Showing papers in "Journal of Drug Targeting in 2012"

Nanostructured lipid carriers system: Recent advances in drug delivery

Abstract: Nanostructured lipid carrier (NLC) is second generation smarter drug carrier system having solid matrix at room temperature. This carrier system is made up of physiological, biodegradable and biocompatible lipid materials and surfactants and is accepted by regulatory authorities for application in different drug delivery systems. The availability of many products in the market in short span of time reveals the success story of this delivery system. Since the introduction of the first product, around 30 NLC preparations are commercially available. NLC exhibit superior advantages over other colloidal carriers viz., nanoemulsions, polymeric nanoparticles, liposomes, SLN etc. and thus, have been explored to more extent in pharmaceutical technology. The whole set of unique advantages such as enhanced drug loading capacity, prevention of drug expulsion, leads to more flexibility for modulation of drug release and makes NLC versatile delivery system for various routes of administration. The present review gives insights on the definitions and characterization of NLC as colloidal carriers including the production techniques and suitable formulations. This review paper also highlights the importance of NLC in pharmaceutical applications for the various routes of drug delivery viz., topical, oral, pulmonary, ocular and parenteral administration and its future perspective as a pharmaceutical carrier.

Chitosan nanoparticles: a survey of preparation methods

Abstract: The application of macromolecules in therapy is frequently hindered by stability and/or permeation issues. These limitations have been addressed by the pharmaceutical industry through the development of suitable noninjectable drug carriers. In this context, nanoparticles have emerged as one of the most exciting tools due to the increased surface-to-volume ratio, which provides an intimate interaction with epithelial surfaces. Nanoparticles further enable the encapsulated molecules to retain their biological activity, from the production steps to the final release. Chitosan has reached a prominent position as carrier-forming material, as diverse methods can be applied to produce nanoparticles using that excipient. These involve either hydrophilic or lipophilic environments that generally result in mild conditions or aggressive and time-consuming processes, respectively. In this review, a detailed description of methods used to produce chitosan nanocarriers is provided, accompanied by illustrative schemes of the procedures. The emphasis is on the variables reported to affect the final properties of the vehicles.

Role of CD44 in tumour progression and strategies for targeting.

Abstract: CD44 or hyaluronan receptor is a transmembrane receptor associated with aggressive tumour growth, proliferation, and metastasis. In normal physiology, this receptor has a crucial role in cell adhesion, inflammation, and repair processes. However, many tumour cells over-express this receptor and abuse it to become progressive and perpetual units. The article comments from common functioning of the CD44 receptor, to its diabolic multi-dimensional effects in promotion of malignant cells. It also illuminates the relations of CD44 endorsed processes with other biomolecular events in cancer progression. In an end, the review focuses comprehensively at ongoing researches to exploit the CD44 over-expression as a probable target in treatment, management, and diagnosis of malignancy.

G-quadruplexes: targets and tools in anticancer drug design

Abstract: Background: Guanosine (G)-rich DNA and RNA sequences can adopt a defined secondary structure, the G-quadruplex, which consists of multiple stacked G-tetrads. Each G-tetrad has four Gs arranged in a planar configuration and held together by hydrogen bonding. G-quadruplexes are found in chromosomal DNA and RNA transcripts, particularly in telomeric sequences, and in regulatory regions of many genes including oncogenes.Purpose: This review summarizes how G-quadruplexes can be employed for anticancer therapies and discusses possible mechanisms. Methods: The Medline database was searched using the terms “G-rich oligonucleotide (GRO)”, “G-tetrad”, and “G-quadruplex”.Results: Drugs which bind to and stabilize G-quadruplexes can be employed to suppress the elongation of telomers and the gene transcription and translation of oncogenes. G-quadruplex stabilization results in senescence and apoptosis of cancer cells. Besides long-chain nucleic acids, also GRO are able to acquire G-quadruplex conformation to build up ...

Pharmacotherapy in pregnancy; effect of ABC and SLC transporters on drug transport across the placenta and fetal drug exposure.

Abstract: Pharmacotherapy during pregnancy is often inevitable for medical treatment of the mother, the fetus or both. The knowledge of drug transport across placenta is, therefore, an important topic to bear in mind when deciding treatment in pregnant women. Several drug transporters of the ABC and SLC families have been discovered in the placenta, such as P-glycoprotein, breast cancer resistance protein, or organic anion/cation transporters. It is thus evident that the passage of drugs across the placenta can no longer be predicted simply on the basis of their physical-chemical properties. Functional expression of placental drug transporters in the trophoblast and the possibility of drug-drug interactions must be considered to optimize pharmacotherapy during pregnancy. In this review we summarize current knowledge on the expression and function of ABC and SLC transporters in the trophoblast. Furthermore, we put this data into context with medical conditions that require maternal and/or fetal treatment during pregnancy, such as gestational diabetes, HIV infection, fetal arrhythmias and epilepsy. Proper understanding of the role of placental transporters should be of great interest not only to clinicians but also to pharmaceutical industry for future drug design and development to control the degree of fetal exposure.

Microbubble-mediated ultrasonic techniques for improved chemotherapeutic delivery in cancer.

Abstract: Background: Ultrasound (US) exposed microbubble (MB) contrast agents have the capability to transiently enhance cell membrane permeability. Using this technique in cancer treatment to increase the efficiency of chemotherapy through passive, localized delivery has been an emerging area of research.Purpose: Investigation of the influence of US parameters on MB-mediated drug delivery in cancer.Methods: The 2LMP breast cancer cells were used for in vitro experiments and 2LMP tumor-bearing mice were used during in vivo experiments. Changes in membrane permeability were investigated after the influence of MB-mediated US therapy parameters (i.e. frequency, mechanical index, pulse repetition period, US duration, and MB dosing and characteristics) on cancer cells. Calcein, a non-permeable fluorescent molecule, and Taxol, chemotherapeutic, were used to evaluate membrane permeability. Tumor response was also assessed histologically.Results: Combination chemotherapy and MB-mediated US therapy with optimized parameter...

Recent advances in ligand targeted therapy.

Abstract: Background: Ligand targeted therapy (LTT) is a powerful pharmaceutical strategy to achieve selective drug delivery to pathological cells, for both therapeutic and diagnostic purposes, with the advantage of limited side effects and toxicity. This active drug targeting approach is based on the discovery that there are receptors overexpressed on pathological cells, compared to their expression in normal tissues.Purpose: The purpose of this article is to review recently published data on LTT with applications, both in the field of cancer therapy and other diseases. Moreover, data on LTT exploiting receptors overexpressed at cytoplasmatic level are also reviewed.Methods: Data were deduced from Medline (PubMed) and SciFinder and their selections were made with preference to papers where the most relevant receptors were involved.Results: Several groups have reported improved delivery of targeted nanocarriers, as compared to nontargeted ones, to pathological cells. LTT offers several advantages, but there are als...

Solanum tuberosum lectin-conjugated PLGA nanoparticles for nose-to-brain delivery: in vivo and in vitro evaluations

Abstract: Solanum tuberosum lectin (STL) conjugated poly (DL-lactic-co- glycolic acid) (PLGA) nanoparticle (STL-NP) was constructed in this paper as a novel biodegradable nose-to-brain drug delivery system. The in vitro uptake study showed markedly enhanced endocytosis of STL-NP compared to unmodified PLGA nanoparticles (NP) in Calu-3 cells and significant inhibition of uptake in the presence of inhibitor sugar (chitin hydrolysate). Following intranasal administration, coumarin-6 carried by STL-NP was rapidly absorbed into blood and brain. The AUC((0→12 h)) of coumarin-6 in blood, olfactory bulb, cerebrum and cerebellum were about 0.77-, 1.48-, 1.89- and 1.45-fold of those of NP, respectively (p < 0.05). STL-NP demonstrated 1.89-2.45 times (p < 0.01) higher brain targeting efficiency in different brain tissues than unmodified NP. Enhanced accumulation of STL-NP in the brain was also observed by near infrared fluorescence probe image following intranasal administration. The fluorescence signal of STL-NP appeared in olfactory bulb, cerebrum and brainstem early at 0.25 h. The signal in olfactory bulb decreased gradually after 2 h, while the obvious signal in brainstem, cerebrum and cerebellum lasted for more than 8 h. The STL-NP safety experiments showed mild cytotoxicity and negligible cilia irritation. These intriguing in vitro and in vivo results suggest that STL-NP might serve as a promising brain drug delivery system.

Lipid-based vectors for siRNA delivery.

Abstract: siRNA therapeutics has developed rapidly and already there are clinical trials ongoing or planned; however, the delivery of siRNA into cells, tissues or organs remains to be a major obstacle Lipid-based vectors hold the most promising position among non-viral vectors, as they have a similar structure to cell or organelle membranes But when used in the form of liposomes, these vectors have shown some problems Therefore, either the nature of lipids themselves or forms used should be improved As a novel class of lipid like materials, lipidoids have the advantages of easy synthesis and the ability for delivering siRNA to obtain excellent silencing activity However, the toxicities of lipidoids have not been thoroughly studied pH responsive lipids have also gained great attention recently, though some of the amine-based lipids are not novel in terms of chemical structures More complex self-assembly structures, such as LPD (LPH) and LCP, may provide a good solution to siRNA delivery They have demonstrate

Chlorotoxin-modified stealth liposomes encapsulating levodopa for the targeting delivery against Parkinson's disease in the MPTP-induced mice model

Abstract: Chlorotoxin (ClTx), originally isolated from scorpion venom of Leiurus quinquestriatus, is a 36-amino acid peptide and specifically binds to the brain gliomas and proliferating vascular endothelial cells. In this paper, it was first used to establish the ClTx-modified stealth liposomes (ClTx-LS) encapsulating levodopa (LD) for the targeting drug delivery against the Parkinson's disease (PD). After the DSPE-PEG-ClTx was synthesized and identified, the ClTx-LS system was prepared and characterized. Its targeting capability was studied in vitro and in vivo, and finally its anti-PD activity was evaluated, with non-modified liposomes (LS) as control. It was demonstrated through flow cytometry and confocal microscopy that ClTx modification highly facilitated the uptake of LS by brain microvascular endothelial cells in vitro. After intraperitoneal injection to mice, the active targeting system loaded with LD significantly increased the distribution of dopamine and dihydroxyphenyl acetic acid, the metabolites of LD, in the substantia nigra and striata. In the methyl-phenyl-tetrahydropyridine (MPTP)-induced PD mice model, LD-loaded ClTx-LS significantly attenuated the serious behavioral disorders and diminished the MPTP-induced loss of tyrosine hydroxylase-positive dopaminergic neurons. In conclusion, ClTx-modified LS might serve as a targeting delivery system to transport more drugs into the brain for a better PD therapy.

Formulation and evaluation of microemulsion-based in situ ion-sensitive gelling systems for intranasal administration of curcumin.

Abstract: The purpose of our study was to develop a microemulsion-based in situ ion-sensitive gelling system for intranasal administration of curcumin. A new microemulsion composition for curcumin was optimized with the simple lattice design. And the microemulsion-based in situ ion-sensitive gelling system consisted of Capryol 90 as oil phase, Solutol HS15 as surfactant, Transcutol HP as cosurfactant and 0.3% DGG solution as water phase. The physicochemical properties such as morphology, droplet size distribution, zeta value and the in vitro release were investigated. In addition, the histological section studies on the reaction between the obtained formulation and nasal mucosa showed that the microemulsion-based in situ ion-sensitive gelling system could not produce obvious damage to nasal mucosa. The pharmacokinetics results showed that the absolute bioavailability of curcumin in the microemulsion-based in situ ion-sensitive gelling system was 55.82% by intranasal administration. And the brain targeting index (BTI) was 6.50, and in the tissue distribution experiment, the value of (AUC(brain)/AUC(blood)) following intranasal administration was higher than that following intravenous administration, suggesting that the obvious brain targeting property by nasal delivery be attributed to a direct nose-to-brain drug transport. It can be concluded that the microemulsion-based in situ gelling as an effective and safe vehicle could greatly enhance the in vivo absorption and facilitate the delivery of curcumin to brain by intranasal administration.

Development of a peptide-targeted, myocardial ischemia-homing, mesenchymal stem cell.

Abstract: Directing stem cells to the heart is critical in producing an effective cell therapy for myocardial infarction (MI). Mesenchymal stem cells (MSCs) offer an exquisite drug delivery platform with environment-sensing cytokine release and MSCs have shown therapeutic potential in MI. Peptide-based targeting offers a novel method to increase cell homing, wherein MI-specific peptides, identified by phage display, are synthesized with a palmitic acid tail to facilitate cell membrane integration. Phage-peptides were screened in a mouse MI model and four peptides (CRPPR, CRKDKC, KSTRKS, and CARSKNKDC) were selected and synthesized as palmitated derivatives for further investigation. Cell coating was optimized and coating persistence and cytotoxicity were evaluated. MSCs were coated with peptides, injected into mice with MI, and MSCs in the heart quantified. Greater numbers of MSCs were found in heart of animals treated with the peptide-coated MSCs compared to uncoated controls. MSC numbers had positive correlation with MI severity in peptide-coated cells but a negative correlation in MSCs alone. A transient cell coating ("painting") method has been developed that labels cells efficiently, non-toxically and increases cell localization in MI hearts.

Macrophages targeting of amphotericin B through mannosylated multiwalled carbon nanotubes

Abstract: The objective of the present investigation was to assess the potential of polysaccharide (mannose) conjugated engineered multiwalled carbon nanotubes (MWCNTs) bearing Amphotericin B (AmB) formulation for site-specific delivery to macrophages. The mannosylated carbon nanotubes (CNTs) were synthesized and AmB was efficiently loaded using dialysis diffusion method. The synthesized mannosylated MWCNTs were characterized by various physicochemical and physiological parameters such as fourier transform infrared (FTIR) spectroscopy, scanning and transmission electron microscopy (SEM & TEM), drug loading and entrapment efficiency, in-vitro release kinetics, in-vivo study and toxicological investigation. AmB loaded mannosylated MWCNTs (AmBitubes) was found to be nanometric in size (500 nm) with tubular structure and good entrapment efficiency (75.46 ± 1.40%). In-vitro AmB from AmBitubes was found to be released in a controlled manner at pH 4, 7.4 and 10, with enhanced cell uptake and higher disposition in macropha...

Nucleic-acid based gene therapeutics: delivery challenges and modular design of nonviral gene carriers and expression cassettes to overcome intracellular barriers for sustained targeted expression

Abstract: The delivery of nucleic acid molecules into cells to alter physiological functions at the genetic level is a powerful approach to treat a wide range of inherited and acquired disorders. Biocompatible materials such as cationic polymers, lipids, and peptides are being explored as safer alternatives to viral gene carriers. However, the comparatively low efficiency of nonviral carriers currently hampers their translation into clinical settings. Controlling the size and stability of carrier/nucleic acid complexes is one of the primary hurdles as the physicochemical properties of the complexes can define the uptake pathways, which dictate intracellular routing, endosomal processing, and nucleocytoplasmic transport. In addition to nuclear import, subnuclear trafficking, posttranscriptional events, and immune responses can further limit transfection efficiency. Chemical moieties, reactive linkers or signal peptide have been conjugated to carriers to prevent aggregation, induce membrane destabilization and localize to subcellular compartments. Genetic elements can be inserted into the expression cassette to facilitate nuclear targeting, delimit expression to targeted tissue, and modulate transgene expression. The modular option afforded by both gene carriers and expression cassettes provides a two-tier multicomponent delivery system that can be optimized for targeted gene delivery in a variety of settings.

Immunoliposomal delivery of doxorubicin can overcome multidrug resistance mechanisms in EGFR-overexpressing tumor cells.

Abstract: Immunoliposomes (ILs) can be constructed to target the epidermal growth factor receptor (EGFR) to provide efficient intracellular drug delivery in tumor cells. We hypothesized that this approach might be able to overcome drug resistance mechanisms, which remain an important obstacle to better outcomes in cancer therapy. ILs were evaluated in vitro and in vivo against EGFR-overexpressing pairs of human cancer cells (HT-29 and MDA-MB-231) that either lack or feature the multidrug resistance (mdr) phenotype. In multidrug-resistant cell lines, ILs loaded with doxorubicin (DOX) produced 19-216-fold greater cytotoxicity than free DOX, whereas in nonresistant cells, immunoliposomal cytotoxicity of DOX was comparable with that of the free drug. In intracellular distribution studies, free DOX was efficiently pumped out of the multidrug-resistant tumor cells, whereas immunoliposomal DOX leads to 3.5-8 times higher accumulation of DOX in the cytoplasm and 3.5-4.9 times in the nuclei compared with the free drug. Finally, in vivo studies in the MDA-MB-231 Vb100 xenograft model confirmed the ability of anti-EGFR ILs-DOX to efficiently target multidrug-resistant cells and showed impressive antitumor effects, clearly superior to all other treatments. In conclusion, ILs provide efficient and targeted drug delivery to EGFR-overexpressing tumor cells and are capable of completely reversing the multidrug-resistant phenotype of human cancer cells.

Synthesis, characterization and brain targeting potential of paclitaxel loaded thiamine-PPI nanoconjugates

Abstract: Brain tumor is insidious complication which is difficult to treat because of the poor uptake of many potentially useful antitumor drugs through the blood-brain barrier (BBB). Present study was aimed for developing and exploring the use of thiamine conjugated poly(propylene imine) (PPI) dendrimers for increased delivery of paclitaxel (PTX) across the BBB. PTX loaded thiamine conjugated PPI dendrimers (PTX-Tm-PPI) shown increased drug loading and reduced hemolytic toxicity with suitability for prolonged delivery of PTX during in vitro release. Ex vivo cytotoxicity studies of free PTX, PTX-PPI and PTX-Tm-PPI dendrimers over IMR-32 human neuroblastoma cell line revealed higher potential of PTX-Tm-PPI nanoconjugate to retard tumor cell viability as compared to plain PTX or PTX-PPI. In vivo pharmacokinetics studies revealed significant (p < 0.05) slow clearance of PTX from the body via Tm-PPI nanoconjugate. Biodistribution studies confirmed about the targeting efficiency and higher biodistribution of Tm-PPI conjugates into the brain. The results concluded that the developed nanoconjugate has potential to deliver significantly higher amount of drug to brain tumor for improved therapeutic outcome.

Microfold-cell targeted surface engineered polymeric nanoparticles for oral immunization.

Abstract: Present work was envisaged to develop novel M-cell targeted polymeric particles that are capable of protecting the antigen from harsh gastric conditions. Ulex europaeus agglutinin (UEA-1) lectin was anchored for selective delivery of antigen to gut-associated lymphoid tissue (GALT). In the present investigation, chitosan nanoparticles were prepared by ionic gelation followed by antigen (bovine serum albumin, BSA) adsorption. Developed nanoparticles were further coated by UEA-1 lectin conjugated alginate and characterized for size, shape, zeta-potential, entrapment efficiency, and in vitro release. The immunological response of the developed system were performed in Balb/c mice and compared with aluminium hydroxide gel-based conventional vaccine. Results indicated that immunization with UEA-1 lectin conjugated alginate-coated particles induces efficient systemic as well as mucosal immune responses against BSA compared to other formulations. Aluminium-based vaccine dominated throughout the study, while failed in case of mucosal antibody. Additionally, IgG1 and IgG2a isotypes were determined to confirm the TH1/TH2 mixed immune response. The developed formulation exhibited superior systemic response along with dominating mucosal immunity. These data demonstrate the potential of UEA-alginate-coated nanoparticles as effective delivery system via oral route.

Strategies for non-invasive delivery of biologics.

Abstract: Macromolecular therapeutics, in particular, many biologics, is the most advancing category of drugs over conventional chemical drugs. The potency and specificity of the biologics for curing certain disease made them to be a leading compound in the pharmaceutical industry. However, due to their intrinsic nature, including high molecular weight, hydrophilicity and instability, they are difficult to be administered via non-invasive route. This is a major quest especially in biologics, as they are frequently used clinically for chronic disorders, which requires long-term administration. Therefore, many efforts have been made to develop formulation for non-invasive administration, in attempt to improve patient compliance and convenience. In this review, strategies for non-invasive delivery, in particular, oral, pulmonary and nasal delivery, that are recently adopted for delivery of biologics are discussed. Insulin, calcitonin and heparin were mainly focused for the discussion as they could represent protein, p...

Ultrasound-responsive thrombus treatment with zinc-stabilized gelatin nano-complexes of tissue-type plasminogen activator.

Abstract: This study is undertaken to design zinc-stabilized gelatin nano-complexes of tissue-type plasminogen activator (t-PA) for thrombolytic therapy where the t-PA activity can be recovered in the blood circulation upon ultrasound irradiation. Various molecular weights of gelatin were complexed with t-PA by their simply mixing in aqueous solution. Then, zinc acetate, calcium acetate or magnesium acetate was added to form nano-sized gelatin-t-PA complexes. The complexes had the apparent molecular size of about 100 nm. When zinc ions were added to the gelatin-t-PA complexes, the t-PA activity was suppressed most strongly to 57% of the original, free t-PA activity. Upon ultrasound exposure in vitro, the t-PA activity was fully recovered. A cell culture experiment with L929 fibroblasts demonstrated no cytotoxicity of complexes at the concentration used for the in vivo experiment. The half-life of t-PA in the blood circulation prolonged by the complexation with gelatin and zinc ions. The zinc-stabilized t-PA-gelatin complex is a promising t-PA delivery system which can manipulate the thrombolytic activity by the local ultrasound irradiation.

Molecular considerations for development of phage antibody libraries

Abstract: Nowadays, phage display libraries are used as robust tools for discovery and evolution of peptide/protein based drugs as well as targeting molecules, in particular monoclonal antibodies (mAbs) and its fragments (i.e., scFvs, Fabs, or bivalent F(ab′)2). Phage display technology, as a molecular diversity approach, enables selection of antibody fragments (e.g., scFv/Fab) with high affinity, specificity and effector functions against various targets. However, such selection process itself is largely dependent upon various molecular factors such as methods for construction of phage library, phage/phagemid vectors, helper phage, host cells and biopanning processes. The current review article provides important molecular considerations for successful development of phage antibody libraries that may be used as a platform for translation of antibody fragments into viable diagnostic/therapeutic reagents.

Ocular delivery of cyclosporine A based on glyceryl monooleate/poloxamer 407 liquid crystalline nanoparticles: preparation, characterization, in vitro corneal penetration and ocular irritation.

Abstract: The purpose of this study was to develop an ophthalmic drug delivery system for cyclosporine A (CsA) based on glyceryl monooleate (GMO)/poloxamer 407 liquid crystalline nanoparticles with reduced ocular irritancy and improved corneal penetration. CsA-loaded liquid crystalline nanoparticles were prepared via fragmentation of a bulk GMO/poloxamer 407 cubic phase gel by high-pressure homogenization and characterized. Corneal permeation and retention was evaluated using modified Franz diffusing cells. Intra-corneal transportation was investigated with fluorescein isothiocyanate (FITC)-labeled liquid crystalline nanoparticles. Ocular irritation was then evaluated using the Draize method. The mean particle size of liquid crystalline nanoparticles was 193.5 nm and the entrapment efficiency was 95.11 ± 0.67%. A bicontinuous cubic phase of cubic P-type was determined using cryo-transmission electron microscopy (cryo-TEM) observation and small angle X-ray diffraction (SAXD) analysis. A 1.52-fold increase in J(s) and a 2.2-fold increase in corneal retention was achieved by liquid crystalline nanoparticles compared with oil solution. In vitro corneal permeation investigated with FITC-labeled liquid crystalline nanoparticles revealed that CsA penetrated across the cornea under the transportation of liquid crystalline nanoparticles. Liquid crystalline nanoparticles exhibited excellent ocular tolerance in the ocular irritation test. This low-irritant vehicle based on liquid crystalline nanoparticles might be a promising system for effective ocular CsA delivery.

Recent progress in copolymer-mediated siRNA delivery.

Abstract: RNAi-mediated gene silencing has great potential for treating various diseases, including cancer, by delivering a specific short interfering RNA (siRNA) to knock down pathogenic mRNAs and suppress protein translation. Although many researchers are dedicated to devising polymer-based vehicles for exogenous in vitro siRNA transfection, few synthetic vehicles are feasible in vivo. Recent studies have presented copolymer-based vectors that are minimally immunogenic and facilitate highly efficient internalizing of exogenous siRNA, compared with homopolymer-based vectors. Cationic segments, organelle-escape units, and degradable fragments are essential to a copolymer-based vehicle for siRNA delivery. The majority of these cationic segments are derived from polyamines, including polylysine, polyarginine, chitosan, polyethylenimines and polyamidoamine dendrimers. Not only do these cationic polyamines protect siRNA, they can also promote disruption of endosomal membranes. Degradable fragments of copolymers must be derived from various polyelectrolytes to release the siRNA once the complexes enter the cytoplasm. This review describes recent progress in copolymer-mediated siRNA delivery, including various building blocks for biocompatible copolymers for efficient in vitro siRNA delivery, and a useful basis for addressing the challenges of in vivo siRNA delivery.

Nanotherapeutics for Alzheimer's disease (AD): Past, present and future.

Abstract: Drug delivery to the brain still remains highly challenging for the treatment of Alzheimer’s disease (AD). The development of new practical treatment modalities for the treatment of AD is currently a highly active area of research. Our lack of success in the development of effective therapies for AD is attributed to, but not limited to a number of factors including the complexity of the brain. Besides this, it is recognized that AD is multisystemic in nature and this presents numerous difficulties for the potential treatment of these disorders. Another important reason for the lack of development of effective drugs and drug delivery system for AD is inability to deliver drugs effectively to the brain due to the numerous protective barriers surrounding the CNS i.e. blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB) and circumventricular organs (CVOs). Solutions to these problems require enhanced novel research activities that can address each of these problems. This review article provide...

PEG-detachable cationic polyaspartamide derivatives bearing stearoyl moieties for systemic siRNA delivery toward subcutaneous BxPC3 pancreatic tumor

Abstract: For systemic siRNA delivery into tumor tissues, a safe and efficient vehicle is strongly required. Therefore, we designed a block copolymer of detachable poly(ethylene glycol) (PEG) polycation bear...

Formulation, evaluation and pharmacokinetics of colon targeted pulsatile system of flurbiprofen

Abstract: Objective: The intent of the present investigation is to develop colon targeted compression coated flurbiprofen pulsatile release tablets that retard the drug release in the upper gastro intestinal system but progressively release in the colon.Materials and methods: Flurbiprofen core tablets were prepared by direct compression method and were compression coated with hydroxypropyl methylcellulose and Eudragit S100. The formulation is optimized based on the in vitro drug release study and further evaluated by X-ray imaging and pharmacokinetic studies in healthy humans for colonic delivery.Results and discussions: The optimized formulation showed negligible drug release (7.26 ± 0.05%) in the initial lag period followed by progressive release (99.27 ± 0.46%) for 24 h. The X-ray imaging study in human volunteers showed that the tablets reached the colon without disintegrating in the upper gastrointestinal tract. The Cmax of colon targeted tablets was 10792.62 ng/mL at Tmax 10 h where as in case of immediate re...

Nano-sized cationic polymeric magnetic liposomes significantly improves drug delivery to the brain in rats.

Abstract: In recent years, cationic polymeric magnetic liposomes have shown greater stability and prolonged circulation half-life over traditional liposomes. Here, we examined the capability of cationic poly...

A mini review of nanosuspensions development.

Abstract: Nanosuspension drug delivery has obtained great success in the preparation of insoluble drugs. The nanosuspension technology can confer a series of special characteristics to the drugs, such as the enhanced dissolution rate and saturation solubility. This mini review first described the differences between the nanocrystals and nanosuspensions. Next, the product techniques, the stable measures, the special features, and the routes of administration of the nanosuspensions were reviewed and compared. Finally, some existing shortcomings of the nanosuspensions were mentioned and the perspectives of the nanosuspensions were also made.

Improvement of tetracaine antinociceptive effect by inclusion in cyclodextrins.

Abstract: Local anesthetics (LA) are among the most important pharmacological compounds used to attenuate or eliminate pain. However, systemic toxicity is still a limitation for LA application, especially for ester-type drugs, such as tetracaine (TTC) that presents poor chemical stability (due to hydrolysis by plasma esterases). Several approaches have been used to improve LA pharmaceutical properties, including the employment of drug-delivery systems. Here we used beta-cyclodextrin (β-CD) or hydroxypropyl-beta-cyclodextrin (HP-β-CD) to develop two new TTC formulations (TTC:β-CD and TTC:HP-β-CD). The inclusion complexes formation, in a 1:1 stoichiometry, was confirmed by differential scanning calorimetry, X-ray diffraction, UV-VIS absorption and fluorescence. Nuclear magnetic resonance (DOSY experiments) revealed that TTC association with HP-β-CD is stronger (Ka=1200 mol/L(-1)) than with β-CD (Ka=845 mol/L(-1)). Moreover, nuclear Overhauser effect (NOE) experiments provided information on the topology of the complexes, where TTC aromatic ring is buried inside the CD hydrophobic cavity. In vitro tests with 3T3 fibroblast cells culture revealed that complexation decreased TTC cytotoxicity. In addition, the total analgesic effect of TTC, tested in rats through the infraorbital nerve test, was improved in 36% with TTC:β-CD and TTC:HP-β-CD. In conclusion, these formulations presented potential for future clinical use, by reducing the toxicity and increasing the antinociceptive effect of tetracaine.

Attenuation of early liver fibrosis by pharmacological inhibition of smoothened receptor signaling

Abstract: Hedgehog (Hh) signaling is involved in the pathogenesis of liver fibrosis. It has been previously shown that Hh-inhibitor cyclopamine (CYA) can reduce liver fibrosis in rats. However, CYA is not stable in vivo, which limits its clinical application. This study compares the antifibrotic potential of two known Hh antagonists, vismodegib (GDC-0449, abbreviated to GDC) and CYA. GDC is a synthetic molecule presently in clinical cancer trials and has been reported to be safe and efficacious. These drugs attenuated early liver fibrosis in common bile duct ligated rats, improved liver function, and prevented hepatic stellate cell (HSC) activation, thereby suppressing epithelial to mesenchymal transition (EMT). While both CYA and GDC increased the number of proliferating cell nuclear antigen positive liver cells in vivo, only CYA increased Caspase-3 expression in HSCs in rat livers, suggesting that while GDC and CYA effectively attenuate early liver fibrosis, their hepatoprotective effects may be mediated through different modes of action. Thus, GDC has the potential to serve as a new therapeutic agent for treating early liver fibrosis.

Oral microparticulate vaccine for melanoma using M-cell targeting.

Abstract: Cancer vaccines are limited in their use, because of their inability to mount a robust anti-tumor immune response. Thus, targeting M-cells in the small intestine, which are responsible for entry of many pathogens, will be an attractive way to elicit a strong immune response toward particulate antigens. Therefore, in the present investigation, we demonstrated that efficient oral vaccination against melanoma antigens could be accomplished by incorporating the antigens in an albumin-based microparticle with a ligand AAL (Aleuria aurantia lectin) targeted specifically to M-cells. The oral microparticulate vaccine effectively protected the mice from subcutaneous challenge with tumor cells in prophylactic settings. The animals were vaccinated with antigen microparticles having a size range of around 1-1.25 µm where one prime and four booster doses were administered every 14 days over 10 weeks of duration, followed by challenge with live tumor cells, which showed complete tumor protection after oral vaccination. With the inclusion of ligand in the microparticles, we observed significantly higher IgG titers (1565 μg/mL) as compared to the microparticle formulations without AAL (872 μg/mL). This data suggests that ligand loaded microparticles may have the potential to target antigens to M-cells for an efficient oral vaccination.