Recent Developments of Nanostructures for the Ocular Delivery of Natural Compounds.

Ocular disorders comprising various diseases of the anterior and posterior segments are considered as the main reasons for blindness. Natural products have been identified as potential treatments for ocular diseases due to their anti-oxidative, antiangiogenic, and anti-inflammatory effects. Unfortunately, most of these beneficial compounds are characterised by low solubility which results in low bioavailability and rapid systemic clearance thus requiring frequent administration or requiring high doses, which hinders their therapeutic applications.

Worm-like micelles of triblock copolymer of ethylene oxide and styrene oxide characterised using light scattering and Taylor dispersion analysis.

A triblock ESE copolymer (ESE, S = styrene oxide and E = ethylene oxide) was synthesised by sequential oxyanionic copolymerisation of styrene oxide followed by ethylene oxide. Light scattering studies demonstrated a shape transition from spherical micelles to worm-like micelles above a critical temperature of approximately 18 °C. Taylor dispersion analysis (TDA) also indicated a size growth when the temperature increased from 25 to 40 °C due to the formation of worm-like micelles.

In Vitro Evaluation of Third Generation PAMAM Dendrimer Conjugates.

The present study compares the use of high generation G3 and low generation G0 Polyamidoamine (PAMAM) dendrimers as drug carriers of naproxen (NAP), a poorly water soluble drug. Naproxen was conjugated to G3 in different ratios and to G0 in a 1:1 ratio via a diethylene glycol linker. A lauroyl chain (L), a lipophilic permeability enhancer, was attached to G3 and G0 prodrugs.

Recent advances in exosome-based nanovehicles as RNA interference therapeutic carriers.

RNA interference (RNAi) therapeutics (siRNA, miRNA, etc.) represent an emerging medicinal remedy for a variety of ailments. However, their low serum stability and low cellular uptake significantly restrict their clinical applications.

Preparation of core-crosslinked linear-dendritic copolymer micelles with enhanced stability and their application for drug solubilisation.

In this study we explore the preparation of core-crosslinked micelles of linear-dendritic methoxy-poly(ethylene glycol) (MPEG)-co-poly(ester-sulfide) (PES) polymers to improve the stability of such polymeric micelle systems against premature disintegration and drug release. A series of MPEG-PES copolymers were synthesised via stepwise reactions of acetylation and thiol-ene photoreaction. Surface tension measurement showed that the copolymers with ethenyl surface groups could self-associate in dilute aqueous solutions to form micelles.

RNAi-combined nano-chemotherapeutics to tackle resistant tumors.

The merger of nanotechnology and combination chemotherapy has shown notable promise in the therapy of resistant tumors. The latest scientific attention encompasses the engagement of anticancer drugs in combination with small interfering (si)RNAs, such as VEGF, XLAP, PGP, MRP-1, BCL-2 and cMyc, to name but a few. siRNAs have shown immense promise to knockout drug resistance genes as well as to recover the sensitivity of resistant tumors to anticancer therapy.

PAMAM dendrimers as aerosol drug nanocarriers for pulmonary delivery via nebulization.

Polyamidoamine (PAMAM) dendrimers were evaluated as nanocarriers for pulmonary delivery of the model poorly soluble anti-asthma drug beclometasone dipropionate (BDP) using G3, G4 and G4(12) dendrimers. BDP-loaded dendrimers were characterized for drug solubility, in vitro drug release and aerosolization properties using three nebulizers: Pari LC Sprint (air-jet), Aeroneb Pro (actively vibrating-mesh) and Omron MicroAir (passively vibrating-mesh) nebulizers. Solubilization of BDP using dendrimers was increased by increasing the dendrimer generation and by using higher pH media.

Extraction and RP-HPLC determination of taxol in rat plasma, cell culture and quality control samples.

A rapid, sensitive, selective and validated reverse phase high-performance liquid chromatography (RP-HPLC) method for the estimation of paclitaxel in micro-sample of rat plasma and in culture of cancer cells was performed in this study. The mobile phase consisted of an optimized mixture of methanol:water: trifluroacetic acid (80: 20: 0.1, v/v/v).

Solubility enhancement of paclitaxel using a linear-dendritic block copolymer.

The solubilising capacities of micelles of a linear-dendritic copolymer (BE-PAMAM), formed by conjugating the poly(butylene oxide) (B)-poly(ethylene oxide) (E) block copolymer B16E42 (BE) with a G2 PAMAM dendrimer, have been compared with those of the diblock copolymer B16E42 for the anti-cancer drug paclitaxel. The BE-PAMAM copolymer showed a greater solubility enhancement than BE under equivalent conditions. Drug-loading efficiency was improved using a solvent-loading method compared with the conventional solution-loading method.

Delivery of paclitaxel across cellular barriers using a dendrimer-based nanocarrier.

The aim of this study was to investigate the ability of a third-generation (G3) polyamidoamine (PAMAM) dendrimer-based carrier to enhance the permeability of paclitaxel (pac) and to overcome cellular barriers. G3 dendrimers were surface modified with lauryl chains (L) and conjugated with paclitaxel (pac) via a glutaric anhydride (glu) linker, followed by labeling with FITC. Biological evaluation of the dendrimer and conjugates was conducted using the human colon adenocarcinoma cell line (Caco-2) and primary cultured porcine brain endothelial cells (PBECs).

Oral liquid in situ gelling methylcellulose/alginate formulations for sustained drug delivery to dysphagic patients.

Background: Elderly patients with swallowing dysfunction may benefit from the oral administration of liquid dosage forms with in situ gelling properties.

Aim: We have designed in situ gelling liquid dosage formulations composed of mixtures of methylcellulose, which has thermally reversible gelation properties and sodium alginate, the gelation of which is ion-responsive, with suitable rheological characteristics for ease of administration to dysphagic patients and suitable integrity in the stomach to achieve a sustained release of drug.

Method: The rheological and gelation characteristics of solutions containing methylcellulose (2.

Carbon nanotubes in cancer therapy and drug delivery.

Carbon nanotubes (CNTs) have been introduced recently as a novel carrier system for both small and large therapeutic molecules. CNTs can be functionalized (i.e.

In situ gelling formulation based on methylcellulose/pectin system for oral-sustained drug delivery to dysphagic patients.

Background: Oral-sustained release gel formulations with suitable rheological properties have been proposed as a means of improving the compliance of dysphagic and geriatric patients who have difficulties with handling and swallowing oral dosage forms.

Aim: We have modified the rheological and release properties of thermally reversible methylcellulose solutions by admixture with pectin, the gelation of which is ion-responsive, with the aim of formulating an in situ gelling vehicle suitable for oral-sustained drug delivery.

Method: Gels formed by solutions containing methylcellulose (1.

Effect of D-sorbitol on the thermal gelation of methylcellulose formulations for drug delivery.

The aim of this study was to examine the effect of D-sorbitol on the gelation characteristics of methylcellulose in aqueous solution. The addition of D-sorbitol at concentrations of between 25 and 30% (w/v) to 1.0-2.

In situ gelling xyloglucan/alginate liquid formulation for oral sustained drug delivery to dysphagic patients.

Background: The oral administration of liquid dosage forms of suitable consistency and with sustained release characteristics may provide a means of improving the compliance of geriatric patients who experience difficulties in swallowing conventional solid dosage forms.

Aim: We have designed and evaluated liquid preparations for administration to dysphagic patients, composed of aqueous mixtures of xyloglucan, which has thermally reversible gelation characteristics, and sodium alginate, which has ion-responsive gelation characteristics.

Method: The gelation and in vitro and in vivo release characteristics of liquid formulations containing appropriate concentrations of xyloglucan and sodium alginate with mannuronate/guluronate ratios of either 0.

Surface modification of PAMAM dendrimers modulates the mechanism of cellular internalization.

The aim of this study was to investigate the influence of dendrimer surface properties on cellular internalization and intracellular trafficking in the human colon adenocarcinoma HT-29 cell line. Third-generation (G3) polyamidoamine (PAMAM) dendrimers were modified to contain either two lauroyl chains (G3L2), two propranolol molecules (G3P2), or two lauroyl and two propranolol molecules (G3L2P2) at the dendrimer surface. Surface-modified and unmodified dendrimers were labeled with fluorescein isothiocyanate (FITC) at an average molar ratio of 1:1.

PAMAM dendrimers for the delivery of the antibacterial Triclosan.

Many oral care products incorporate an antibacterial compound to prevent the formation of dental plaque which predisposes teeth to dental caries or periodontal disease. Triclosan (TCN) is a commonly used antiplaque agent in toothpastes. Strategies to increase the delivery efficiency of antibacterials using formulation aids such as polyamidoamine (PAMAM) dendrimers are of interest.

Solubilisation of drugs in worm-like micelles of block copolymers of ethylene oxide and 1,2-butylene oxide in aqueous solution.

Ethylene oxide and 1,2-butylene oxide were sequentially polymerised to form the diblock copolymer E13B10 (E=oxyethylene, B=oxybutylene, subscripts denote number-average block lengths in repeat units). Dynamic and static light scattering over the temperature range 10-30 degrees C demonstrated a transition from compact (spheroidal) micelles to larger, more elongated (worm-like) micelles with temperature increase above a critical onset temperature of about 20 degrees C. Determination of the solubilisation capacity for griseofulvin, carbamazepine and spironolactone of dilute micellar solutions of this copolymer, together with those of E11B8 and E17B12 block copolymers (which also show the sphere-to-worm transition), allowed investigation of the influence on solubilisation characteristics of hydrophobic block length and temperature.

Synthesis of dendrimers and drug-dendrimer conjugates for drug delivery.

Dendrimers constitute a class of polymers that possess a well-defined structure allowing the precise control of size, shape and terminal group functionality. Their utility has been explored for a wide range of pharmaceutical applications. There is growing interest in the design and synthesis of novel biocompatible dendrimers and a number of novel dendrimer architectures are discussed in this review.

Synthesis and assessment of first-generation polyamidoamine dendrimer prodrugs to enhance the cellular permeability of P-gp substrates.

The aim of this study is to evaluate the potential use of first-generation (G1) polyamidoamine (PAMAM) dendrimers as drug carriers to enhance the permeability, hence oral absorption, of drugs that are substrates for P-glycoprotein (P-gp) efflux transporters. G1 PAMAM dendrimer-based prodrugs of the water-insoluble P-gp substrate terfenadine (Ter) were synthesized using succinic acid (suc) or succinyl-diethylene glycol (suc-deg) as a linker/spacer (to yield G1-suc-Ter and G1-suc-deg-Ter, respectively). In addition, the permeability of G1-suc-deg-Ter was enhanced by attaching two lauroyl chains (L) to the dendrimer surface (L2-G1-suc-deg-Ter).

In vitro evaluation of dendrimer prodrugs for oral drug delivery.

Dendrimer-based prodrugs were used to enhance the transepithelial permeability of naproxen, a low solubility model drug. The stability of the dendrimer-naproxen link was assessed. Naproxen was conjugated to G0 polyamidoamine (PAMAM) dendrimers either by an amide bond or an ester bond.

Crossing cellular barriers using dendrimer nanotechnologies.

Dendrimers represent a class of polymers characterised by their well-defined structure, with a high degree of molecular uniformity and low polydispersity. They have found a wide-range of pharmaceutical applications; however, more recently, they have been shown to function as effective intracellular carriers for drugs. In addition, dendrimers have been shown to be capable of bypassing efflux transporters.

Synthesis, characterization and stability of dendrimer prodrugs.

The design, synthesis and characterization of a series of zero generation (G0) PAMAM dendrimer-based prodrugs for the potential enhancement of drug solubility and bioavailability are described. Naproxen, a poorly water-soluble drug, was conjugated to dendrimers either directly by an amide bond or by ester bonds using either L-lactic acid or diethylene glycol as a linker. All of the prodrugs were more hydrophilic than the parent drug, as evaluated by drug partitioning between 1-octanol and phosphate buffer (pH 7.

Dendrimer-drug interactions.

The interaction between drugs and dendrimers is reviewed with particular reference to the entrapment of drugs within the dendrimer architecture and the electrostatic and covalent complexation of drugs to the dendrimer surface. The application of dendrimer-drug complexation in the enhancement of drug solubility and bioavailability and the use of the complexes as vehicles for the controlled release of drugs and drug targeting is discussed.