http://www.mdpi.com/journal/molecules/special_issues/m-a-p/ Summary This special issue, “Macromolecules applied to Pharmaceutics” is devoted to a peculiar branch of polymer science that is rapidly growing in the last decades. It is of interest, therefore, to publish both reviews and original research papers to illustrate the general trend in current research. Polymers can act, in different ways, as carriers for drug delivery and as peculiar therapeutic agents to be delivered. In the past few decades macromolecules have evolved from off-the-shelf materials originally developed for applications unrelated to biomedicine to materials specifically designed for particular applications and exhibiting intended biomedical functions. The design of new polymeric devices requires the combination of knowledge among scientist from different fields such biology, medicine, pharmaceutical sciences, chemistry, physics and materials science. In that sense I wish to thank all the authors for their cooperation and support in the preparation of the present issue.   Submission All papers should be submitted to molecules@mdpi.com with copy to the guest editor. To be published continuously until the deadline and papers will be listed together at the special websites. Submitted papers should not have been previously published nor be currently under consideration for publication elsewhere. All papers are refereed through a peer review process. A guide for authors, sample copies and other relevant information for submitting papers are available on the Instructions for Authors page. Molecules is an international peer-reviewed monthly journal published by MDPI. Please visit the Instructions for Authors page before submitting a paper. Open Access publication fees are 800 CHF per paper. English correction fees (250 CHF) will be added in certain cases (1050 CHF per paper for those papers that require extensive additional formatting and/or English corrections.). http://www.mdpi.com/1420-3049/14/11/4370/ Freeze-dried systems (L) comprising chitosan (CS) and caffeine (CAF) have been developed for oral administration. Different proportions of CS and CAF have been used in the preparation of the systems. Hot stage microscopy (HSM), differential scanning calorimetry (DSC) and X-ray diffraction powder have been used to characterize the systems prepared. X-ray diffraction patterns showed that there were no interactions between CAF and CS molecules within the freeze-dried systems and the crystallinity of CAF was decreased. Swelling and dissolution tests were carried out in two different media (demineralized water and pH progressive medium) in order to establish their influence over CAF/CS system behaviour. Characteristic swelling behaviour of freeze-dried CS systems (imbibition and dissolution processes) was influenced by the proportions of CS and CAF in the formulations, and by the nature of the medium due to the pH-dependent solubility of CS. Release of CAF from lyophilized systems was conditioned by the swelling process and it should be possible to obtain a CAF/CS binary system with a specific time for total drug release including concrete proportions of both components. Furthermore, the freeze-drying process allowed us to obtain feasible systems for controlled release of CAF until the total amount of drug was released. http://www.mdpi.com/1420-3049/14/11/4370/ Fri, 30 Oct 2009 00:00:00 CET Molecules 2009-10-30 14 11 Article 4370 4386 1420-3049 Characterization and Dissolution Study of Chitosan Freeze-Dried Systems for Drug Controlled Release 2009-10-30 doi: 10.3390/molecules14114370 Roberto Ruiz-Caro María Dolores Veiga-Ochoa http://www.mdpi.com/1420-3049/14/9/3754/ Nasal drug delivery may be used for either local or systemic effects. Low molecular weight drugs with are rapidly absorbed through nasal mucosa. The main reasons for this are the high permeability, fairly wide absorption area, porous and thin endothelial basement membrane of the nasal epithelium. Despite the many advantages of the nasal route, limitations such as the high molecular weight (HMW) of drugs may impede drug absorption through the nasal mucosa. Recent studies have focused particularly on the nasal application of HMW therapeutic agents such as peptide-protein drugs and vaccines intended for systemic effects. Due to their hydrophilic structure, the nasal bioavailability of peptide and protein drugs is normally less than 1%. Besides their weak mucosal membrane permeability and enzymatic degradation in nasal mucosa, these drugs are rapidly cleared from the nasal cavity after administration because of mucociliary clearance. There are many approaches for increasing the residence time of drug formulations in the nasal cavity resulting in enhanced drug absorption. In this review article, nasal route and transport mechanisms across the nasal mucosa will be briefly presented. In the second part, current studies regarding the nasal application of macromolecular drugs and vaccines with nanoand micro-particulate carrier systems will be summarised. http://www.mdpi.com/1420-3049/14/9/3754/ Wed, 23 Sep 2009 00:00:00 CEST Molecules 2009-09-23 14 9 Review 3754 3779 1420-3049 Nasal Delivery of High Molecular Weight Drugs 2009-09-23 doi: 10.3390/molecules14093754 Yıldız Ozsoy Sevgi Gungor Erdal Cevher http://www.mdpi.com/1420-3049/14/9/3662/ Synergistic hydrogels are often encountered in polysaccharide mixtures widely used in food and biopharma products. The xanthan and konjac glucomannan pair provides one of the most studied synergistic hydrogels. Recently we showed that the junction zones stabilizing the 3D structure of this gel are present as macromolecular complexes in solution formed by the partially depolymerised polysaccharidic chains. The non-covalent interactions stabilizing the structure of the polysaccharidic complex cause the melting of the ordered structure of the complex in the solution and of the hydrogels. Introduction of chemical cross-links in the 3D structure of the synergistic hydrogel removes this behaviour, adding new features to the swelling and to the viscoelastic properties of the cured hydrogel. The use of epichlorohydrin as low molecular weight cross-linker does not impact unfavourably on the viability of NIH 3T3 fibroblasts. http://www.mdpi.com/1420-3049/14/9/3662/ Thu, 17 Sep 2009 00:00:00 CEST Molecules 2009-09-17 14 9 Article 3662 3675 1420-3049 Adding Chemical Cross-Links to a Physical Hydrogel 2009-09-17 doi: 10.3390/molecules14093662 Gaio Paradossi Ivana Finelli Barbara Cerroni Ester Chiessi http://www.mdpi.com/1420-3049/14/9/3376/ Innovative hydrogels obtained by physical and chemical crosslinking of deacylated Gellan gum have been characterized in terms of water uptake, rheological properties and compressibility, and the behaviour of the tested materials, according to the type of the obtained network, is thoroughly discussed. The release from the various gels of loaded model molecules of different steric hindrance was also investigated and the trend of the release profiles has been related to the structures proposed for the physical and the chemical hydrogel. http://www.mdpi.com/1420-3049/14/9/3376/ Thu, 03 Sep 2009 00:00:00 CEST Molecules 2009-09-03 14 9 Article 3376 3391 1420-3049 Preparation and Characterization of Novel Gellan Gum Hydrogels Suitable for Modified Drug Release 2009-09-03 doi: 10.3390/molecules14093376 Pietro Matricardi Claudia Cencetti Roberto Ria Franco Alhaique Tommasina Coviello http://www.mdpi.com/1420-3049/14/8/3003/ In this paper we have concentrated on the characterization of calcium alginate hydrogels loaded with a model drug (myoglobin) by means of a mechanical approach; in addition, release tests of myoglobin from alginate hydrogels were performed. At a fixed temperature, relaxation tests (mechanical study) were carried out on matrices constituted by different polymer concentrations. The interpretation of the relaxation behavior of the different matrices was conducted using the generalized Maxwell model; as a result of this investigation it was possible to conclude that for polymer concentrations greater than 0.5 g/ 100 mL the matrices behaved as solid materials. In addition, it was observed that the mechanical properties of the matrices increased with polymer concentration. With regard to the release tests, the diffusion coefficient of myoglobin in the matrix in relation to polymer concentrations was determined. The mechanical and release data where then analyzed by Flory’s theory and by a modified free-volume theory, respectively, to estimate the network mesh size ξ. The comparison between the mesh sizes obtained by the two approaches showed a satisfactory agreement for polymer concentrations greater than 0.5 g/100 mL. It should be noted that the approach proposed here to determine the polymeric network meshes is absolutely general and can be advantageously applied to the characterization of other similar polymeric systems. http://www.mdpi.com/1420-3049/14/8/3003/ Wed, 12 Aug 2009 00:00:00 CEST Molecules 2009-08-12 14 8 Article 3003 3017 1420-3049 Structural Characterization of Calcium Alginate Matrices by Means of Mechanical and Release Tests 2009-08-12 doi: 10.3390/molecules14083003 Mario Grassi Chiara Sandolo Danilo Perin Tommasina Coviello Romano Lapasin Gabriele Grassi http://www.mdpi.com/1420-3049/14/8/2801/ Oligonucleotides (ONs) are synthetic fragments of nucleic acid designed to modulate the expression of target proteins. DNA-based ONs (antisense, antigene, aptamer or decoy) and more recently a new class of RNA-based ONs, the small interfering RNAs (siRNAs), have gained great attention for the treatment of different disease states, such as viral infections, inflammation, diabetes, and cancer. However, the development of therapeutic strategies based on ONs is hampered by their low bioavailability, poor intracellular uptake and rapid degradation in biological fluids. The use of a non-viral carrier can be a powerful tool to overcome these drawbacks. Lipid or polymer-based nanotechnologies can improve biological stability and cellular uptake of ONs, with possibility of tissue and/or cellular targeting. The use of polymeric devices can also produce a prolonged release of the ON, thus reducing the need of frequent administrations. This review summarizes advantages and issues related to the main non-viral vectors used for ON delivery. http://www.mdpi.com/1420-3049/14/8/2801/ Wed, 29 Jul 2009 00:00:00 CEST Molecules 2009-07-29 14 8 Review 2801 2823 1420-3049 Nano and Microtechnologies for the Delivery of Oligonucleotides with Gene Silencing Properties 2009-07-29 doi: 10.3390/molecules14082801 Giuseppe De Rosa Maria Immacolata La Rotonda http://www.mdpi.com/1420-3049/14/8/2699/ The effect of three different types of polymer chain structures on the polymer release from hydrophilic matrix tablets was investigated by comparing a synthetic semi-crystalline linear polymer (PEO), a branched amorphous polysaccharide (dextran) and an amorphous substituted cellulose derivative (HPMC). The polymer release rates for tablets containing mixtures of high and low molecular weight grades in different ratios were determined by using a modified USP II method and a SEC-RI chromatography system. The results showed that independent of polymer type: (i) plots of the release versus time had similar shapes, (ii) the release of long and short polymer chains was equal and no fractionation occurred during the release and (iii) the release rate could be related to the average intrinsic viscosity of the polymer mixtures. This confirms the hypothesis that the release rate can be related to a constant viscosity on the surface of the hydrophilic matrix tablet and that it is valid for all the investigated polymers. http://www.mdpi.com/1420-3049/14/8/2699/ Fri, 24 Jul 2009 00:00:00 CEST Molecules 2009-07-24 14 8 Article 2699 2716 1420-3049 Influence of Different Polymer Types on the Overall Release Mechanism in Hydrophilic Matrix Tablets 2009-07-24 doi: 10.3390/molecules14082699 Anna Körner Lennart Piculell Frida Iselau Bengt Wittgren Anette Larsson http://www.mdpi.com/1420-3049/14/8/2684/ A carboxymethyl derivative of scleroglucan (Scl-CM) with a 65±5% carboxylic group degree of derivatization (DD) was recently synthesized and characterized. Aqueous solutions of the polymer underwent to a sharp transition toward a gel like behaviour in the presence of divalent ions such as Ca+2. Physical hydrogels with different Scl-CM/Ca+2 ratios were prepared and characterized for their rheological behaviour. Their potential as drug delivery systems was also evaluated. To this end three non steroidal anti-inflammatory drugs (NSAIDs) were loaded into the hydrogels obtained with 2% w/v solution of Scl-CM and 0.05 and 0.1 M CaCl2. The release rate of the drugs was critically related to the salt concentration. By an appropriate combination of the hydrogels prepared using different amounts of salt, it was possible to obtain a system able to release diclofenac with zero-order kinetics. Primary skin irritation tests showed a good biocompatibility of the new polymer, as well as of its hydrogels. These results suggest a potential of the new hydrogels for the development of modified delivery systems in topical formulations. http://www.mdpi.com/1420-3049/14/8/2684/ Fri, 24 Jul 2009 00:00:00 CEST Molecules 2009-07-24 14 8 Article 2684 2698 1420-3049 Physical Carboxymethylscleroglucan/Calcium Ion Hydrogels as Modified Drug Delivery Systems in Topical Formulations 2009-07-24 doi: 10.3390/molecules14082684 Federica Corrente Pietro Matricardi Patrizia Paolicelli Beatrice Tita Federica Vitali Maria Antonietta Casadei http://www.mdpi.com/1420-3049/14/7/2602/ Drug dosage forms contain many components in addition to the active pharmaceutical ingredient(s) to assist in the manufacturing process as well as to optimise drug delivery. Due to advances in drug delivery technology, excipients are currently included in novel dosage forms to fulfil specific functions and in some cases they directly or indirectly influence the extent and/or rate of drug release and absorption. Since plant polysaccharides comply with many requirements expected of pharmaceutical excipients such as non-toxicity, stability, availability and renewability they are extensively investigated for use in the development of solid oral dosage forms. Furthermore, polysaccharides with varying physicochemical properties can be extracted from plants at relatively low cost and can be chemically modified to suit specific needs. As an example, many polysaccharide-rich plant materials are successfully used as matrix formers in modified release dosage forms. Some natural polysaccharides have even shown environmental-responsive gelation characteristics with the potential to control drug release according to specific therapeutic needs. This review discusses some of the most important plant-derived polymeric compounds that are used or investigated as excipients in drug delivery systems. http://www.mdpi.com/1420-3049/14/7/2602/ Thu, 16 Jul 2009 00:00:00 CEST Molecules 2009-07-16 14 7 Review 2602 2620 1420-3049 Polymeric Plant-derived Excipients in Drug Delivery 2009-07-16 doi: 10.3390/molecules14072602 Carien E. Beneke Alvaro M. Viljoen Josias H. Hamman http://www.mdpi.com/1420-3049/14/7/2410/ Raloxifene HCl is a drug with poor bioavailability and poor water solubility. Furthermore nο pharmaceutically acceptable organic solvent has been reported before to dilute the drug. It was observed that Raloxifene HCl can be diluted in a solvent mixture of acetone/water or ethanol/water. The aim of this study was to use biodegradable polymers in order to prepare Raloxifene HCl nanoparticles. For this purpose a series of novel biodegradable poly(ethylene succinate-co-propylene adipate) P(ESu-co-PAd) polyesters were synthesized following the polycondensation method and further, poly(ethylene succinate) (PESu) and poly(propylene adipate) (PPAd) were used. The prepared polyesters were characterized by intrinsic viscosity measurements, end group analysis, enzymatic hydrolysis, Nuclear Magnetic Resonance Spectroscopy (1Η-NMR and 13C-NMR) and Wide-angle X-ray Diffractometry (WAXD). The drug nanoparticles have been prepared by a variation of the co-precipitation method and were studied by Wide-angle X-ray Diffractometry (WAXD), FTIR spectrometry, light scattering size distribution, Scanning Electron Microscopy (SEM) and release behavior measurements. The interactions between the polymers and the drug seem to be limited, so the drug occurs in crystalline form in all nanoparticles. The size of the nanoparticles seems to be in the range of 150-350 nm, depending on the polymer that was used. The drug release depends on the melting point and degree of crystallinity of the polyesters used. An initial high release rate was recorded followed by very slow rates of controlled release. http://www.mdpi.com/1420-3049/14/7/2410/ Tue, 07 Jul 2009 00:00:00 CEST Molecules 2009-07-07 14 7 Article 2410 2430 1420-3049 Novel Biodegradable Polyesters. Synthesis and Application as Drug Carriers for the Preparation of Raloxifene HCl Loaded Nanoparticles 2009-07-07 doi: 10.3390/molecules14072410 Dimitrios Bikiaris Vassilios Karavelidis Evangelos Karavas http://www.mdpi.com/1420-3049/14/6/1999/ A well characterized, peptide derivative of bovine lactoferrin, L12, has been shown to possess anticancer properties in multiple cell lines. However, adverse side effects in normal tissues and poor plasma kinetics that hinder the clinical effectiveness of current chemotherapeutics also deter the potential for effective delivery of this L12 peptide. To overcome these limitations, we have developed an Elastin-like polypeptide (ELP) carrier that has the potential to thermally target therapeutic peptides and chemotherapeutics to a tumor site. The coding sequence of ELP was modified with the L12 peptide at the C-terminus and a membrane transduction domain derived from the HIV-1 Tat protein at the N-terminus (Tat-ELP-L12). The thermally responsive Tat-ELP1-L12 is soluble in aqueous solutions at 37°C but aggregates near 41°C, which makes Tat-ELP1-L12 ideal for targeting to solid tumors on application of focused hyperthermia. We observed that under hyperthermia conditions at 42°C, Tat-ELP1-L12 mediated cytotoxicity in MIA PaCa-2 pancreatic adenocarcinoma cells was enhanced by nearly thirty-fold. We investigated the mechanisms of cell death and found evidence of mitochondrial membrane depolarization and caspase activation, which are characteristic of apoptosis, as well as, increased membrane permeability, as shown by LDH release. These results suggest that Tat-ELP1-L12 possesses cytotoxic properties to cancer cells in vitro and may have the potential to provide an effective vehicle to thermally target solid tumors. http://www.mdpi.com/1420-3049/14/6/1999/ Thu, 04 Jun 2009 00:00:00 CEST Molecules 2009-06-04 14 6 Article 1999 2015 1420-3049 Application of Thermally Responsive Elastin-like Polypeptide Fused to a Lactoferrin-derived Peptide for Treatment of Pancreatic Cancer 2009-06-04 doi: 10.3390/molecules14061999 Iqbal Massodi Emily Thomas Drazen Raucher