A biodegradable triblock copolymer poly(ethylene glycol)-b-poly(L-lactide)-b-poly(L-lysine): Synthesis, self-assembly and RGD peptide modification

A novel biodegradable triblock copolymer poly(ethylene glycol)-b-poly(L-lactide)-b-poly(L-lysine) (PEG-PLA-PLL) was synthesized by acidolysis of poly(ethylene glycol)-b-poly(L-lactide)-b-poly(F-benzyloxycarbonyl-L-lysine) (PEG-PLA-PZLL) obtained by the ring-opening polymerization (ROP) of epsilon-benzyloxycarbonyl-L-lysine N-carboxyanhydride (ZLys NCA) with amino-terminated PEG-PLA-NH2 as a macro-initiator, and the pendant amino groups of the lysine residues were modified with a peptide known to modulate cellular functions, Gly-Arg-Gly-Asp-Ser-Tyr (GRGDSY, abbreviated as RGD) in the presence of 1,1'-carbonyldiimidazole (CDI). The structures of PEG-PLA-PLL/RGD and its precursors were confirmed by H-1 NMR, FT-IR, amino acid analysis and XPS analysis. The cell adhesion and cell spread on the PEG-PLA-PLL/RGD film were enhanced compared to those on pure PLA film. Therefore, the novel RGD-grafted triblock copolymer is promising for cell or tissue engineering applications. Both copolymers PEG-PLA-PZLL and PEG-PLA-PLL showed an amphiphilic nature and could self-assemble into micelles of homogeneous spherical morphology. The micelles were determined by fluorescence technique, dynamic light scattering (DLS), and field emission scanning electron microscopy (ESEM) and could be expected to find application in drug and gene delivery systems.

Synthesis and characterization of photo-cross-linked hydrogels based on biodegradable polyphosphoesters and poly(ethylene glycol) copolymers

Novel biodegradable hydrogels by photo-cross-linking macromers based on polyphosphoesters and poly(ethylene glycol) (PEG) are reported. Photo-cross-linkable macromers were synthesized by ring-opening polymerization of the cyclic phosphoester monomer 2-(2-oxo-1,3,2-dioxaphospholoyloxy) ethyl methacrylate (OPEMA) using PEG as the initiator and stannous octoate as the catalyst. The macrorners were characterized by H-1 NMR, Fourier transform infrared spectroscopy, and gel permeation chromatography measurements. The content of polyphosphoester in the macromer was controlled by varying the feed ratio of OPEMA to PEG. Hydrogels were fabricated by exposing aqueous solutions of macromers with 0.05% (w/w) photoinitiator to UV light irradiation, and their swelling kinetics as well as degradation behaviors were evaluated. The results demonstrated that cross-linking density and pH values strongly affected the degradation rates. The macromers was compatible to osteoblast cells, not exhibiting significant cytotoxicity up to 0.5 mg/mL. "Live/dead" cell staining assay also demonstrated that a large majority of the osteoblast cells remained viable after encapsulation into the hydrogel constructs, showing their potential as tissue engineering scaffolds.

Novos sistemas terapêuticos nanotecnológicos

Monografia apresentada à Universidade Fernando Pessoa para obtenção do grau Licenciada em Ciências Farmacêuticas

Formulações nanobiotecnológicas para vetorização da Curcumina e seus derivados

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Nanopartículas lipídicas na promoção da absorção oral de fármacos

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

An investigation of the stability and diffusivity of flexible lipid vesicles for transdermal insulin delivery

Gemstone Team No More Needles

ATR-FTIR spectroscopy and spectroscopic imaging of solvent and permeant diffusion across model membranes

The uptake and diffusion of solvents across polymer membranes is important in controlled drug delivery, effects on drug uptake into, for example, infusion bags and containers, as well as transport across protective clothing. Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy has been used to monitor the effects of different solvents on the diffusion of a model compound, 4-cyanophenol (CNP) across silicone membrane and on the equilibrium concentration of CNP obtained in the membrane following diffusion. ATR-FTIR spectroscopic imaging of membrane diffusion was used to gain an understanding of when the boundary conditions applied to Fick's second law, used to model the diffusion of permeants across the silicone membrane do not hold. The imaging experiments indicated that when the solvent was not taken up appreciably into the membrane, the presence of discrete solvent pools between the ATR crystal and the silicone membrane can affect the diffusion profile of the permeant. This effect is more significant if the permeant has a high solubility in the solvent. In contrast, solvents that are taken up into the membrane to a greater extent, or those where the solubility of the permeant in the vehicle is relatively low, were found to show a good fit to the diffusion model. As such these systems allow the ATR-FTIR spectroscopic approach to give mechanistic insight into how the particular solvents enhance permeation. The solubility of CNP in the solvent and the uptake of the solvent into the membrane were found to be important influences on the equilibrium concentration of the permeant obtained in the membrane following diffusion. In general, solvents which were taken up to a significant extent into the membrane and which caused the membrane to swell increased the diffusion coefficient of the permeant in the membrane though other factors such as solvent viscosity may also be important.

Neighboring Group-Controlled Hydrolysis: Towards “Designer” Drug Release Biomaterials

To give the first demonstration of neighboring group-controlled drug delivery rates, a series of novel, polymerizable ester drug conjugates was synthesized and fully characterized. The monomers are suitable for copolymerization in biomaterials where control of drug release rate is critical to prophylaxis or obviation of infection. The incorporation of neighboring group moieties differing in nucleophilicity, geometry, and steric bulk in the conjugates allowed the rate of ester hydrolysis, and hence drug liberation, to be rationally and widely controlled. Solutions (2.5 x 10-5 mol dm-3) of ester conjugates of nalidixic acid incorporating pyridyl, amino, and phenyl neighboring groups hydrolyzed according to first-order kinetics, with rate constants between 3.00 ( 0.12 10-5 s -1 (fastest) and 4.50 ( 0.31 10- 6 s-1 (slowest). The hydrolysis was characterized using UV-visible spectroscopy. When copolymerized with poly(methyl methacrylate), free drug was shown to elute from the resulting materials, with the rate of release being controlled by the nature of the conjugate, as in solution. The controlled molecular architecture demonstrated by this system offers an attractive class of drug conjugate for the delivery of drugs from polymeric biomaterials such as bone cements in terms of both sustained, prolonged drug release and minimization of mechanical compromise as a result of release. We consider these results to be the rationale for the development of 'designer' drug release biomaterials, where the rate of required release can be controlled by predetermined molecular architecture.

Photosensitiser delivery for photodynamic therapy. Part 1: Topical carrier platforms

Photodynamic therapy (PDT) is a medical treatment in which a combination of a photosensitising drug and visible light causes destruction of selected cells. Due to the lack of true selectivity of preformed photosensitisers for neoplastic tissue and their high molecular weights, PDT of superficial skin lesions has traditionally been mediated by topical application of the porphyrin precursor 5-aminolevulinic acid (ALA). Objective: This article aims to review the traditional formulation-based approaches taken to topical delivery of ALA and discusses the more innovative strategies investigated for enhancement of PDT mediated by topical application of ALA and preformed photosensitisers. Methods: All of the available published print and online literature in this area was reviewed. As drug delivery of agents used in PDT is still something of an emerging field, it was not necessary to go beyond literature from the last 30 years. Results/conclusion: PDT of neoplastic skin lesions is currently based almost exclusively on topical application of simple semisolid dosage forms containing ALA or its methyl ester. Until expiry of patents on the current market-leading products, there is unlikely to be a great incentive to engage in design and evaluation of innovative formulations for topical PDT, especially those containing the more difficult-to-deliver preformed photosensitisers.

Photosensitiser delivery for photodynamic therapy. Part 2: systemic carrier platforms

Background: The treatment of solid tumours and angiogenic ocular diseases by photodynamic therapy (PDT) requires the injection of a photosensitiser (PS) to destroy target cells through a combination of visible light irradiation and molecular oxygen. There is currently great interest in the development of efficient and specific carrier delivery platforms for systemic PDT. Objective: This article aims to review recent developments in systemic carrier delivery platforms for PDT, with an emphasis on target specificity. Methods: Recent publications, spanning the last five years, concerning delivery carrier platforms for systemic PDT were reviewed, including PS conjugates, dendrimers, micelles, liposomes and nanoparticles. Results/conclusion: PS conjugates and supramolecular delivery platforms can improve PDT selectivity by exploiting cellular and physiological specificities of the targeted tissue. Overexpression of receptors in cancer and angiogenic endothelial cells allows their targeting by affinity-based moieties for the selective uptake of PS conjugates and encapsulating delivery carriers, while the abnormal tumour neovascularisation induces a specific accumulation of heavy weighted PS carriers by enhanced permeability and retention (EPR) effect. in addition, polymeric prodrug delivery platforms triggered by the acidic nature of the tumour environment or the expression of proteases can be designed. Promising results obtained with recent systemic carrier platforms will, in due course, be translated into the clinic for highly efficient and selective PDT protocols.

Vaginal delivery of the recombinant HIV-1 clade-C trimeric gp140 envelope protein CN54gp140 within novel rheologically structured vehicles elicits specific immune responses

Rheologically structured vehicle (RSV) gels were developed as delivery systems for vaginal mucosal vaccination with an HIV-1 envelope glycoprotein (CN54gp140). RSVs comprised a mucoadhesive matrix forming and vaginal fluid absorbing polymer. The mucoadhesive and rheological properties of the RSVs were evaluated in vitro, and the distribution, antigenicity and release of CN54gp140 were analysed by ELISA. CN54gp140 was uniformly distributed within the RSVs and continuously released in vitro in an antigenically intact form over 24 h. Vaginal administration to rabbits induced specific serum IgG, and IgG and IgA in genital tract secretions. The RSVs are a viable delivery modality for vaginal immunization.

Microporation Techniques for Enhanced Delivery of Therapeutic Agents

Perhaps the greatest barrier to development of the field of transmembrane drug delivery is that only a limited number of drugs are amenable to administration by this route. The highly lipophilic nature and barrier function of the uppermost layer of the skin, the stratum corneum, for example, restricts the permeation of hydrophilic, high molecular weight and charged compounds into the systemic circulation. Other membranes in the human body can also present significant barriers to drug permeation. In order to successfully deliver hydrophilic drugs, and macromolecular agents of interest, including peptides, DNA and small interfering RNA, many research groups and pharmaceutical companies Worldwide are focusing on the use of microporation methods and devices. Whilst there are a variety of microporation techniques, including the use of laser, thermal ablation, electroporation, radiofrequency, ultrasound, high pressure jets, and microneedle technology, they share the common goal of enhancing the permeability of a biological membrane through the creation of transient aqueous transport pathways of micron dimensions across that membrane. Once created, these micropores are orders of magnitude larger than molecular dimensions and, therefore, should readily permit the transport of hydrophilic macromolecules. Additionally, microporation devices also enable minimally-invasive sampling and monitoring of biological fluids. This review deals with the innovations relating to microporation-based methods and devices for drug delivery and minimally invasive monitoring, as disclosed in recent patent literature. © 2010 Bentham Science Publishers Ltd.

Delivery of Methylene Blue and meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate from cross-linked poly(vinyl alcohol) hydrogels: A potential means of photodynamic therapy of infected wounds

Poly(vinyl alcohol)-borate complexes were evaluated as a potentially novel drug delivery platform suitable for in vivo use in photodynamic antimicrobial chemotherapy (PACT) of wound infections. An optimised formulation (8.0%w/w PVA, 2.0% w/w borax) was loaded with 1.0 mg ml(-1) of the photosensitisers Methylene Blue (MB) and meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP). Both drugs were released to yield receiver compartment concentrations (>5.0 mu g ml(-1)) found to be phototoxic to both planktonic and bicifilm-grown methicillin-resistant Staphylococcus aureus (MRSA), a common cause of wound infections in hospitals. Newborn calf serum, used to simulate the conditions prevalent in an exuding wound, did not adversely affect the properties of the hydrogels and had no significant effect on the rate of TMP-mediated photodynamic kill of MRSA, despite appreciably reducing the fluence rate of incident light. However, MB-mediated photodynamic kill of MRSA was significantly reduced in the presence of calf serum and when the clinical isolate was grown in a biofilm. Results support the contention that delivery of MB or TMP using gel-type vehicles as part of PACT could make a contribution to the photodynamic eradication of MRSA from infected wounds. (C) 2009 Elsevier B.V. All rights reserved.