and their brain targeting capability and selective glioma accumulation was comparatively evaluated in vitro and in vivo. Among all TfR targeting or non-targeting groups, T7-modified liposomes (T7-LS) showed the highest BBB penetration capacity and brain distribution and displayed an enhanced accumulation in glioma cells. When loaded with vincristine (VCR), as a model chemotherapeutic, T7-LS/VCR could achieve the best anti-glioma outcome by means of targeted cytotoxicity and apoptosis in vitro. The obtained results suggested T7-LS as a potential platform for effective brain targeted delivery and glioma therapy in clinic.

Cytotoxicity and Immunogenicity Evaluation of Synthetic Cell-penetrating Peptides for Methotrexate Delivery.

Methotrexate (MTX) is one of the most effective therapeutics to treat different types of solid tumors; however, it suffers low permeability limiting its bioavailability and cellular uptake. To tackle this, we aim to design and fabricate different types of cell-penetrating peptides (CPPs) to improve the intracellular uptake of MTX without causing any immunogenic response. CPPs were synthesized by the solid-phase peptide synthesis method. Peptide-MTX conjugates were prepared via covalent binding of peptide and drug molecule. CPPs and peptide-E8 nanoparticles were characterized using zeta-sizer and scanning electron microscopy. Cytotoxicity of CPPs and peptide-MTX conjugates was evaluated by MTT assay. An enzyme-linked immunosorbent assay was employed to assess the IL-6 and TNF-α cytokine release profile. Amongst all sequences, W4R4-MTX possessed the highest loading efficiency (97%) and drug to peptide percentage (24.02%). The lowest loading efficiency (36%) and drug to peptide percentage (8.76%) were seen for NGRWK-MTX conjugates. The NGRWR peptide and NGRWR-E8 nanoparticles had acceptable size (~100 nm) with spherical and rod-like structures, respectively. The selected CPPs and peptide-MTX conjugates did not show any cytotoxicity or immunogenicity. The fabricated peptides are represented as promising carriers to improve the intracellular delivery of MTX to cancer cells with low immunogenic and cytotoxic effects on normal cells.

Surface modification with cholesteryl acetyl carnitine, a novel cationic agent, elevates cancer cell uptake of the PEGylated liposomes.

The present study aimed to synthesize cholesteryl acetyl carnitine (CAC), and surface modify the PEGylated liposomes with the intention of enhanced cancer cell uptake. For this, CAC synthesis was performed in amine-free esterification conditions and then four liposomal formulations of unmodified, CAC/PEG, and CAC + PEG-modified were prepared by ethanol injection method. Cytotoxicity of the liposomes was investigated in A549 cells, followed by cellular uptake assessments of coumarin 6 (C6)-loaded liposomes. The results of ATR-FTIR, 1HNMR, and 13CNMR demonstrated successful formation of CAC. A molecular docking study showed efficient binding affinities rather than carnitine to the active site of four carnitine transporters. Liposomal formulations possessed spherical morphology with a mean particle size range of 112-138 nm, narrow size distribution, and negative surface charge. All formulations had low cytotoxicity at 0.5 mg/ml, but high cytotoxicity at around 2.5 mg/ml. The lowest IC50 was obtained for CAC modified liposomes. CAC + PEG-modified liposomes had the highest cellular uptake. In conclusion, CAC + PEG modification of liposomes is an effective approach for increasing A549 cellular uptake, with low cytotoxicity at commonly applied liposome concentrations. The elevated uptake may be due to the involvement of the organic cation transporter, cationic structure, and the metabolic preference of CAC in cancer cells.

Oral delivery of solid lipid nanoparticles: underlining the physicochemical characteristics and physiological condition affecting the lipolysis rate.

INTRODUCTION: Lipid-based nano-drug delivery systems (LBNDDSs) have gained widespread attention in oral drug delivery due to their tunable and versatile properties such as biocompatibility and biodegradability, which makes them promising delivery systems for a variety of therapeutics. Currently, different types of LBNDDSs including liposomes, micelles, nanoemulsions, and solid lipid nanoparticles (SLNs) are developed for drug delivery applications. SLNs can be used as a controlled drug delivery system for oral delivery applications. However, its lipidic context makes that susceptible to lipolysis. The lipolysis rate of SLNs is affected by many factors that raise many questions for developing a more efficient delivery system. AREAS COVERED: In the present work, we highlighted different factors affecting the digestion rate/level of SLNs in the gastrointestinal tract. This paper can be most useful for those researchers who are keen to develop a properly controlled drug delivery system based on SLNs for oral delivery applications. EXPERT OPINION: SLNs can be used as a controlled drug delivery system for oral delivery applications. However, its lipidic context makes that susceptible to lipolysis. The lipolysis rate of SLNs is affected by many factors that raise many questions for developing a more efficient delivery system.

Effects of self-assembled cell-penetrating peptides and their nano-complexes on ABCB1 expression and activity.

OBJECTIVES: Doxorubicin (Dox) is one of the most well-known chemotherapeutics that are commonly applied for a wide range of cancer treatments. However, in most cases, efflux pumps like P-glycoprotein (P-gp), expel the taken drugs out of the cell and decrease the Dox bioavailability. Expression of P-gp is associated with elevated mRNA expression of the ATP-binding cassette B1 (ABCB1) gene. MATERIALS AND METHODS: In the current study, different sequences of cell-penetrating peptides (CPPs) containing tryptophan, lysine, and arginine and their nano-complexes were synthesized and their impact on the expression and activity of the ABCB1 gene was evaluated in the A549 lung carcinoma cell line. Furthermore, the cellular uptake of designed CPPs in the A549 cell line was assessed. RESULTS: The designed peptides, including [W4K4], [WR]3-QGR, R10, and K10 increased Dox cytotoxicity after 48 hr. Furthermore, arginine-rich peptides showed higher cellular uptake. Rhodamin123 accumulation studies illustrated that all the obtained peptides could successfully inhibit the P-gp pump. The designed peptides inhibited the ABCB1 gene expression, of which, [W4K4] resulted in the lowest expression ratio. CONCLUSION: [W4K4], [WR]3-QGR, R10, and K10 could successfully increase the Dox cytotoxicity by decreasing the efflux pump gene expression.

Preparation and In Vitro Characterization of Enoxaparin Nano-liposomes through Different Methods.

Purpose: Enoxaparin has been widely used as a choice drug for treatment and prevention of different coagulation disorders. Orally administered enoxaparin encounters with gastrointestinal barrier because of its high water solubility, high molecular weight and significant negative charge. Since, the nano-liposomes has gained great interest for oral drug delivery, we decided to introduce the best protocol for preparing enoxaparin nano-liposomes through in vitro characterization. Methods: Nano-liposomes were prepared by ethanol injection, thin film hydration, and double emulsion/solvent evaporation methods. Size distribution, zeta potential, loading efficiencies, and in vitro drug release of nano-liposomes were also studied. Results: The mean vesicle size was obtained under 100 nm, and the zeta potential was highly negative through all preparation methods. Nano-liposomes prepared by double emulsion/ solvent evaporation (DE) technique could entrap more of this hydrophilic drug (43 ± 7.1 %), but through thin layer hydration (TL) and ethanol injection (EI) only 28.4± 3.2% and 17.3 ± 2.5% of drug could be loaded into synthesized carriers. Drug release from these carriers was also obtained 42.17±1.72%, 29.43±0.34% and 32.27±0.14%, in 24 hours for EI, TL, and DE methods, respectively. Conclusion: Here, we can introduce double emulsion/solvent evaporation method as an acceptable method for enoxaparin loading, although some toxicity and in-vivo tests are also necessary to fully understand the potential of this formulation.