Soluble Polymeric Carriers Research Articles

Preparation and characterization of a novel water soluble amino chitosan (amino-CS) derivative for facilitated transport of CO2

With the goal of obtaining a water soluble polymeric carrier for preparation of fixed facilitated transport membranes, a water soluble amino containing chitosan derivative was prepared through Michael-addition reaction between chitosan and ethyl acrylate followed by amidation of the ester groups with an appropriate diamine. This derivative was characterized using 1H-NMR spectroscopy. Then, facilitated transport membranes were prepared by casting a thin layer of chitosan derivative/poly(vinyl alcohol) blend on a porous polysolfune support; and the effect of fixed carrier’s content, feed temperature and feed pressure on the CO2 permeance, and CO2/CH4 selectivity of produced membranes were studied. A facilitated transport mechanism for CO2 through this membrane was concluded.

STRATEGIES AND INNOVATIVE APPROACHES DEVELOPED FOR THE ACTIVE TARGETING OF DRUGS

The ability to selectively deliver a drug to a specific organs or tissues is called “drug targeting”. This approach was initially reported by Paul Erlich describing a magic bullet able to act selectively towards a specific pharmacological target. In the pharmaceutical technology field the concept described by Ehrlich defines products able to selectively deliver and release the drug in a specific site thanks to the action of three components: i) an inert and water soluble polymeric carrier; ii) a biodegradable spacer linking polymer and drug; iii) a drug covalently linked to the spacer. Moreover, it is possible to add to the system a targeting agent that improve the targeting ability towards target cells reducing the nonspecific interaction of the system with normal ones. The active targeting is obtained through functionalization with portions that confer the ability to: i) recognize and specifically bind receptors overexpressed on the target cells or tissues (i.e. monoclonal antibodies or fragments, folate, transferrin); ii) be able to respond to local stimuli present in the pathological area; iii) allow the penetration of the drug into the target cells. The active targeting approach lead to an increased binding of the nanosystems to the specific site. The targeting ability is obtained thanks to the interaction of the targeting agents with specific antigens or receptors overexpressed on the target cells or tissues. The active targeted nanocarriers are characterized by increased drug uptake and reduced side effects.

Water soluble poly(ethylene glycol) prodrug of silybin: Design, synthesis, and characterization

AbstractSilybin, the main component of silymarin, is an antihepatotoxic agent. But it presents numerous challenges associated with its poor aqueous solubility which has been realized as the major problem in its dosage form development and clinical application. The objective of our study was to solubilize silybin by designing and synthesizing its aqueous soluble prodrug using high aqueous soluble polymeric carrier—poly(ethylene glycol) (PEG). A novel soluble silybin prodrug was synthesized with a linear PEG and succinic ester linkage, and was extensively characterized using proton NMR, FTIR, and TOF‐MS. Furthermore, the prodrug was evaluated for its drug loading capability which was 6.65% and the solubility was 800 mg/mL. The results indicate significantly higher solubility of the prodrug in comparison with silybin. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

Electrophoresis of Derivatized Polyethylene Glycols: A Useful Method for Monitoring of Reactions on Soluble Polymeric Carrier

A useful method for monitoring of peptide synthesis on polyethylene glycol (PEG) was developed and is described in this paper. The course of reactions such as loading, acylation, detachment and others where a charge of reactant and product differ, can be easily determined. The loading of the first amino acid is quantified with errors fitting well to those from other known analytical methods.

The place of polymer prodrugs in cancer therapy

The administration of current cancer chemotherapy agents is associated with significant toxicity and makes these agents ideal candidates for more selective drug targeting. Polymer prodrug therapy is a strategy that provides a means of targeting cytotoxic agents to specific organs or tumour tissues. The principle structure of a polymer prodrug consists of a water soluble polymeric carrier or backbone, linked to the chemotherapeutic drug of choice. The modification of a specific anticancer drug in this way can theoretically allow specific tumour targeting, thus protecting normal cells and allowing higher doses of the drug to be administered whilst reducing the potential toxicity profile.

Safe as mother's milk: carbohydrates as future anti-adhesion drugs for bacterial diseases.

The majority of infectious diseases are initiated by adhesion of pathogenic organisms to the tissues of the host. In many cases, this adhesion is mediated by lectins present on the surface of the infectious organism that bind to complementary carbohydrates on the surface of the host tissues. Lectin-deficient mutants often lack ability to initiate infection. Soluble carbohydrates recognized by the bacterial lectins block the adhesion of the bacteria to animal cells in vitro. Moreover, they have also been shown to protect against experimental infection by lectin-carrying bacteria in different organs of mammals such as mice, rabbits, calves and monkeys. In a phase II clinical trial, a pentasaccharide shown to have anti-adhesive activity against Streptococcus pneumoniae and Hemophilus influenzae in vitro failed to protect young children from nasopharyngeal colonization with these organisms and from developing otitis media. This could be because insufficient drug was delivered via nasal spray, because bacteria express multiple specificities, the inhibition of which may require a cocktail of oligosaccharides, or because children have different carbohydrate receptors from those of adults. The results of a clinical trial in which N-acetylneuraminyl(alpha2-3)lactose was administered orally to Helicobacter pylori positive patients in an effort to reduce or eradicate bacterial colonization, are awaited with interest. Although the high cost of production of the required oligosaccharides is falling with the recent introduction of enzymatic methods of synthesis, new technologies, in particular the use of engineered bacteria, promise to lower it even further. Attachment of the oligosaccharides to soluble polymeric carriers will increase greatly their effectiveness as antiadhesion agents. There is no doubt that anti-adhesive oligosaccharides will in the near future join the arsenal of drugs for the therapy of bacterial diseases.

Chemoenzymatic oligosaccharide synthesis on a soluble polymeric carrier

A facile and efficient method for the chemical and enzymatic syntheses of oligosaccharides using a new type of soluble polymeric sugar acceptor substrate is described. The water soluble glycopolymers having N-acetyl-D-glucosamine (GlcNAc) branches derived from a p-substituted benzyl glycosides were galactosylated with bovine milk galactosyl transferase. The flexible GlcNAc branches of the polymer chains allow quantitative galactosylation and subsequent hydrogenolysis proceeded smoothly to release the desired N-acetyl-lactosamine from the polymer support in high yield.

Synthesis and Photoproperties of a Substituted Zinc(II) Phthalocyanine-N-(2-hydroxypropyl)methacrylamide Copolymer Conjugate

In cancer photodynamic therapy (PDT), improved efficiency of photosensitizer delivery to tumors may be obtained by binding them to targetable water soluble polymeric carriers. However, attachment of photosensitizers to Macromolecular carriers may alter their spectral and photosensitizing properties. In this study, a new monosubstituted phthalocyanine derivative, N-glycyl zinc(II) 4,9,16,23-tetraaminophthalocyanine (G-TAPC-Zn) was synthesized by the reaction of zinc(II) 4,9,16,23-tetraaminophthalocyanine (TAPC-Zn) with N-tert-butoxycarbonyl-glycine N'-hydroxybenzotriazole ester followed by deprotection of the tert-butoxycarbonyl (BOC) group. G-TAPC-Zn contains an aliphatic amino group suitable for attachment to water soluble polymeric carriers. By aminolysis of a polymeric precursor, an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer containing oligopeptide (GFLG) side-chains terminated in p-nitrophenyl ester groups, with G-TAPC-Zn a polymeric derivative of the latter (P-GFLGG-TAPC-Zn) was synthesized. Spectral data indicated that in aqueous solutions P-GFLGG-TAPC-Zn formed aggregates. The degree of aggregation decreased with increasing concentration of detergents or organic solvents in buffer solutions. Consequently, the release of the drug from carrier catalyzed by thiol proteinases, papain or cathepsin B, took place only in the presence of detergents or organic solvents, i.e., under conditions with a lower probability of aggregate formation. Binding of G-TAPC-Zn to HPMA copolymers decreased the quantum yield of singlet oxygen generation from 0.24 to 0.063 and significantly increased its resistance to photobleaching.

Soluble Polymeric Carriers for Drug Delivery - Part 6: Preparation and Biodistribution of N5-Hydroxyethyl-L-Glutamine-co-L-Glutamic Acid Copolymers in Rats

The purpose of this work was to examine the biodistribution of poly( N5-hydroxyethyl-L-glutamine- co-L-glutamic acid) [poly(HEG- co-GA)] after intravenous administration to rats. Poly(γ-methyl-L-glutamate- co-γ-benzyl-L- glutamate) was prepared by ring-opening polymerization of the amino acid N-carboxyanhydride (NCA) derivatives. Sequential removal of the copolymer benzyl groups followed by reaction of the methyl ester groups with 2-amino ethanol gave poly(HEG- co-GA). Three samples of poly(HEG-co-GA) were pre pared with nominal HEG:GA compositions of 50:50, 95:5 and 90:10 mole %, and with weight average molecular weights ( Mw) of 37,000, 50,000 and 110,000 respectively. Following reaction with N-2[4-hydroxyphenyl]ethylamine (tyra mine), the copolymers were radioiodinated with 125 I and administered intra venously to male Wistar rats. 125 I-copolymer tissue distribution was assessed after 10, 15, 30 and 120 min and 8 h. It was found that the copolymer was removed rapidly from the blood compartment and excreted from the body via the kidneys. Only very low amounts of radioactivity were found in the liver and in other organs of the mononuclear phagocyte system. Degradation of the co polymer in vitro, as assessed by size exclusion chromatography (SEC), in plasma and urine over the time scale of the biodistribution experiment ap peared to be minimal.

Soluble Polymeric Carriers for Drug Delivery: Part 5: Solution Properties and Biodistribution Behaviour of N-(2-Hydroxypropyl)Methacrylamide-co-N-(2-[4-Hydroxyphenyl]Ethyl) Acrylamide Copolymer Substituted with Cholesterol

A copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) and N-(2-[4-hydroxyphenyl]ethyl)acrylamide (HPEA) was derivatized with 2-4 mole% of N-(2-[(cholest-5-en-3-yl(3β)oxycarbonyl)oxypropyl]methacrylamide residues (cholesteryl residues). The effect of polymer modification on some of its solution properties, and on its behaviour in vivo in experimental animals, has been examined.

Drug-polymer conjugates: potential for improved chemotherapy.

Use of polymeric drug delivery systems is rapidly becoming an established approach for improvement of cancer chemotherapy. Zoladex, a poly lactide-co-glycolide subcutaneous implant that delivers a luteinizing hormone releasing hormone analog over 28 days, is now the treatment of choice for prostate cancer, and a polyanhydride matrix containing BCNU is currently in phase III evaluation for treatment of glioma multiforme. Soluble polymers were first proposed as targetable drug carriers in the mid-1970s, and although the first conjugates are still at an early stage of development some, e.g. SMANCS (styrene maleic acid-neocarzinostatin) and monomethoxypolyethyleneglycolasparaginase, are now undergoing clinical evaluation and show considerable promise. Polymeric drug delivery systems are usually designed to produce an improved pharmacokinetic profile of an antitumor agent (controlled release) and in addition soluble carriers can achieve either first-order (organ specific) or second-order (tumor specific) drug targeting by virtue of the fact that they are usually administered intravenously and should theoretically access primary and secondary disease. Soluble polymeric carriers have the potential to improve the activity of conventional antitumor agents, peptide and protein drugs, and have recently been used in constructs for delivery of oligonucleotides. With increased awareness that the successful design of a polymeric drug delivery systems can only be achieved with prior consideration of the pathology and stage of the disease, tumor accessibility, biochemistry and cell biology of the target site, choice of appropriate therapeutic agent(s) and understanding of their fundamental mode of action, we have seen the emergence of a number of exciting and potentially more selective antitumor therapies based on polymer technologies. Here, the basic principles for design of soluble polymeric drug delivery systems are explained and illustrated using examples drawn from our studies on the development of N-(2-hydroxypropyl)methacrylamide copolymer conjugates for use in cancer chemotherapy. Those soluble polymeric carriers that are undergoing clinical evaluation are briefly reviewed.

Soluble Polymeric Carriers for Drug Delivery—Part 4: Tissue Autoradiography, and Whole-Body Tissue Distribution in Mice, of N-(2-Hydroxypropyl)Methacrylamide Copolymers Following Intravenous Administration

The tissue distribution of water-soluble, non-biodegradable co polymers prepared from N-(2-hydroxypropyl)methacrylamide (HPMA) and N-[2-(4-hydroxyphenyl)ethyl]acrylamide (HPEA) is described, and their poten tial for use as carriers in drug delivery is discussed. Copolymers with weight- average molecular weights (Mw) of 4, 18, 75, and 90 x 103 Daltons, of low poly dispersity ( ≅Mw/Mn ≤ 1.40), were radiolabelled with 125I and administered intravenously to mice. The biodistribution of the radioiodinated copolymers was determined at 10 min, 0.5, 2, 6, 12, 24, 48, 72, and 168 h. All the copoly mers exhibited a molecular weight related clearance from the blood compart ment. Over the time course of our experiments the copolymers were found to access and be retained within different tissues of the body, in particular the skin and muscle, their rate of access and retention being governed by their molecular size (indicated here by molecular weight). No fractionation of molec ular weight occurred in vivo, as determined by Gel Permeation Chromatog raphy of extracted radioiodinated material from the mice. Comparatively little poly(HPMA/HPEA) was found associated with the liver and spleen, (organs of the mononuclear phagocyte system). Autoradiography of animal tissue sug gested that the copolymers appeared to be located in vivo in the muscle, dermis, at the interface of fat deposits (but not over the fat), hair follicles, and epider mis. The copolymers appeared not to be located intracellularly. For drug- delivery applications it is unlikely that these nonbiodegradable polymers will be of clinical use in chronic situations unless it can be categorically demon strated that the polymers are able to be completely removed from the body.

Soluble polymeric carriers for drug delivery. Part I: Free radical copolymerization of N-(2-hydroxypropyl) methacrylamide with N-[2-(4-hydroxyphenyl) ethyl]acrylamide

Radioiodation du copolymere obtenu en masse ou en solution avec Na 125 I en presence de chloramine T

Soluble polymeric carriers for drug delivery. Part 2. Preparation and in vivo behaviour of N-acylethylenimine copolymers

The preparation, characterization and in vivo behaviour of novel N-acylethylenimine (NAEI) copolymers are described and the potential use of such materials for drug-delivery applications is discussed. 2-Methyl-2-oxazoline (MeOZO) and 2-(4-hydroxyphenyl)-2-oxazoline (HOPheOZO) were copolymerised in bulk, in vacuo to give water-soluble copolymers of weight average molecular weights ( M w ) of below 30,000 Da. M w was determined by GPC using poly(oxyethylene) (POE) as calibrant. Poly[ N-(2-hydroxypropyl)methacrylamide] [poly(HPMA)] was also examined by GPC and the results were compared with those from the NAEI copolymers. Narrow molecular weight fractions of the copolymers were radioiodinated to give two 125I-labelled copolymers of M w = 15,300 Da , and M w = 29,300 Da , with polydispersity M w M n ⩽ 1.3 , in both cases. These were administered intravenously to mice and an assessment was made of their biodistribution. 24 h after administration of the 15,300 Da ( M w ) 125I-labelled copolymer, 7% of the injected dose was found in whole blood. This compares with 28% of the injected dose remaining after 24 h, following administration of the 29,300 Da ( M w ) 125I-labelled copolymer. The overall biodistribution pattern of both iodinated copolymers was found to be very similar. A significant amount of the copolymers appeared to remain in the body after leaving the vascular compartment, with a tendency to accumulate in the skin and muscle. No accumulation of radioactivity was found associated with organs of the mononuclear phagocyte system.