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Drug delivery

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Micro / nanoparticles

Controlled release of protein from degradable multi-block copolymer microspheres.

About the project:

Contact:

Xavier Garric
Xavier Garric
Cédric Paniagua
Cédric Paniagua
Jean Coudane
Jean Coudane

Collaborations:

Pr Venier and Dr Montero-Venei (Micro et Nanomédecines Translationnelles , MINT UMR 1066-CNRS 6021)

Funding:

None

Pharmacologically active microcarriers delivering BDNF within a hydrogel: Novel strategy for human bone marrow-derived stem cells neural neuronal differentiation guidance and therapeutic secretome enhancement

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Acta Biomater. 49, 167–180 (2017)

Kandalam, S., Sindji, L., Delcroix, G. J.-R., Violet, F., Garric, X., Andre, E. M., Schiller, P. C., Venier-Julienne, M.-C., des Rieux, A., Guicheux, J. & Montero-Menei, C. N.

ABSTRACT

Stem cells combined with biodegradable injectable scaffolds releasing growth factors hold great promises in regenerative medicine, particularly in the treatment of neurological disorders. We here integrated human marrow-isolated adult multilineage-inducible (MIAMI) stem cells and pharmacologically active microcarriers (PAMs) into an injectable non-toxic silanized-hydroxypropyl methylcellulose (Si-HPMC) hydrogel. The goal is to obtain an injectable non-toxic cell and growth factor delivery device. It should direct the survival and/or neuronal differentiation of the grafted cells, to safely transplant them in the central nervous system, and enhance their tissue repair properties. A model protein was used to optimize the nanoprecipitation conditions of the neuroprotective brain-derived neurotrophic factor (BDNF). BDNF nanoprecipitate was encapsulated in fibronectin-coated (FN) PAMs and the in vitro release profile evaluated. It showed a prolonged, bi-phasic, release of bioactive BDNF, without burst effect. We demonstrated that PAMs and the Si-HPMC hydrogel increased the expression of neural/neuronal differentiation markers of MIAMI cells after 1 week. Moreover, the 3D environment (PAMs or hydrogel) increased MIAMI cells secretion of growth factors (b-NGF, SCF, HGF, LIF, P1GF-1, SDF-1 alpha, VEGF-A & D) and chemokines (MIP-la & RANTES, IL-8). These results show that PAMs delivering BDNF combined with Si-HPMC hydrogel represent a useful novel local delivery tool in the context of neurological disorders. It not only provides neuroprotective BDNF but also bone marrow-derived stem cells that benefit from that environment by displaying neural commitment and an improved neuroprotective/reparative secretome. It provides preliminary evidence of a promising pro-angiogenic, neuroprotective and axonal growth-promoting device for the nervous system. Statement of Significance Combinatorial tissue engineering strategies for the central nervous system are scarce. We developed and characterized a novel injectable non-toxic stem cell and protein delivery system providing regenerative cues for central nervous system disorders. BDNF, a neurotrophic factor with a wide-range effect, was nanoprecipitated to maintain its structure and released in a sustained manner from novel polymeric microcarriers. The combinatorial 3D support, provided by fibronectin-microcarriers and the hydrogel, to the mesenchymal stem cells guided the cells towards a neuronal differentiation and enhanced their tissue repair properties by promoting growth factors and cytokine secretion. The long-term release of physiological doses of bioactive BDNF, combined to the enhanced secretion of tissue repair factors from the stem cells, constitute a promising therapeutic approach.

Novel Biopolymers for Sustained Delivery of Drugs to the Eye

About the project:

The objective of this project is to design novel biopolymers for sustained delivery of drugs to the eye

Contact:

Benjamin Nottelet
Benjamin Nottelet
Jean Coudane
Jean Coudane
Vincent Darcos
Vincent Darcos

Students:

Floriane Bahuon
Floriane Bahuon

Collaborations:

Dr. G. Schwach & Dr. S. Patel (Hoffmann – La Roche)

Funding:

Hoffmann – La Roche

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Micelles:

Multifunctional polyesters for stimuli-responsive drug delivery systems

About the project:

This project is dedicated to the design and synthesis of multifunctional and degradable amphiphilic copolymers for drug delivery applications. Original architectures are in particular investigated and compared to classical linear copolymers.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Jean Coudane
Jean Coudane
Audrey Bethry
Audrey Bethry
Sylvie Hunger
Sylvie Hunger

Students:

Assala Al Samad
Assala Al Samad
Ayman El Jundi
Ayman El Jundi

Collaborations:

Prof. Bakkour (Lebanese University, Lebanon) Dr. Etrych, Dr. Koziolova, Dr. Janouskova (Institute of Macromolecular Chemistry, Czech Republic), Dr. Coll (University Grenoble-Alpes), Prof. Subra (IBMM-peptides, UMR 5247), Dr. Pound-Lana & Prof. Mosqueira⁠ (Federal University of Ouro Preto, Brazil)

Funding:

Doctoral grants for LASER and Azm & Saade Associations

Phthalocyanine photosensitizer in polyethylene glycol-block-poly(lactide-co-benzyl glycidyl ether) nanocarriers: Probing the contribution of aromatic donor-acceptor interactions in polymeric nanospheres

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Mater. Sci. Eng. C-Mater. Biol. Appl. 94, 220–233 (2019)

Pound-Lana, G. E. N., Garcia, G. M., Trindade, I. C., Capelari-Oliveira, P., Pontifice, T. G., Vilela, J. M. C., Andrade, M. S., Nottelet, B., Postacchini, B. B. & Mosqueira, V. C. F.

ABSTRACT

For best photosensitizer activity phthalocyanine dyes used in photodynamic therapy should be molecularly dispersed. Polyethylene glycol-block-polylactide derivatives presenting benzyl side-groups were synthesized to encapsulate a highly lipophilic phthalocyanine dye (AlClPc) and evaluate the effect of π-π interactions on the nanocarrier colloidal stability and dye dispersion. Copolymers with 0, 1, 2 and 6mol% of benzyl glycidyl ether (BGE) were obtained via polyethylene glycol initiated ring-opening copolymerization of D,l-lactide with BGE. The block copolymers formed stable, monodisperse nanospheres with low in vitro cytotoxicity. AlClPc loading increased the nanosphere size and affected their colloidal stability. The photo-physical properties of the encapsulated dye, studied in batch and after separation by field flow fractionation, demonstrated the superiority of plain PEG-PLA over BGE-containing copolymers in maintaining the dye in its monomeric (non-aggregated) form in aqueous suspension. High dye encapsulation and sustained dye release suggest that these nanocarriers are good candidates for photodynamic therapy.

Iterative Photoinduced Chain Functionalization as a Generic Platform for Advanced Polymeric Drug Delivery Systems

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Macromol. Rapid Commun. 39, 1700502 (2018)

Al Samad, A., Bethry, A., Janouskova, O., Ciccione, J., Wenk, C., Coll, J.-L., Subra, G., Etrych, T., El Omar, F., Bakkour, Y., Coudane, J. & Nottelet, B.

ABSTRACT

Advanced drug delivery systems (DDS) are easily designed following a photoiterative strategy. Multifunctional polymers are obtained by coupling building blocks of interest to an alkynated poly(ε‐caprolactone) (PCL) platform via an efficient thiol–yne photoaddition. Fine‐tuning over the design is achieved, as illustrated with targeting and enzyme‐responsive DDS.

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From nanospheres to micelles: simple control of PCL-g-PEG copolymers’ amphiphilicity through thiol-yne photografting

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Polym. Chem. 6, 5093–5102 (2015)

Al Samad, A., Bakkour, Y., Fanny, C., El Omar, F., Coudane, J. & Nottelet, B

 

ABSTRACT

A simple method for the synthesis of a family of poly(ɛ-caprolactone)-g-polyethylene glycol (PCL-g-PEG) copolymers of controlled amphiphilicity and their use to generate nanospheres or micelles are reported. PCL-g-PEG with various compositions are prepared from a single strategy relying on a combination of post-polymerization modification and subsequent thiol-yne photografting. Alkyne-functional PCL (PCL-yne) are first obtained by anionic activation and reaction with propargyl bromide to yield PCL-yne with 8% alkyne groups. PEG-thiol is then reacted on PCL-yne under UV activation to yield the targeted graft copolymer by thiol-yne photoaddition. The advantage of the approach is that control over the composition is easily achieved yielding to amphiphilic graft copolymers with ethylene glycol/ caprolactone (EG/CL) ratios ranging from 0.1 to 1.3. Starting from this single strategy, it was therefore possible to obtain nanospheres (DH~55 nm) or micelles (DH~30 nm) by copolymers self-assembly depending on the ratio EG/CL. The potential of the PCL-g-PEG micelles as drug carrier was finally evaluated with curcumin that was efficiently encapsulated, protected and released over 80 days. Interestingly it was found that drug encapsulation efficiency and drug loading were higher for PCL-g-PEG copolymers compared to block PCL-b-PEG.

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Stabilized micelles for prolonged drug delivery

About the project:

In this project, we take advantage of weak interactions (Pi-Pi stacking, hydrogen bonding, coordination) to stabilize micellar systems in order to increase their therapeutic benefice.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Jean Coudane
Jean Coudane
Audrey Bethry
Audrey Bethry

Students:

Sytze Buwalda
Sytze Buwalda
Assala Al Samad
Assala Al Samad
Ayman El Jundi
Ayman El Jundi

Collaborations:

Dr. Kok (Utrecht University)

Funding:

Marie Skłodowska-Curie grant, doctoral grants for LASER and Azm & Saade Associations

Reversibly core-crosslinked PEG-P(HPMA) micelles: Platinum coordination chemistry for competitive-ligand-regulated drug delivery

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J. Colloid Interface Sci. 535, 505–515 (2019)

Buwalda, S., Nottelet, B., Bethry, A., Kok, R. J., Sijbrandi, N. & Coudane, J.

ABSTRACT

Hypothesis. The presence of pendant thioether groups on poly(ethylene glycol)-poly(N(2-hydroxypropyl) methacrylamide) (PEG-P(HPMA)) block copolymers allows for platinum-mediated coordinative micellar core-crosslinking, resulting in enhanced micellar stability and stimulus-responsive drug delivery.

Experiments. A new PEG-P(HPMA) based block copolymer with pendant 4-(methylthio)benzoyl (MTB) groups along the P(HPMA) block was synthesized by free radical polymerization of a novel HPMA-MTB monomer using a PEG based macro-initiator. As crosslinker the metal-organic linker [ethylenediamineplatinum(II)]2+ was used, herein called Lx, which is a coordinative linker molecule that has been used for the conjugation of drug molecules to a number of synthetic or natural carrier systems such as hyperbranched polymers and antibodies.

Findings. The introduction of Lx in the micellar core results in a smaller size, a lower critical micelle concentration and a better retention of the hydrophobic drug curcumin thanks to coordination bonds between the central platinum atom of Lx and thioether groups on different polymer chains. The drug release from Lx crosslinked micelles is significantly accelerated under conditions mimicking the intracellular environment due to competitive coordination and subsequent micellar de-crosslinking. Because of their straightforward preparation and favorable drug release characteristics, core-crosslinked Lx PEG-P(HPMA) micelles hold promise as a versatile nanomedicine platform.

Stabilization of poly(ethylene glycol)-poly(epsilon-caprolactone) star block copolymer micelles via aromatic groups for improved drug delivery properties

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Colloid Interface Sci. 514, 468–478 (2018)

Buwalda, S., Al Samad, A., El Jundi, A., Bethry, A., Bakkour, Y., Coudane, J. & Nottelet, B

ABSTRACT

Hypothesis

The functionalization of poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) block copolymers with moieties allowing for core-crosslinking is expected to result in improved micellar stability and drug delivery properties.

Experiments

PEG-(PCL)8 star block copolymers were functionalized with pendant benzylthioether (BTE) groups by applying an anionic post-polymerization modification technique followed by photoradical thiol-yne addition of benzyl mercaptan. The micellar properties of PEG-(PCL)8 and PEG-(PCL-BTE)8 were studied and compared in terms of critical micelle concentration (CMC), size, morphology, drug loading and release and in vitro cytotoxicity.

Findings

In comparison with unmodified PEG-(PCL)8 micelles, PEG-(PCL-BTE)8 micelles exhibited a 15-fold lower CMC, a 15-fold smaller size and a 50% higher drug loading and encapsulation efficiency thanks to the presence of pendant benzyl groups which provide the possibility for micellar core-crosslinking via supramolecular π-π stacking and additional hydrophobic interactions. Whereas the PEG-(PCL)8 micelles showed significant aggregation during in vitro cytotoxicity experiments, the PEG-(PCL-BTE)8 micelles showed no signs of aggregation and were capable of solubilizing high concentrations of curcumin, resulting in a significant decrease in MCF-7 cell viability after 48 h. Their ease of synthesis combined with promising results regarding drug delivery make the PEG-(PCL-BTE)8 micelles appealing for application in the field of encapsulation.

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Polyester-g-oligosaccharide micelles for cancer therapy

About the project:

Contact:

Hélène Van Den Berghe
Hélène Van Den Berghe
Jean Coudane
Jean Coudane
Stéphane Dejean
Stéphane Dejean
Sylvie Hunger
Sylvie Hunger

Students:

Victor Demorme
Victor Demorme

Collaborations:

Dr. Magali Gary-Bobo, Pr Alain Morère Kok (« Glyco and nanovectors for therapeutic targeting » team, IBMM, University of Montpellier), Dr. Ghislain David (IAM team, ICGM, University of Montpellier)

Funding:

“Emergence project” funding from the “Cancéropôle Grand Sud Ouest”, Doctoral Grant from the French Ministry

Thermo-responsive poly(lactic acid)-base micelles for drug delivery

About the project:

Contact:

Vincent Darcos
Vincent Darcos
Jean Coudane
Jean Coudane

Students:

Fanny Coumes
Fanny Coumes
Yanfei Hu

Collaborations:

Prof. Sébastien Lecommendoux (LCPO, Bordeaux)

Funding:

CNRS

Thermo-responsive drug release from self-assembled micelles of brush-like PLA/PEG analogues block copolymers

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Int. J. Pharm. 491, 152–161 (2015)

Hu, Y., Darcos, V., Monge, S. & Li, S.

 

ABSTRACT

Thermo-responsive brush-like amphiphilic poly[2-(2-methoxyethoxy) ethyl methacrylate-co-oligo(ethylene glycol) methacrylate]-b-poly(l-lactide)-b-poly[2-(2-methoxyethoxy) ethyl methacrylate-co-oligo(ethylene glycol) methacrylate] [P(MEO2MA-co-OEGMA)-b-PLLA-b-P(MEO2MA-co-OEGMA)] triblock copolymers were synthesized by atom transfer radical polymerization of MEO2MA and OEGMA co-monomers using a α,ω-Bromopropionyl poly(l-lactide) (Br-PLLA-Br) macroinitiator. The resulting copolymers with MEO2MA/OEGMA molar ratio ranging from 79/21 to 42/58 were characterized by 1H nuclear magnetic resonance and size exclusion chromatography. Thermo-responsive micelles were obtained by self-assembly of copolymers in aqueous medium. The micelles are spherical in shape with sizes varying from 20.7 to 102.5 nm. A hydrophobic anticancer drug, curcumin, was encapsulated in micelles by using membrane hydration method. The properties of drug loaded micelles were determined by dynamic light scattering, transmission electron microscopy and lower critical solution temperature (LCST) measurements. The micelles size decreases from 102.5 nm for blank micelles to 37.6 nm with 10.8% drug loading, suggesting that the drug plays an important role in the micellization procedure. The LCST decreases from 45.1 °C for blank micelles to 40.6 and 38.3 °C with 5.9 and 10.8% drug loading, respectively. In vitro drug release was performed in pH 7.4 PBS at different temperatures. Data show that the release rate was significantly enhanced above the LCST comparing with that below the LCST. The amount of released drug at 41 °C was ca. 20% higher than that at 37 °C. Burst-like release was depressed due to enhanced interaction between drug with hydrophobic PLA and PMA chains.

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Biocompatibility of thermo-responsive PNIPAAm-PLLA-PNIPAAm triblock copolymer as potential drug carrier.

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Polym. Adv. Technol. 26, 1567–1574 (2015)

Su, F., Shen, X., Hu, Y., Darcos, V. & Li, S

 

ABSTRACT

This work aims to evaluate the cytocompatibility and hemocompatibility of thermo‐responsive polymers as potential drug carrier. Thermo‐responsive poly(N‐isopropyl acrylamide) (PNIPAAm) and poly(N‐isopropyl acrylamide)‐poly(l‐lactide)‐poly(N‐isopropyl acrylamide) (PNIPAAm‐PLLA‐PNIPAAm) triblock copolymer were synthesized by atom transfer radical polymerization using ethyl α‐bromoisobutyrate or Br‐PLLA‐Br as initiator under mild conditions. The self‐assembly and thermo‐responsive properties of the copolymer in aqueous medium were investigated by critical micelle concentration, dynamic light scattering, transmission electron microscopy, and lower critical solution temperature measurements. The critical micelle concentration was 0.014 mg ml−1. Dynamic light scattering and transmission electron microscopy results show that the micelles are spherical in shape with sizes between 20 and 40 nm. The lower critical solution temperature of PNIPAAm and PNIPAAm‐PLLA‐PNIPAAm is 34.8°C and 32.8°C, respectively. 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay was carried out to evaluate the cytotoxicity of polymers, and the hemocompatibility was assessed from hemolysis ratio and plasma recalcification time measurements. The results show that PNIPAAm‐PLLA‐PNIPAAm presents outstanding biocompatibility and could be promising for applications in targeted drug delivery.

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Hydrogels:

Robust, fast gelling and tunable degradable hydrogels for drug delivery

About the project:

In this project we synthesize hydrogels based on degradable polymers. Our aim is to improve gelation times and/or gel mechanical properties by either adjusting the copolymers compositions/architectures, or by introducing moeities that ensure fast gelations.

Contact:

Benjamin Nottelet
Benjamin Nottelet
Jean Coudane
Jean Coudane
Audrey Bethry
Audrey Bethry

Students:

Sytze Buwalda
Sytze Buwalda

Collaborations:

Funding:

Marie Skłodowska-Curie grant

Ultrafast in situ forming poly(ethylene glycol)-poly(amido amine) hydrogels with tunable drug release properties via controllable degradation rates

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Eur. J. Pharm. Biopharm. 139, 232-239 (2019)

Buwalda S., Bethry A., Hunger S., Kandoussi S., Coudane J., Nottelet B.

ABSTRACT

Fast in situ forming, chemically crosslinked hydrogels were prepared by the amidation reaction between N-succinimidyl ester end groups of multi-armed poly(ethylene glycol) (PEG) and amino surface groups of poly(amido amine) (PAMAM) dendrimer generation 2.0. To control the properties of the PEG/PAMAM hydrogels, PEGs were used with different arm numbers (4 or 8) as well as different linkers (amide or ester) between the PEG arms and their terminal N-succinimidyl ester groups. Oscillatory rheology measurements showed that the hydrogels form within seconds after mixing the PEG and PAMAM precursor solutions. The storage moduli increased with crosslink density and reached values up to 2.3 kPa for hydrogels based on 4-armed PEG. Gravimetrical degradation experiments demonstrated that hydrogels with ester linkages between PEG and PAMAM degrade within 2 days, whereas amide-linked hydrogels were stable for several months. The release of two different model drugs (fluorescein isothiocyanate-dextran with molecular weights of 4·103 and 2·106 g/mol, FITC-DEX4K and FITC-DEX2000K, respectively) from amide-linked hydrogels was characterized by an initial burst followed by diffusion-controlled release, of which the rate depended on the size of the drug. In contrast, the release of FITC-DEX2000K from ester-containing hydrogels was governed mainly by degradation of the hydrogels and could be modulated via the ratio between ester and amide linkages. In vitro cytotoxicity experiments indicated that the PEG/PAMAM hydrogels are non-toxic to mouse fibroblasts. These in situ forming PEG/PAMAM hydrogels can be tuned with a broad range of mechanical, degradation and release properties and therefore hold promise as a platform for the delivery of therapeutic agents.

Robust & thermosensitive poly(ethylene glycol)-poly(e-caprolactone) star block copolymer hydrogels

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Polym. Degrad. Stabil. 137, 173–183 (2017)

Buwalda, S. J., Nottelet, B. & Coudane, J.

ABSTRACT

Novel 8-armed poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) star block copolymers, possessing an amide or an ester group between the PEG core and the PCL arms (PEG20K-(NHCO)-(PCL9)8 and PEG20K-(OCO)-(PCL9)8), are synthesized by ring opening polymerization of ε-caprolactone in toluene at 110 °C initiated by 8-armed star PEG20K-(NH2)8 and PEG20K-(OH)8, respectively. Compared to linear triblock copolymers with a similar hydrophilic/hydrophobic balance and molecular weight, star block copolymers show better aqueous solubility and yield more homogeneous and transparent hydrogels. PEG20K-(NHCO)-(PCL9)8 hydrogels exhibit a significantly higher storage modulus and in vitro stability in comparison with PEG20K-(OCO)-(PCL9)8 hydrogels of similar concentration and molecular weight. 1H NMR analysis of degrading hydrogel samples clearly demonstrates different degradation mechanisms for the ester and amide type star block copolymers. Their robust mechanical properties, the possibility to be formed in situ and their excellent resistance against hydrolytic degradation make these PEG-PCL star block copolymer hydrogels, especially those based on PEG20K-(NHCO)-(PCL9)8, appealing for various biomedical applications.

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Biopolymers based hydrogels for drug delivery

About the project:

In this project coordinated by our colleagues of the AO Research Institute Davos, the objective is to investigate how antibiotics can affect the physico-chemical characteristics of alginate gels, which could help in elucidating the problem of antibiotic tolerance.

Contact:

Xavier Garric
Xavier Garric
Benjamin Nottelet
Benjamin Nottelet
Hélène Van Den Berghe
Hélène Van Den Berghe

Students:

Sytze Buwalda
Sytze Buwalda

Collaborations:

Dr. D’Este, Dr. Richards, Dr. Moriarty, Dr. Eglin, Dr. Guillaume (AO Research Institute, Switzerland)

Funding:

Marie Skłodowska-Curie grant

Interaction of gentamicin sulfate with alginate and consequences on the physico-chemical properties of alginate-containing biofilms

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Int. J. Biol. Macromol. 121, 390–397 (2019)

Heriot, M., Nottelet, B., Garric, X., D’Este, M., Richards, G. R., Moriarty, F. T., Eglin, D. & Guillaume, O.

ABSTRACT

Background: Alginate is one of the main extracellular polymeric substances (EPS) in biofilms of Cystic Fibrosis (CF) patients suffering frompulmonary infections. Gentamicin sulfate (GS) can strongly bind to alginate resulting in loss of pharmacological activity; however neither the mechanism nor its repercussion is fully understood. In this study, we investigated how GS modifies the alginate macromolecular network and its microenvironment. Material and methods: Alginate gels of two different compositions (either enriched in guluronate units (G) or enriched inmannuronate units(M))were crosslinkedwith Ca2+ and exposed to GS at varying times and concentrations.

The complexes formed were characterized via turbidimetry, mechanical tests, swelling assay, calorimetry techniques, nuclear magnetic resonance, Ca2+ displacement, macromolecular probe diffusion and pH alteration.

Results: In presence of GS, the alginate network and its environment undergo a tremendous reorganization in terms of gel density, stiffness, diffusion property, presence and state of the water molecules. We noted that the intensity of those alterations is directly dependent on the polysaccharide motif composition (ratio M/G).

Conclusion: Our results underline the importance of alginate as biofilm component, its pernicious role during antibiotherapy and could represent a potential macromolecular target to improve anti-infectious

therapies.

A method to slow down the ionization-dependent release of risperidone loaded in a thermoresponsive poly(N-acryloyl glycinamide) hydrogel

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ABSTRACT

Poly(N-acryloyl glycinamide) polymers are soluble in hot aqueous media that gel rapidly on cooling. This gelatin-like behavior was previously compared with drug delivery requirements. Slow releases were demonstrated in vitro using different model molecules and macromolecules and in vivo using methylene blue. Risperidone is a weak basic drug sparingly soluble in water frequently used to treat patients suffering of schizophrenia. A standard risperidone-poly(N-acryloyl glycinamide) hydrogel formulation was selected from which the drug was allowed to release comparatively in buffered and non-buffered isotonic media at 37 °C under pseudo sink conditions. Linear release was observed in pH = 7.4 phosphate buffer whereas in buffer-free 0.15 M NaCl, the release was initially faster than in the buffer but became rapidly slower as the pH increased from 6.8 to 8.2. These features were related to the ionization-dependent solubility of risperidone. In order to minimize the ionization and thus the solubility of the drug inside the hydrogel despite outside buffering at 7.4, Mg(OH2), a sparingly soluble mineral base, was added to the standard formulation. This addition resulted in a c.a. threefold increase of the zero-order release duration. The method should be applicable to other sparingly soluble weakly basic drugs.

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