Novel inulin-based mucoadhesive micelles loaded with corticosteroids as potential transcorneal permeation enhancers

In this work a new copolymer of inulin (INU) derivatized with ethylendiamine (EDA) and retinoic acid (RA), named INU-EDA-RA, was synthetized, characterized and employed to produce micelles as carriers for topical administration of corticosteroids for the potential treatment of diseases of posterior eye segment. Spectroscopic analysis confirmed a molar derivatization degree of 11.30 and 4.30% in EDA and RA, respectively. INU-EDA-RA micelles are capable of strong mucoadhesive interactions which result time-independent and stable over time but concentration depending. Moreover micelles are able to encapsulate efficiently from 3 to 13% (w/w) of lipophilic drugs, as dexamethasone, triamcinolone …

HYALURONIC ACID DERIVATIVE MICELLES AS OCULAR PLATFORMS TO DRUG RELEASE AND CORNEAL PERMEATION

In traditional ocular formulations, only small amount of the administered drug penetrates the cornea to reach the intraocular tissue. One approach to improve the drug ocular bioavailability was to develop colloidal drug delivery systems. Polymeric micelles seem to be very promising for their capacity to dissolve a variety of hydrophobic drugs by enhancing their water solubility and so their bioavailability. They are able to increase ocular drug permeability due to interact with the complex corneal structure. Considering the advantages to use mucoadhesive polymer to increase drug residence time on the ocular surface, the aim of this work was to prepare hyaluronic acid-based micelles as a pla…

Blend scaffolds with polyaspartamide/polyester structure fabricated via TIPS and their RGDC functionalization to promote osteoblast adhesion and proliferation

Target of this work was to prepare a RGDC functionalized hybrid biomaterial via TIPS technique to achieve a more efficient control of osteoblast adhesion and diffusion on the three-dimensional (3D) scaffolds. Starting from a crystalline poly(l-lactic acid) (PLLA) and an amorphous alpha,beta-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-d,l-aspartamide-graft-polylactic acid (PHEA-EDA-g-PLA) copolymer, blend scaffolds were characterized by an appropriate porosity and pore interconnection. The PHEA-EDA-PLA interpenetration with PLLA improved hydrolytic susceptibility of hybrid scaffolds. The presence of free amino groups on scaffolds allowed to tether the cyclic RGD peptide (RGDC) via Michael…

Hyaluronic acid and beta cyclodextrins films for the release of corneal epithelial cells and dexamethasone

In this work we prepared hydrogels based on hyaluronic acid and β-cyclodextrins to sustain the release of both corneal epithelial cells and dexamethasone. This steroid is administered as eye drops several times per day to reduce the risk of rejection in the post operative period after the cornea transplantation and cell release techniques. Hydrogels were produced by crosslinking an amino derivative of hyaluronic acid, with the divinyl sulfone derivative of β-cyclodextrins, this last employed as a crosslinker and solubilizing agent. Drug release studies revealed that dexamethasone containing samples are able to extend the release of this drug for at least five days. Biological studies, condu…

Micelles of hyaluronic acid-hexadecylamine derivatives for ocular release of hydrophobic durgs

The topical route is the ideal way to release drugs to the eye. Unfortunately, the low ocular drug bioavailability associated with this route of administration, makes not very efficient the treatment of several ocular diseases. Nowadays, polymeric micelles occupy a significant role in the field of ocular drug delivery thanks to the advantages that they offer in comparison with the administration of drugs in the free form. Indeed, polymeric micelles are suitable for delivering hydrophobic drugs and they seem to be very promising in ocular drug delivery for their high kinetic and thermodynamic stability. Also, micellar systems are able to give a controlled drug release and to act as absorptio…

Microfibers and Nanoparticles with Controlled Dimensions of a Hyaluronic Acid Derivative

Microfluidics is defined as the technology that deals with the precise control and manipulation of small quantities of fluids constrained in micro-channels of small cross-sectional dimensions [1]. Microfluidics has recently emerged as a very promising route for the production of polymeric fibers at the micro and nanoscale, providing a fine control over fiber shape, size, chemical anisotropy and biological activity [2]. Furthermore, the ability to manipulate nanoliter volumes of liquid and to control mixing and reaction precisely, opens up the possibility of creating smart targeted drug delivery systems as nanoparticles, especially with uniform and narrow size distribution [3]. This work des…

Inulin-Based Polymeric Micelles Functionalized with Ocular Permeation Enhancers: Improvement of Dexamethasone Permeation/Penetration through Bovine Corneas

Ophthalmic drug delivery is still a challenge due to the protective barriers of the eye. A common strategy to promote drug absorption is the use of ocular permeation enhancers, while an innovative approach is the use of polymeric micelles. In the present work, the two mentioned approaches were coupled by conjugating ocular permeation enhancers (PEG2000, carnitine, creatine, taurine) to an inulin-based co-polymer (INU-EDA-RA) in order to obtain self-assembling biopolymers with permeation enhancer properties for the hydrophobic drug dexamethasone (DEX). Inulin derivatives were properly synthetized, were found to expose about 2% mol/mol of enhancer molecules in the side chain, and resulted abl…

NUOVE MICELLE A BASE DI ACIDO IALURONICO PER IL POTENZIALE RILASCIO DI CORTICOSTEROIDI NELLA REGIONE POSTERIORE DELL’OCCHIO

Micelles of hyaluronic acid-hexadecylamine derivatives for ocular release of hydrophobic drugs

Mucoadhesive micelles based on inulin derivative for ocular release of corticosteroids

Microfluidic Fabrication of Physically Assembled Nanogels and Micrometric Fibers by Using a Hyaluronic Acid Derivative

The employ of a hyaluronic acid (HA) derivative, bearing octadecyl (C18) and ethylenediamine (EDA) groups, for microfluidic fabrication of nanogels and microfibers is reported in this study. Two HA-EDA-C18 derivatives (125 and 320 kDa) having ionic strength sensitive properties are synthesized and characterized. The control of the rheological properties of HA-EDA-C18 aqueous dispersions by formation of inclusion complexes with hydroxypropyl-β-cyclodextrins (HPCD) is described. Reversibility of C18/HPCD complexation and physical crosslinking is detected in media with different ionic strength through oscillation frequency tests. HA-EDA-C18 125 kDa is employed for nanogel fabrication. Control …

Hyaluronic Acid-Based Micelles as Ocular Platform to Modulate the Loading, Release, and Corneal Permeation of Corticosteroids

The aim of this work is to prepare hyaluronic acid-based micelles as a platform to load corticosteroid drugs and to improve their corneal permeation after administration on the ocular surface. Three amphiphilic derivatives of hyaluronic acid (HA) are synthesized using different amounts of hexadecylamine (C16 -NH2 ). HAC16 a, HAC16 b, and HAC16 c derivatives are able to form micelles by the cosolvent evaporation method and to entrap corticosteroids (dexamethasone, triamcinolone, triamcinolone acetonide). HAC16 a and HAC16 b micelles show the best results in terms of drug loading and particle size. They are also able to improve drug release compared to free drug solution or suspension. In add…

OCULAR DRUG CARRIERS NANOSTRUTTURATI PER IL TRATTAMENTO DELLE PATOLOGIE DEGENERATIVE DELLA RETINA

Il lavoro di ricerca svolto è stato incentrato sulla preparazione e caratterizzazione di diversi ocular drug carriers nanostrutturati in grado di veicolare molecole bioattive per il trattamento delle retinopatie. Tali sistemi sono stati preparati utilizzando differenti derivati polimerici, ottenuti a partire dall’acido ialuronico (HA) a differente peso molecolare (10-240 kDa). Allo scopo di ottenere micelle polimeriche per la veicolazione di corticosteroidi, sono stati sintetizzati diversi derivati polimerici partendo dall’HA con MW di 10 kDa. Il derivato siglato HAC16b ha mostrato delle caratteristiche vantaggiose, in termini di dimensione, proprietà mucoadesive, valori di drug loading e p…

Modulation of physical and biological properties of a composite PLLA and polyaspartamide derivative obtained via thermally induced phase separation (TIPS) technique.

Abstract In the present study, blend of poly l -lactic acid (PLLA) with a graft copolymer based on α,β-poly(N-hydroxyethyl)- dl -aspartamide and PLA named PHEA-PLA, has been used to design porous scaffold by using Thermally Induced Phase Separation (TIPS) technique. Starting from a homogeneous ternary solution of polymers, dioxane and deionised water, PLLA/PHEA-PLA porous foams have been produced by varying the polymers concentration and de-mixing temperature in metastable region. Results have shown that scaffolds prepared with a polymer concentration of 4% and de-mixing temperature of 22.5 °C are the best among those assessed, due to their optimal pore size and interconnection. SEM and DSC…

Composite Hydrogels of Alkyl Functionalized Gellan Gum Derivative and Hydroxyapatite/Tricalcium Phosphate Nanoparticles as Injectable Scaffolds for bone Regeneration

An alkyl functionalized gellan gum derivative was here used to produce hydrogels containing hydroxyapatite and tricalcium phosphate nanoparticles as injectable nanostructured scaffolds for bone regeneration. The amphiphilic nature of the polysaccharide derivative along with its thermotropic behavior and ionotropic crosslinking features made possible to produce injectable bone mimetic scaffolds that can be used to release viable cells and osteoinductive biomolecules. The influence of different nanoparticles concentration on the rheological and physicochemical properties of the injectable systems was studied. We found that the presence of inorganic nanoparticles reinforces the three-dimension…

HYALURONIC ACID BASED-MICELLES FOR OFF-LABEL USE OF IMATINIB IN RETINOPATHIES TREATMENT

The aim of this work was to obtain polymeric micelles able to cross corneal barrier and to improve the permeation of imatinib free base. Micelles were prepared by using hyaluronic acid (HA) derivatives containing ethylenediamine (EDA), chains of hexadecyl (C16), polyethylene glycol (PEG) and/or L-carnitine (CRN). The resulting samples, named as HA-EDA-C16, HA-EDA-C16-PEG and HA-EDA-C16-CRN micelles, were designed to allow a non-invasive way of administration, i.e. topical ocular instillation. These nanocarriers showed an optimal particle size in aqueous media and mucoadhesive properties. Imatinib-loaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal…

Imatinib-Loaded Micelles of Hyaluronic Acid Derivatives for Potential Treatment of Neovascular Ocular Diseases

In this work, new micellar systems able to cross corneal barrier and to improve the permeation of imatinib free base were prepared and characterized. HA-EDA-C-16, HA-EDA-C-16-PEG, and HA-EDA-C-16-CRN micelles were synthesized starting from hyaluronic acid (HA), ethylenediamine (EDA), hexadecyl chains (C-16), polyethylene glycol (PEG), or L-carnitine (CRN). These nanocarriers showed optimal particle size and mucoadhesive properties. Imatinib-loaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal permeation and penetration. In addition, a study was conducted to understand the in vitro imatinib inhibitory effect on a choroidal neovascularization process…

Mucoadhesive PEGylated inulin-based self-assembling nanoparticles: In vitro and ex vivo transcorneal permeation enhancement of corticosteroids

Abstract As transcorneal drug delivery is still a challenge, the scope of the present study was to prepare useful nanosystems able to enhance transcorneal permeation/penetration of drugs. Moreover, this work aims to evaluate the effectiveness of inulin-based nanosystems in the specific field of ocular drug delivery and the effect of PEG chains to promote mucoadhesion, stability and transcorneal penetration/permeation enhancer effect of self-assembling nanoparticles in vitro (transwell systems and HCE) and ex vivo (Franz cells and bovine cornea). In particular, inulin was chosen as the starting natural polysaccharide polymer to design a novel amphiphilic derivative named INU-EDA-RA-PEG capab…

A New Hyaluronic Acid Derivative Obtained from Atom Transfer Radical Polymerization as a siRNA Vector for CD44 Receptor Tumor Targeting

Two derivatives of hyaluronic acid (HA) have been synthesized by atom transfer radical polymerization (ATRP), starting from an ethylenediamino HA derivative (HA-EDA) and by using diethylaminoethyl methacrylate (DEAEMA) as a monomer for polymerization. Both samples, indicated as HA-EDA-pDEAEMA a and b, are able to condense siRNA, as determined by gel retardation assay and resulting complexes show a size and a zeta potential value dependent on polymerization number, as determined by dynamic light scattering measurements. In vitro studies performed on HCT 116 cell line, that over express CD44 receptor, demonstrate a receptor mediated uptake of complexes, regardless of their surface charge.