Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: part 2.

Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.

Endogenous carriers and ligands in non-immunogenic site-specific drug delivery.

Targeted drug delivery has gained recognition in modern therapeutics and attempts are being made to explore the potentials and possibilities of cell biology related bioevents in the development of specific, programmed and target oriented systems. The components which have been recognized to be tools include receptors and ligands, where the receptors act as molecular targets or portals, and ligands, with receptor specificity and selectivity, are trafficked en route to the target site. Although ligands of exogenous or synthetic origin contribute to the selectivity component of carrier constructs, they may impose immunological manifestations of different magnitudes. The latter may entail a continual quest for bio-compatible, non-immunogenic and target orientated delivery. Endogenous serum, cellular and extracellular bio-ligands interact with the colloidal carrier constructs and influence their bio-fate. However, these endogenous bio-ligands can themselves serve as targeting modules either in their native form or engineered as carrier cargo. Bio-regulatory, nutrient and immune ligands are sensitive, specific and effective site directing handles which add to targeted drug delivery. The present review provides an exhaustive account of the identified bio-ligands, which are not only non-immunogenic in nature but also site-specific. The cell-related bioevents which are instrumental in negotiating the uptake of bio-ligands are discussed. Further, a brief account of ligand-receptor interactions and the set of biological events which ensures ligand-driven trafficking of the ligand-receptor complex to the cellular interior is also presented. Since ligand-receptor interaction is a critical pre-requisite for negotiating cellular uptake of endogenous ligands and anchored carrier cargo, an attempt has been made to identify differential expression of receptors and bio-ligands under normal and etiological conditions. Studies which judiciously utilized bio-ligands or their analogs in negotiating site-specific drug delivery have been reviewed and presented. Targeted delivery of bioactives using endogenous bio-ligands offers enormous options and opportunities through carrier construct engineering and could become a future reality in clinical practice.

Ligand-receptor-mediated drug delivery: an emerging paradigm in cellular drug targeting.

Receptor-mediated cellular events have received major attention in the field of drug/gene delivery in the past few years. These events, which are mediated through the endogenous ligands/epitopes, could be exploited for designing site-specific and target-oriented delivery systems. The past decade has seen the development of endogenous ligands and their mimics of exogenous origins to selectively deliver the contained or immobilized moieties to the cellular interiors using a wide range of cell surface receptors/epitopes. Ligand-mediated active targeting has emerged as a novel paradigm in targeting either vascular compartment (first-order), cellular (second-order), or intracellular (third-order) levels. Most carrier systems or bioconjugates explored so far can be used as cargo units for the site-specific presentation and delivery of various bioactives using biorelevant ligands, including antibodies, polypeptides, oligosaccharides (carbohydrates), viral proteins, fusogenic residues, and molecules of endogenous origin. In this review, we describe various ligand-receptor systems that have been investigated to date for targeted or cellular drug delivery. These include blood carbohydrate (lectin) receptors, Fc receptors, complement receptors, interleukin receptors, lipoprotein receptors, transferin receptors, scavenger receptors, receptors/epitopes expressed on tumor cells, and cell adhesion receptors. The role of receptors as molecular target has opened new opportunities for cellular or intracellular targeting using carrier systems appended with targeting handles (ligands). Research in the field of ligand-receptor-based targeted system is expected to be an armamentarium and the focal point of research in the next millennium.

Potential of polysaccharide anchored liposomes in drug delivery, targeting and immunization.

PURPOSE: Recently the emphasis has been laid upon the carbohydrate mediated liposomal interactions with the target cells. Among the various carbohydrate ligands, such as glycoproteins, glycolipids, viral proteins, polysaccharides, lipo-polysaccharides and other oligosaccharides, this review deals with the polysaccharide anchored liposomal system for their potential in drug delivery, targeting and immunization. Over the years, various strategies have been developed which include coating of the liposomal surface with natural or hydrophobized polysaccharides, namely mannan, pullulan, amylopectin, dextran etc., or their palmitoyl or cholesteroyl derivatives. The polysaccharide(s) coat tends vesicular constructs physicochemically stable in bio-environments and site-specific. The aim of improving the physical and biochemical stability of liposomes and the ability to target liposomes to specific organs and cells, were the major attributes of the polysaccharide anchored liposomes. In this review the authors attempted to overview various applications of polysaccharide bearing liposomes, including lung therapeutics, targeted chemotherapy, cellular targeting, cellular or mucosal immunity and macrophage activation. Future prospects of the delivery module are also discussed. The review in general explores the concepts, options and opportunities of polysaccharide anchored liposomes with newer perspectives.

Ligand directed macrophage targeting of amphotericin B loaded liposomes.

Two types of ligand anchored multilamellar liposomes (MLVs) containing amphotericin B (Amp B) were prepared. The MLVs consisting of soya phosphatidylcholine (PC) and cholesterol (Chol) were coated with O-palmitoyl mannan (OPM). Similarly, the MLVs with the same Amp B content consisting of soya PC, Chol and phosphatidylethanolamine (PE) were prepared and covalently anchored with p-aminophenyl-mannopyranoside (PAM). The surface modified MLVs and their plain counterparts were characterised for size, shape, lamellarity, entrapment efficiency and ligand density. The stability in serum and in vivo bio-distribution in albino rats were also determined. It was observed that extent of accumulation of liposomal Amp B in macrophage rich organs, particularly liver, spleen and lungs was significantly high when compared against the free drug. The rates and extent of accumulation were found to increase further on ligand anchoring. In either of the cases, the macrophagic uptake of ligand anchored liposomes was inhibited significantly on pre-injection of hydrolysed mannan, being suggestive of receptor mediated uptake of ligand anchored liposomes. Comparison of biodistruibution pattern of ligand anchored MLVs revealed that PAM linked liposomes exhibited a higher hepato-splenic accumulation where as drug accumulation in lungs was highest in the case of OPM coated liposomes. It was thus observed that mannopyranoside is a specific ligand for targeting bioactives to the macrophages of liver and spleen while OPM could preferentially negotiate the targeting of bioactives to the alveolar macrophages.

Polysaccharide coated niosomes for oral drug delivery: formulation and in vitro stability studies.

Non-ionic surfactant vesicles (niosomes) were prepared and appended with a polysaccharide cap using hydrophobic anchors. Hydrophobized polysaccharides, O-palmitoyl pullulan (OPPu) and cholesteroyl pullulan (CHPu) were anchored onto propranolol.HCL containing preformed niosomes. The coated niosomes were characterized for average vesicle size, size distribution, shape, encapsulation efficiency and in vitro release profile and were compared with their uncoated counterparts. No significant difference was observed in % encapsulation (P > 0.05 in a rank sum test) of polysaccharide coated and uncoated vesicles. In vitro release studies however, revealed a significant lowering (P < 0.01) of drug release for the coated systems in simulated gastric and intestinal fluids with a biphasic release profile. The influence of the hydrophobized polysaccharide cap on niosomal membrane integrity and stabilization against harsh bio-environment conditions was also investigated. The parameters investigated include detergent and bile (bile salts and fresh-pooled rat bile) challenge, freeze-thaw cycling, osmotic stress, and long term and shelf stability studies. It was seen that at higher bile salt concentrations and detergent content, uncoated niosomes underwent bilayer solubilization into intermediate micellar structures, whereas coated niosomes were able to maintain their structural integrity as reflected from their higher % latency for the entrapped water soluble agent. Similarly, freeze-thaw cycling could not bring any fusion or collapse of the niosomal membrane (unlike uncoated ones). Furthermore, the exceptional shelf stability of the coated vesicles both at 37 +/- 1 degrees and at 4 +/- 1 degrees C establishes the potential of polysaccharide coated niosomes as an oral delivery system for water-soluble agents. Results from OPPu and CHPu coated niosomal systems for their oral stability potential are compared.

Preparation, characterization and in vitro antimicrobial activity of metronidazole bearing lectinized liposomes for intra-periodontal pocket delivery.

Liposomes constructed of egg phosphatidylcholine (EPC), cholesterol (Chol) and stearoylamine (SA) were coated with lectin (Concanavalin-A). These lectinized liposomes were found to retain the ligand binding activity of surface coated concanavalin A (Con-A) as demonstrated by bovine submaxillary mucin (BSM) binding assay. Moreover the ligand specificity of Con-A was maintained even after coating the liposome surface because the presence of competing sugar alpha-methyl mannoside, significantly inhibited the interaction of lectinized liposomes and BSM. The significance of divalent cations for these interactions was studied. The Con-A coating was found to be stable in simulated salivary fluids (SSF, pH 7.2) and under various pH conditions. In vitro targeting studies of lectinized liposomes with gram-negative bacilli (Streptococcus mutans) that harbor in the periodontal pocket (biofilm) demonstrated nearly 100% bacterial growth inhibition (% BGI). The antimicrobial effect was maintained for 360 min. The results were compared with metronidazole bearing plain (protein free/uncoated) liposomes and the free drug at the same dose levels. Mechanisms involved are also discussed. These observations suggest that liposomes coated with lectin (Con-A) were able to maintain the sugar affinity and specificity of the associated ligand and could be targeted to the surface 'glyco-calyx' of bacterial bio-film.

Exploring novel vaccines against Helicobacter pylori: protective and therapeutic immunization.

Infection of human stomach by Helicobacter pylori, a gram negative spiral bacterium first isolated in 1983 from a patient with chronic active gastritis (1), causes nearly all duodenal ulcers and most gastric ulcers and is associated with an increased risk of gastric adenocarcinoma (2). Current therapies for gastric infections include combination triple or quadruple therapy of antimicrobial and/or antiulcer agents for eradication of H. pylori infection (3). Development of the resistant strains and ecological niche (habitant) of the bacteria may cause relapse after the termination of the therapy. However, if effective, the high cost, difficulty of patient compliance and risk of selection for resistant strains make these therapeutic regimens impractical on a large scale, though effective on the laboratory trial stages. Studies of the pathogenesis of H. pylori have led to the identification of bacterial antigens and adherin proteins as candidates for inclusion as novel vaccines against these diseases (4-7). Both prophylactic and therapeutic vaccination have been demonstrated in animal models of H. pylori infection (8-10).

Biofilm consortia on biomedical and biological surfaces: delivery and targeting strategies.

Microbial biofilms have been observed as congregates and attached communities on a diverse range of microecosystems of medicinal and industrial importance. Until recently, most investigations have been performed on planktonic (floating or fluid phase) microorganisms. After realization of the biofilm existence and their recalcitrance toward conventionally adopted preventive strategies and antimicrobial agents, research has been shifted toward novel therapeutics based drug delivery and targeting approaches. With the emergence of various biofilm models and methods to assess biofilm formation and physiology, it is pivotal to discuss various novel strategies that may become the therapeutic tools and clinically adaptable strategies of the future. This review explores various novel research strategies studied to date for their potential in effective biofilm eradication.

Controlled and targeted drug delivery strategies towards intraperiodontal pocket diseases.

Advances in the understanding of the aetiology, epidemiology, pathogenesis and microbiology of periodontal pocket flora have revolutionized the strategies for the management of intraperiodontal pocket diseases. Intra-pocket, sustained release, drug delivery devices have been shown to be clinically effective in the treatment of periodontal infections. Several degradable and non-degradable devices are under investigation for the delivery of antimicrobial agents into the periodontal pocket including non-biodegradable fibres, films (biodegradable and non-biodegradable), bio-absorbable dental materials, biodegradable gels/ointments, injectables and microcapsules. With the realization that pocket bacteria accumulate as biofilms, studies are now being directed towards eliminating/killing biofilm concentrations rather than their planktonic (fluid phase) counterparts. Intraperiodontal pocket drug delivery has emerged as a novel paradigm for the future research. Similarly, bioadhesive delivery systems are explored that could significantly improve oral therapeutics for periodontal disease and mucosal lesions. A strategy is to target a wide range of molecular mediators of tissue destruction and hence arrest periodontal disease progression. Research into regenerating periodontal structures lost as a result of disease has also shown substantial progress in the last 25 years.