Cross-linked, degradable starch microspheres as carriers of paramagnetic contrast agents for magnetic resonance imaging: synthesis, degradation, and relaxation properties.

Biodegradable particles were produced by the cross-linking of starch with epichlorohydrin. Diethylenetriaminepenta-acetic acid (DTPA) was covalently linked to the particles by using DTPA bisanhydride. The small, gadolinium-labelled particles were 40-260% more efficient in vitro proton relaxation agents than the corresponding unbound chelate gadolinium-DTPA. The relaxation properties were dependent on the metal chelate, the particle size, the metal content, and the degree of substitution (d.s.). For the small gadolinium-DTPA particles, an increased d.s. decreased the rate of degradation by alpha-amylase.     

Fluorescent quantum dots: An insight on synthesis and potential biological application as drug carrier in cancer

Quantum dots (QDs) are nanocrystals of semiconducting material possessing quantum mechanical characteristics with capability to get conjugated with drug moieties. The particle size of QDs varies from 2 to 10 nm and can radiate a wide range of colours depending upon their size. Their wide and diverse usage of QDs across the world is due to their adaptable properties like large quantum yield, photostability, and adjustable emission spectrum. QDs are nanomaterials with inherent electrical characteristics that can be used as drug carrier vehicle and as a diagnostic in the field of nanomedicine. Scientists from various fields are aggressively working for the development of single platform that can sense, can produce a microscopic image and even be used to deliver a therapeutic agent. QDs are the fluorescent nano dots with which the possibilities of the drug delivery to a targeted site and its biomedical imaging can be explored. This review is mainly focused on the different process of synthesis of QDs, their application especially in the areas of malignancies and as a theranostic tool. The attempt is to consolidate the data available for the use of QDs in the biomedical applications.     

2-Arylbenzoxazoles as novel cholesteryl ester transfer protein inhibitors: optimization via array synthesis

2-Arylbenzoxazole 5 was identified as a hit from a fluorescence-based high-throughput screen for CETP inhibitors. The synthesis and SAR investigation employing array synthesis of the A- and B-rings are described.     

Carboxylic acid and phosphate ester derivatives of fluconazole: synthesis and antifungal activities

Two classes of fluconazole derivatives, (a) carboxylic acid esters and (b) fatty alcohol and carbohydrate phosphate esters, were synthesized and evaluated in vitro against Cryptococcus neoformans, Candida albicans, and Aspergillus niger. All carboxylic acid ester derivatives of fluconazole (1a-l), such as O-2-bromooctanoylfluconazole (1g, MIC=111 microg/mL) and O-11-bromoundecanoylfluconazole (1j, MIC=198 microg/mL), exhibited higher antifungal activity than fluconazole (MIC > or = 4444 microg/mL) against C. albicans ATCC 14053 in SDB medium. Several fatty alcohol phosphate triester derivatives of fluconazole, such as 2a, 2b, 2f, 2g, and 2h, exhibited enhanced antifungal activities against C. albicans and/or A. niger compared to fluconazole in SDB medium. For example, 2-cyanoethyl-omega-undecylenyl fluconazole phosphate (2b) with MIC value of 122 microg/mL had at least 36 times greater antifungal activity than fluconazole against C. albicans in SDB medium. Methyl-undecanyl fluconazole phosphate (2f) with a MIC value of 190 microg/mL was at least 3-fold more potent than fluconazole against A. niger ATCC 16404. All compounds had higher estimated lipophilicity and dermal permeability than those for fluconazole. These results demonstrate the potential of these antifungal agents for further development as sustained-release topical antifungal chemotherapeutic agents.     

TACN-containing cationic lipids with ester bond: preparation and application in gene delivery

A series of novel cationic lipids based on 1,4,7-triazacyclononane (TACN) with different hydrophobic chains were synthesized via the formation of a biodegradable ester bond. These lipids were found to have good buffering capacity at the pH range of 5.0-6.5, which is similar to that of the acidic endosomal compartments. The liposomes formed from these lipids and DOPE could condense DNA into nanoparticles with proper sizes. In vitro experiments showed moderate to good gene transfection efficiency of the formed lipoplexes. The structure-activity relationships of this type of lipids were discussed.     

Nucleoside phosphate analogues of biological interest, and their synthesis via aryl nucleoside H-phosphonates as intermediates.

This review presents a brief account of the chemistry and mechanistic aspects of aryl H-phosphonates, and selected applications of this class of compounds as intermediates in the synthesis of a wide range of biologically important analogues of nucleoside phosphates, and oligonucleotides, in which the phosphate moieties are replaced by other structurally related groups. The aryl nucleoside H-phosphonates, compounds of controlled reactivity, have proven to be more versatile and superior to various mixed anhydrides as synthetic intermediates, particularly for preparation of nucleotide analogues bearing P-N or P-S bonds in various configurational arrangements at the phosphate moiety.     

pH-sensitive unimolecular polymeric micelles: synthesis of a novel drug carrier

Novel amphiphilic star-shaped polymers showing pH-sensitivity were synthesized by atom transfer radical polymerization. These new polymers present a core-shell structure similar to polymeric micelles, but are inherently stable to dilution and are referred to as unimolecular polymeric micelles. A four-armed multifunctional initiator was used for the sequential polymerization of hydrophobic ethyl methacrylate and tert-butyl methacrylate and hydrophilic poly(ethylene glycol)methacrylate. Polymers of molecular weight ranging from 9000 to 20,000 were obtained. Results of dynamic light scattering showed micelle size ranging from 11 to 40 nm. Unimolecular micelles were also analyzed by static light scattering in aqueous environment. Star-shaped polymers which presented the highest molar ratio of hydrophobic monomers tended to form high molecular weight aggregates in water. Hydrolysis of the tert-butyl methacrylate units permitted the introduction of ionizable methacrylic acid functions. Size distributions were bimodal at both acidic and basic pH. Since, the polymers were designed as potential delivery systems for the oral administration of hydrophobic drugs, they were titrated to evaluate the degree of ionization as a function of pH. In the stomach, the carboxylic functions are expected to be fully protonated. However, in the intestine, the micelles will be more than 40% ionized. Fluorescence studies were conducted in order to evaluate the polarity of the micellar core. Results showed an increase in polarity with pH due to the ionization of the acid functions present along the polymer chains. The pH rise was associated with an increase in the in vitro release rate of progesterone, which was used as hydrophobic drug model.     

Investigation diffusion mechanism of β-lactam conjugated telechelic polymers of PEG and β-cyclodextrin as the new nanosized drug carrier devices

Six new prodrugs including conjugated telechelic polymer of β-cyclodextrin-poly (ethylene glycol)-β-cyclodextrin (β-CD-PEG- β-CD) and or parent β-cyclodextrin (β-CD) were designated as the new drug carrier agents containing β-lactam antibiotics such as ampicillin (AMP), amoxicillin (AMO) and cephalexin (CEP) prodrugs for potentially local administration pharmaceutical applications. Investigation of the drug release dynamics in buffered media with pH 7.4 showed that the drug released through the prodrug matrix with slightly deviation, follows Fickian diffusion mechanism. Using equation “log (M_t/M_∞) = log k + n log t” it has revealed that the synthesized prodrugs 5a–c, 6a–c have the “n” values 0.333, 0.334, 0.390, 0.540, 0.514 and 0.473, respectively. In fact, the prodrug 6c showed the least deviation from Fickian diffusion mechanism.     

Cholesteryl ester transfer protein: gathering momentum as a genetic marker and as drug target

PURPOSE OF REVIEW: Cholesteryl ester transfer protein facilitates the exchange of neutral lipids between HDL and apolipoprotein B containing lipoproteins, which hold powerful opposing roles as risk factors for coronary artery disease. The question as to whether cholesteryl ester transfer protein promotes or protects from atherosclerosis, however, has not been answered. RECENT FINDINGS: This review considers studies dealing with cholesteryl ester transfer protein variants and their effect on blood lipids in various metabolic and clinical settings. Other studies discussed deal with the association between the transfer protein and cardiovascular disease. Research on the biological activity of the cholesteryl ester transfer protein molecule is described including a first clinical study where pharmacological inhibition of the protein proved to be effective in raising HDL cholesterol. SUMMARY: Data concerning the potential marker role of cholesteryl ester transfer protein, although accumulating, are still inconclusive and, at present, not useful for clinical decision making. Inhibition of the protein was demonstrated to be feasible and appears to be promising.     

Cross-linked amylose as matrix for drug controlled release. X-ray and FT-IR structural analysis

For cross-linked amylose (CLA) tablets prepared by direct compression, a linear increase in cross-linking degree (cld) defined as percentage of epichlorohydrin cross-linker/polymer, generates non-monotonous variation of drug release time. Controlled release (up to 20–24 h) properties were obtained only for tablets from CLA (Contramid^TM) with relatively low cld (CLA-2 up to CLA-6). Moderate increase in cld (CLA-15) generates a sharp decrease in the release time (2–6 h). This is a particular characteristic of the CLA matrix. The controlled release properties were related to the X-ray pattern of the dry CLA network. The increase in cld induces a transition from B-type (double helix) to a predominat V-type (single helix) and to more amorphous conformation of CLA powders. Furthermore, FT-IR data indicated low free water content at low cld. For low cross-linked CLA, chains are closely located and stabilized by HO groups involved in hydrogen bonding and thus more resistant to hydration and more appropriate for the control of drug release.     

Synthesis and evaluation of novel phosphate ester analogs as neutral sphingomyelinase inhibitors

A novel sphingomyelin inhibitor RY221B-a, which contains a bipyridyl moiety as a metal coordination site was designed based upon the mechanism of phosphate ester hydrolysis. RY221B-a was synthesized from N-Boc-sphingosine in three steps via selective etherification using stannyl acetal. Synthesized RY221B-a exhibited relatively-strong inhibitory activity against Bc-SMase (IC₅₀ = 1.2 μM).     

Folate-targeted PEG as a potential carrier for carboplatin analogs. Synthesis and in vitro studies

Like most low molecular weight drugs, carboplatin has a short blood circulation time, which reduces tumor uptake and intracellular DNA binding. Drugs conjugated to PEG carriers benefit from prolonged blood circulation, but suffer from reduced cell permeability. In this work we attempted to develop long-circulating PEGylated carboplatin analogues with improved cell permeation abilities, by conjugating the platinum moiety to folate-targeted PEG carriers capable of utilizing the folate receptor-mediated endocytosis (FRME). Two bifunctional FA-PEG conjugates, FA-PEG-Pt and FA-PEG-FITC, were prepared, and their cell uptake, DNA binding, and cytotoxicity were studied by fluorescent microscopy, FACS, and platinum analysis. Folate-targeted PEG conjugates enter the cells efficiently by the FRME pathway but form relatively few DNA adducts and have higher IC(50) values than carboplatin and their nontargeted analogues. Nontargeted PEG-Pt conjugates have a lower cellular uptake but produce higher levels of DNA binding and improved cytotoxicity. Carboplatin, used as a control, has the fastest cellular uptake, but after 16 h of postincubation a large percentage of the drug is excreted from the cells. The findings of this study suggest that folate-targeted conjugates such as FA-PEG-Pt, may not be an optimal prodrug for the carboplatin family compounds, because the conjugates or the active moieties are neutralized or blocked during the FRME process and do not manage to effectively reach the nuclear DNA.     

Resveratrol-based cinnamic ester hybrids: synthesis,characterization, and anti-inflammatory activity

Twenty-three novel resveratrol-based cinnamic ester hybrids were designed and synthesized. All the compounds were evaluated for their anti-inflammatory activity using RAW264.7 cells. Among them, compound D15 was found to be the most potent one in inhibiting NO production in LPS-stimulated RAW264.7 cells. The further study indicated that compound D15 could suppress expression of proteins iNOS, COX-2, p-p65, and p-IκB LPS-induced. Immunofluorescence further revealed compound D15 could reduce activation p65 in nuclei. All the results indicated that the anti-inflammatory activity of title compound may partly due to its inhibitory effect on the NF-κB signaling pathway.     

The enzyme as drug: application of enzymes as pharmaceuticals

Enzymes as drugs have two important features that distinguish them from all other types of drugs. First, enzymes often bind and act on their targets with great affinity and specificity. Second, enzymes are catalytic and convert multiple target molecules to the desired products. These two features make enzymes specific and potent drugs that can accomplish therapeutic biochemistry in the body that small molecules cannot. These characteristics have resulted in the development of many enzyme drugs for a wide range of disorders.     

Metalated hybrid polymers as catalytic reagents for phosphate ester hydrolysis and plasmid modification

Pendant pyrazolylcyclophosphazene containing hybrid cross-linked polymer (CPPL) has been utilized for binding Zn(II). The metalated polymer (CPPL-Zn) has been found to be very effective catalyst for the hydrolysis of a RNA model phosphodiester substrate [2-(hydroxypropyl)-p-nitrophenyl phosphate, hNPP]. In addition, CPPL-Zn also cleaved supercoiled plasmid DNA pBR322 thus providing a novel structural motif of inorganic-organic hybrid polymers as synthetic nucleases.     

Synthesis and characterizations of amphiphilic poly(L-lactide)-grafted chondroitin sulfate copolymer and its application as drug carrier

In this investigation, new biodegradable brush-like amphiphilic copolymers were synthesized by ring opening polymerization. Poly(L-lactide) (PLLA) was grafted onto chondroitin sulfate (CS), which is one of the physiologically significant specific glycosaminoglycans (GAGs), using a tin octanoate [Sn(Oct)2] catalyst in DMSO. The hydroxyl groups of the chondroitin sulfate were used as initiating groups. These functional groups enable specific mucoadhesion or receptor recognition. The degree of substitution (DS), the degree of polymerization (DP) and the chondroitin sulfate content (from 1.1 to 15.4%) were analyzed by 1H NMR. The characteristics of these grafted copolymers, including the structure, the thermal properties and biodegradability, etc., were examined with respect to CS content. Meanwhile, the amphiphilic core (PLLA)-corona (CS) nanoparticles, with size smaller than 200 nm, was examined by dynamic light scattering (DLS). Zeta potential analysis exhibited the value in the range -18.3 to -49.4 mV. The morphologies of the nanoparticles were observed by field-emission scanning electron microscopy (FE-SEM). The nanoparticles with lower cytotoxicity were examined by MTT assay. Furthermore, the in vitro BSA release kinetics of those CSn-PLLA nanoparticles was also determined in this study.     

An acid-labile block copolymer of PDMAEMA and PEG as potential carrier for intelligent gene delivery systems

Intelligent gene delivery systems based on physiologically triggered reversible shielding technology have evinced enormous interest due to their potential in vivo applications. In the present work, an acid-labile block copolymer consisting of poly(ethylene glycol) and poly(2-(dimethylamino)ethyl methacrylate) segments connected through a cyclic ortho ester linkage (PEG- a-PDMAEMA) was synthesized by atom transfer radical polymerization of DMAEMA using a PEG macroinitiator with an acid-cleavable end group. PEG- a-PDMAEMA condensed with plasmid DNA formed polyplex nanoparticles with an acid-triggered reversible PEG shield. The pH-dependent shielding/deshielding effect of PEG chains on the polyplex particles were evaluated by zeta potential and size measurements. At pH 7.4, polyplexes generated from PEG- a-PDMAEMA exhibited smaller particle size, lower surface charge, reduced interaction with erythrocytes, and less cytotoxicity compared to PDMAEMA-derived polyplexes. At pH 5.0, zeta potential of polyplexes formed from PEG- a-PDMAEMA increased, leveled up after 2 h of incubation and gradual aggregation occurred in the presence of bovine serum albumin (BSA). In contrast, the stably shielded polyplexes formed by DNA and an acid-stable block copolymer, PEG- b-PDMAEMA, did not change in size and zeta potential in 6 h. In vitro transfection efficiency of the acid-labile copolymer greatly increased after 6 h incubation at pH 5.0, approaching the same level of PDMAEMA, whereas there was only slight increase in efficiency for the stable copolymer, PEG- b-PDMAEMA.     

Organocobaloximes: Cobalt-carbon bond stability and synthesis

Following the discovery that the naturally occurring vitamin B₁₂ coenzyme contained a stable CoC sigma bond and the further realization that porphyrin-like corrin was an important factor in the stabilization of the CoC bond, has led to the synthesis of a large number of organocobalt complexes. Inspite of the many known examples of such complexes in the literature, the synthesis of the CoC bond with new or modified structural features continues to be a fascinating field of study. Many synthetic routes have been reported and many new ones are frequently emerging. In this article, a complete analysis of the synthetic aspects of organocobalt compounds and organocobaloximes, in particular, is undertaken. The stability of the CoC bond, general methods of synthesis and experimental procedures are discussed.