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Biomedical subjects

S P Vyas

Publications and source records attributed to S P Vyas.

At least 19 recordsLinked to original sources

Mannosylated liposomes for bio-film targeting.

Vesicular systems in general are investigated to achieve bacterial bio-film targeting as their architecture mimics bio-membranes in terms of structure and bio-behavior. This paper elaborates upon the role of the inherent characteristics of the carrier system and further envisages the role of anchored ligands in navigating the contents in the vicinity of bio-films. Vesicles in the present study were coated with hydrophobic derivatives of mannan (cholesteryl mannan and sialo-mannan). The prepared vesicles were characterized for size, shape, percentage entrapment and ligand binding specificity and results were compared with the uncoated versions. Using a set of in vitro and in vivo models, the bio-film targeting potential of plain and mannosylated liposomal formulations were compared. Results suggested that mannosylated vesicles could be effectively targeted to the model bacterial bio-films, compared with plain vesicles. Moreover, the sialo-mannan coated liposomes recorded superior targetability as reflected in the significantly higher percentage growth inhibition when compared with cholesteryl mannan coated liposomes. The engineered systems thus have the potential use for the delivery of anti-microbial agents to the bio-films.

Animals↗

Pegylated protein encapsulated multivesicular liposomes: a novel approach for sustained release of interferon alpha.

Hepatitis C viral chemotherapy suffers from a relatively short half-life of the interferon alpha-2a (IFN alpha). To address this issue, we investigated the effects of polyethylene glycol modification and their subsequent encapsulation in multivesicular liposomes (MVLs), on the release properties of IFN alpha. In the present study, interferon-alpha was conjugated with methoxy-polyethylene glycol (mPEG, MW 5000). Prepared IFN alpha-mPEG5000 conjugate (IFN alpha-mPEG5000) was purified with size exclusion chromatography. The relative in vitro anti-viral activity of pegylated interferon alpha-2a was found to 87.9% of the unmodified IFN alpha. Pegylated IFN alpha encapsulated multivesicular liposomes were prepared by double emulsification technique followed by evaporation of organic solvents from chloroform ether spherules suspended in water. Prepared MVLs were then characterized for shape, size, vesicle count, encapsulation efficiency, and in vitro release rate. In process stability studies of pegylated IFN alpha protein exhibited better stability when exposed to chloroform: diethyl ether (1:1 ratio) mixture as well as variable vortexing time as compared to native IFN alpha. Relatively high percentage of encapsulation of protein ( approximately 75%) was achieved. In vitro release profile of pegylated IFN alpha-mPEG5000 containing MVLs in the PBS showed lower initial burst release with sustained and incomplete release over a period of 1 week. In contrast, native IFN alpha entrapped MVLs were observed as higher initial burst release, i.e., nearly 35% followed by almost complete release. The results confirmed the possibility of multivesicular liposomes as a long-acting or sustained-release delivery system using a combination of pegylation and encapsulation technique for controlled delivery of interferon alpha.

Antiviral Agents↗

Mannosylated niosomes as adjuvant-carrier system for oral mucosal immunization.

The aim of the present study was to develop mannosylated niosomes as oral vaccine delivery carrier and adjuvant for the induction of humoral, cellular, and mucosal immunity. Tetanus toxoid (TT) loaded niosomes composed of sorbiton monostearate (Span 60), cholesterol, and stearylamine were prepared by the reverse-phase evaporation method. They were coated with a modified polysaccharide o-palmitoyl mannan (OPM) to protect them from bile salts caused dissolution and enzymatic degradation in the gastrointestinal tract and to enhance their affinity toward the antigen presenting cells of Peyer's patches. Prepared niosomes were characterized in vitro for their size, shape, entrapment efficiency, ligand binding specificity, and stability in simulated gastric fluid and simulated intestinal fluid. OPM-coated niosomes were found to more stable in simulated gastrointestinal conditions. The immune stimulating activity was studied by measuring serum IgG titer, IgG2a/IgG1 ratio in serum, and sIgA levels in intestinal and salivary secretions following oral administration of niosomal formulations in albino rats. The results were compared with alum-adsorbed TT following oral and intramuscular administration, and it was observed that OPM-coated niosomes produced better IgG levels as compared to plain uncoated niosomes and alum-adsorbed TT upon oral administration. Oral niosomes also elicited a significant mucosal immune response (sIgA levels in mucosal secretions). The developed formulations also elicited a combined serum IgG2a/IgG1 response, suggesting that they were capable of eliciting both humoral and cellular response. The study signifies the potential of OPM-coated niosomes as an oral vaccine delivery carrier and adjuvant. The proposed system is simple, stable, and cost-effective and may be clinically acceptable.

Adjuvants, Immunologic↗

Chitosan nanoparticles encapsulated vesicular systems for oral immunization: preparation, in-vitro and in-vivo characterization.

BSA-loaded chitosan nanoparticles were prepared and encapsulated in vesicles (liposomes and niosomes) to make them acid resistant upon oral administration. Prepared systems were characterized in-vitro for shape, size, entrapment efficiency and stability in simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid (SIF, pH 7.5). The immune stimulating activity was studied by measuring serum IgG titre and secretory IgA (sIgA) levels in mucosal secretions following oral administration of various formulations in albino rats. Significantly higher (P < 0.05) serum IgG titres were achieved following oral administration of novel nanoparticulate vesicular formulations as compared with unmodified chitosan nanoparticles. Further, high sIgA levels in mucosal secretions advocated a possible application of chitosan nanoparticle encapsulated in vesicles as an oral vaccine delivery carrier-adjuvant system.

Administration, Oral↗

Development and characterization of emulsomes for sustained and targeted delivery of an antiviral agent to liver.

In this study we developed emulsomes, a novel lipoidal vesicular system with an internal solid fat core surrounded by a phospholipid bilayer. Plain emulsomal formulations composed of solid lipid (trilaurin or tristearin), cholesterol and soya phosphatidylcholine and stearylamine containing cationic emulsomes loaded with an antiviral drug (zidovudine) were prepared by a simple cast film method followed by sonication to produce emulsomes of nanometric size range. All different types of formulations were optimized for lipid ratios and characterized in-vitro for shape, morphology, size and in-vitro drug release profile. Emulsomal formulations displayed a sufficiently slow drug release profile (12-15% after 24 h). In-vivo organ distribution studies in rats demonstrated better uptake of emulsomal formulations by the liver cells. Further, a significantly higher (P < 0.05) liver concentration of drug was estimated over a period of 24 h for cationic emulsomes than for plain neutral emulsomes. We concluded that cationic emulsomes could fuse with the endosomal membrane due to charge-charge interaction and were released in the cytoplasm before lysosomal degradation and could sustain drug release over a prolonged period. The proposed cationic emulsome-based system showed excellent potential for intracellular hepatic targeting and the strategy could play a vital role in the effective treatment of life-threatening viral infections, such as hepatitis, HIV and Epstein-Barr virus infection.

Amines↗

Mannosylated niosomes as adjuvant-carrier system for oral genetic immunization against hepatitis B.

Aim of the present study was to develop mannosylated niosomes as oral DNA vaccine carriers for the induction of humoral, cellular and mucosal immunity. Niosomes composed of span 60, cholesterol and stearylamine as constitutive lipids were prepared by reverse phase evaporation method and were coated with a modified polysaccharide o-palmitoyl mannan (OPM) in order to protect them from bile salt caused dissolution and enzymatic degradation in the gastrointestinal tract and to enhance their affinity towards the antigen presenting cells of Peyer's patches. Prepared niosomes were characterized in vitro for their size, shape, entrapment efficiency, ligand binding specificity and stability in simulated gastric fluid and simulated intestinal fluid. OPM coated niosomes were found to better stable in simulated GIT conditions. The immune stimulating activity was studied by measuring serum anti-HBsAg titer, secretory IgA level in intestinal and salivary secretions and cyokines level (IL-2 and IFN-gamma) in spleen homogenates following oral administration of niosomal formulations in Balb/c mice and compared with naked DNA as well as pure recombinant HBsAg injected intramuscularly. The serum anti-HBsAg titer obtained after oral administration of OPM coated niosomal formulations was although less as compared to that elicited by naked DNA and pure HBsAg administered intramuscularly, but the mice were seroprotective within 2 weeks and antibody level far above the clinically protective limit for humans was achieved. Intramuscular naked DNA and recombinant HBsAg did not elicited sIgA titer in mucosal secretions that was induced by oral administration of OPM coated niosomes. Similarly, cellular response (cytokines level) was absent in pure HBsAg treated animals. OPM coated niosomes produced humoral (both systemic and mucosal) and cellular immune response upon oral administration. The study signifies the potential of OPM coated niosomes as DNA vaccine carrier and adjuvant for effective oral immunization.

Administration, Oral↗

Non-ionic surfactant based vesicles (niosomes) for non-invasive topical genetic immunization against hepatitis B.

DNA vaccines are capable of eliciting both humoral as well as cellular immune responses. Liposomes have been widely employed for DNA delivery through topical route; however, they suffer from certain drawbacks like higher cost and instability. In present study, non-ionic surfactant based vesicles (niosomes) for topical DNA delivery have been developed. DNA encoding hepatitis B surface antigen (HBsAg) was encapsulated in niosomes. Niosomes composed of span 85 and cholesterol as constitutive lipids were prepared by reverse phase evaporation method. Prepared niosomes were characterized for their size, shape and entrapment efficiency. The immune stimulating activity was studied by measuring serum anti-HBsAg titer and cyokines level (IL-2 and IFN-gamma) following topical application of niosomes in Balb/c mice and results were compared with naked DNA and liposomes encapsulated DNA applied topically as well as naked DNA and pure recombinant HBsAg administered intramuscularly. It was observed that topical niosomes elicited a comparable serum antibody titer and endogenous cytokines levels as compared to intramuscular recombinant HBsAg and topical liposomes. The study signifies the potential of niosomes as DNA vaccine carriers for effective topical immunization. The proposed system is simple, stable and cost effective compared to liposomes.

Administration, Topical↗

Biodisposition of PEG-coated lipid microspheres of indomethacin in arthritic rats.

Conventional lipid microspheres (LM) were prepared using soybean oil and lipid at a 5.5:1 weight ratio with lipid phase consisting of PC (phosphatidyl choline):CH (cholesterol) (1:0.5) by molar ratio. The average diameter of the particles was 150 nm. Long-circulating microspheres (S-LM) were also prepared similarly but the lipid phase consisted of PC:CH:DSPE-PEG (phosphatidyl choline:cholesterol:distearoyl phosphatidyl ethanolamine-polyethylene glycol) 1:0.5:0.16 by molar ratio. A comparative biodistribution study was conducted between free indomethacin and lipo-indomethacin (LM and S-LM) in the arthritic rats by administering the formulations at a dose equivalent to 12 mg of indomethacin/kg. It was observed that the free drug as well as the encapsulated drug followed biphasic clearance from the blood. Pharmacokinetic parameters, such as AUC(0-t), terminal half-life, MRT increased significantly when the drug was used in encapsulated form (p < 0.05). Clearance of the drug was reduced 1.4 times with the conventional lipid microspheres and was reduced three-fold when encapsulated in polyethylene glycol-coated lipid microspheres. The overall drug targeting efficiency (T(e)) with the PEG-coated lipid microspheres was 7.5-fold higher than the conventional lipid microspheres. The high accumulation of the drug in arthritic paw with S-LM system may be accounted for by the reduced uptake by RES cells, and thereby, availability for extravascularization in the inflammatory tissues.

Animals↗

Inverse targeting of diclofenac sodium to reticuloendothelial system-rich organs by sphere-in-oil-in-water (s/o/w) multiple emulsion containing poloxamer 403.

Sphere-in-oil-in-water (s/o/w) multiple emulsions containing diclofenac sodium were prepared by gelatinization of inner aqueous phase. A further modified version (s/o/wp) of s/o/w was formulated by adding 5.0% w/v poloxamer 403 to the external aqueous phase during the second step of emulsification in order to affect the adsorptive coating on the surface (s/o/wp). The inverse targeting of reticuloendothelial system (RES) rich organs was compared with a non reticuloendothelial system after intravenous administration of s/o/w multiple emulsion (treatment I) and poloxamer containing s/o/wp multiple emulsion (treatment II). The amount of diclofenac sodium in the plasma and various organs was measured to elucidate the effect of inverse targeting to RES and targeting to other tissues in terms of the incorporated drug. After i.v. administration, the half life (34.65 vs.16.26 h) and apparent volume of distribution of diclofenac sodium (2815 vs. 1671.5 ml/kg) were significantly higher in treatment II than in treatment I. It is concluded that the amount of drug in RES rich organs (spleen, liver) were significantly lower than the values in non-RES organs such as lungs, inflammatory tissue (synovial fluid) in treatment II than in treatment I.

Algorithms↗

Mannosylated niosomes as carrier adjuvant system for topical immunization.

The aim of this study was to develop mannosylated niosomes as a topical vaccine delivery carrier and adjuvant for the induction of both humoral and cellular immunity. Bovine serum albumin (BSA)-loaded niosomes composed of sorbitan monostearate/sorbitan trioleate (Span 60/Span 85), cholesterol and stearylamine as constitutive lipids were prepared by the reverse-phase evaporation method. The niosomes were coated with a modified polysaccharide O-palmitoyl mannan (OPM) to target them to Langerhan's cells, the major antigen presenting cells found in abundance beneath the stratum corneum. Prepared niosomes were characterized in-vitro for their size, shape, entrapment efficiency and ligand binding specificity. The immune stimulating activity was studied by measuring serum IgG titre and its subclasses (IgG2a/IgG1 ratio) following topical application of various niosomal formulations in albino rats. The results were compared with alum-adsorbed BSA following topical application and intramuscular injection. It was observed that niosomal formulations elicited a significantly higher serum IgG titre upon topical application as compared with topically applied alum adsorbed BSA (P<0.05). The serum IgG levels were significantly higher for the mannosylated niosomes as compared with plain uncoated niosomes (P<0.05). All formulations displayed a combined serum IgG2a/IgG1 response, which suggested that the formulations were capable of eliciting both humoral and cellular responses. The study signified the potential of OPM-coated niosomes as a topical vaccine delivery carrier and adjuvant. The proposed system would be simple, stable, and cost effective and might be clinically acceptable.

Adjuvants, Immunologic↗

Design of liposomal aerosols for improved delivery of rifampicin to alveolar macrophages.

The present study was aimed at preparation, characterization, and performance evaluation of rifampicin-loaded aerosolized liposomes for their selective presentation to alveolar macrophages, that being the most dense site of tuberculosis infection. Egg phosphatidylcholine (PC)- and cholesterol (Chol)-based liposomes were modified by imparting negative charge (using dicetylphosphate, DCP) or by coating them with alveolar macrophage-specific ligands (maleylated bovine serum albumin, MBSA; and O-steroyl amylopectin, O-SAP). The prepared formulations were characterized in vitro for vesicle morphology, mean vesicle size, and percent drug entrapment. Pressurized packed systems based on preformed liposomal formulations in chlorofluorocarbon aerosol propellants were prepared. In vitro airway penetration efficiency of the liposomal aerosols was determined by percent dose reaching the base of the lung, it was recorded 1.5-1.8 times higher as compared to plain drug solution-based aerosol. Percent viability of Mycobacterium smegmatis inside macrophages (in vitro) after administration of drug (in vivo) was in the range of 7-11% in the case of ligand-anchored liposomal aerosols, while it was recorded to be 45.7 and 31.6% in case of plain drug and plain neutral liposomal aerosol (based on PC:Chol)-treated macrophages. Results suggest the preferential accumulation of MBSA- and O-SAP-coated formulations in the lung macrophages, which was further reflected in the periodically monitored in vivo tissue distribution studies. Higher lung drug concentration was recorded in case of ligand-anchored liposomal aerosols and negatively charged liposomal aerosols (based on PC:Chol:DCP) as compared to plain drug and plain liposome-based aerosols. The drug was estimated in the lung in high concentration even after 24h. The drug localization index calculated after 6h was nearly 1.4- and 3.5-fold, respectively, for both ligand-appended liposome-based systems as compared to negatively charged and plain neutral liposome-based aerosolized systems. These results suggest that the ligand-anchored liposomal aerosols are not only effective in rapid attainment of high-drug concentration in lung with high population of alveolar macrophages but also maintain the same over prolonged period of time. The significance of targeting potential of the developed systems was established.

Administration, Inhalation↗

Liposomes modified with cyclic RGD peptide for tumor targeting.

Cyclic RGD peptide anchored sterically stabilized liposomes (RGD-SL) were investigated for selective and preferential presentation of carrier contents at angiogenic endothelial cells overexpressing alphavbeta3 integrins on and around tumor tissue and thus for assessing their targetabilty. Liposomes were prepared using distearoylphosphatidylcholine (DSPC), cholesterol and distearoylphosphatidylethanolamine-polyethyleneglycol-RGD peptide conjugate (DSPE-PEG-RGD) in a molar ratio 56:39:5. The control RAD peptide anchored sterically stabilized liposomes (RAD-SL) and liposome with 5 mol% PEG (SL) without peptide conjugate which had similar lipid composition were used for comparison. The average size of all liposome preparations prepared was approximately 105 nm and maximum drug entrapment was 10.5+/- 1.1%. In vitro endothelial cell binding of liposomes exhibited 7-fold higher binding of RGD-SL to HUVEC in comparison to the SL and RAD-SL. Spontaneous lung metastasis and angiogenesis assays show that RGD peptide anchored liposomes are significantly (p<0.01) effective in the prevention of lung metastasis and angiogenesis compared to free 5-FU, SL and RAD-SL. In therapeutic experiments, 5-FU, SL, RGD-SL and RAD-SL were administered intravenously on day 4 at the dose of 10 mg 5-FU/kg body weight to B16F10 tumor bearing BALB/c mice resulting in effective regression of tumors compared with free 5-FU, SL and RAD-SL. Results indicate that cyclic RGD peptide anchored sterically stabilized liposomes bearing 5-FU are significantly (p<0.01) active against primary tumor and metastasis than the non-targeted sterically stabilized liposomes and free drug. Thus cyclic RGD peptide anchored sterically stabilized liposomes hold potential of targeted cancer chemotherapeutics.

Animals↗

RGD-anchored magnetic liposomes for monocytes/neutrophils-mediated brain targeting.

Negatively charged magnetic liposomes were prepared using soya lecithin (Soya PC), cholesterol and phosphatidyl serine (PS) for their preferential presentation to circulating blood phagocytes (monocytes and neutrophils). PS ratio was optimized in terms of drug and magnetite loading, in vitro magnetic responsiveness and ex vivo monocytes/neutrophils uptake. RGD peptide was covalently coupled to the negatively charged liposomes composed of PC, cholesterol, PS and phopsphatidyl ethanolamine (PE) via carbodiimide-mediated coupling. In vivo cellular sorting study under magnetic guard indicated an increase in relative count of neutrophils and monocytes. Results suggest that selective uptake of RGD-anchored magnetic liposomes by these cells imparts them magnetic property. High levels of a model drug diclofenac sodium was quantified in target organ brain. In case of negatively charged uncoated magnetic liposomes brain levels of the drug was 5.95-fold compared to free drug and 7.58-fold in comparison to non-magnetic formulation, while for RGD-coated magnetic liposomes this ratio was 9.1-fold compared to free drug solution, 6.62-fold compared to non-magnetic RGD-coated liposomes and 1.5-fold when compared to uncoated magnetic liposomes. Liver uptake was significantly bypassed (37.2% and 48.3% for uncoated and RGD-coated magnetic liposomes, respectively). This study suggested the potential of negatively charged and RGD-coated magnetic liposomes for monocytes/neutrophils-mediated active delivery of drugs to relatively inaccessible inflammatory sites, i.e. brain. The study opens a new perspective of active delivery of drugs for a possible treatment of cerebrovascular diseases.

Animals↗

pH-sensitive liposomes: mechanism of triggered release to drug and gene delivery prospects.

A growing amount of literature describes the development and applications of novel targeting and/or release triggering schemes to improve the therapeutic index of drugs encapsulated within liposomes. The composition of liposomal systems can be modified to facilitate site specific release in response to environmental conditions, namely at the gross anatomical level, at the cellular or sub-cellular level. They are designed in order to release their contents in response to acidic pH within the endosomal system while remaining stable in plasma thus improving the cytoplasmic delivery of various polar materials and macromolecules such as anti-tumor drugs, toxins, proteins and DNA. This review covers various aspect of research on pH-sensitive liposomes.

Animals↗

Preparation and in vitro evaluation of liposomal/niosomal delivery systems for antipsoriatic drug dithranol.

Dithranol is one of the mainstays in the topical treatment of psoriasis. However, the use of dithranol in psoriatic condition is inconvenient and troublesome, as it has irritating, burning, staining and necrotizing effect on the normal as well as the diseased skin. The entrapment of drug in vesicles is viewed to help in the localized delivery of the drug and an improved availability of the drug at the site will reduce the dose and in turn, the dose-dependent side effects like irritation and staining. The investigations deal with critical parameters controlling the formulation and stabilization of dithranol loaded liposomes and niosomes. The entrapment efficiency of dithranol in liposomes was optimized by altering the proportion of phosphatidyl choline and cholesterol, and in case of niosomes it was between Span 60 and cholesterol. Hydration and permeation mediums were also established keeping in view the poor solubility and stability of dithranol. The mean liposome and niosomes sizes were 4+/-1.25 and 5+/-1.5 microm, respectively. The drug-leakage study carried out at different temperatures of 4-8, 25+/-2 and 37 degrees C for a period of two months affirms that the drug leakage increased at a higher temperature. The in vitro permeation study using mouse abdominal skin shows significantly enhanced permeation with vesicles as indicated by flux of dithranol from liposomes (23.13 microg/cm(2)/h) and niosomes (7.78 microg/cm(2)/h) as compared with the cream base (4.10 microg/cm(2)/h).

Administration, Topical↗

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.

Anti-Bacterial Agents↗

Pelleted bioadhesive polymeric nanoparticles for buccal delivery of insulin: preparation and characterization.

The study was an attempt to develop an alternative buccal delivery system for insulin. Insulin bearing nanoparticles were prepared by the emulsion internal phase evaporation method. The effect of some formulation variables viz., polymer/drug ratio and emulsifier concentration was studied on particle size and entrapment efficiency. Nanoparticles were pelleted to impart three-dimensional structural conformity and coherence thereby facilitating buccal application. Solid lateral and horizontal sedimentaton in the pellet can be avoided by nanoparticulation and ensuring uniform drug distribution throughout the pellet. The in vitro studies of the pellets included bioadhesion and drug release profile. In vivo studies were performed on diabetic rats. A significant hypoglycemic response was observed after 7 h, without any detectable fluctuation in blood glucose profile and risk of hypoglycemia.

Acrylic Resins↗

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.

Drug Carriers↗