Controlled-release nanotherapeutics: State of translation.

This is a review of nanotherapeutic systems, specifically those that exhibit controlled release of the encapsulated bioactive compound. The survey includes the delivery of a range of bioactive compounds, from lipophilic small molecules to hydrophilic proteins and siRNA molecules. The research into enabling sustained delivery of these compounds from nanocarriers has been prolific, but clinical success has been harder to achieve. This is partly because achieving true sustained duration of action over several days is difficult when the carrier dimensions become less than about 400 nm, due to the much shorter diffusion path length compared to micron-sized carrier systems. Other options must be sought to control the efflux of incorporated bioactives, particularly when these bioactives have moderate to high hydrophilicity. A few of these options are discussed critically in this review. We also answer the question: is controlled release needed for nanotherapies? We present the case for controlled release in specific conditions, with two examples from our own work: one for treatment of glaucoma, and the second for inhibition of fibrosis following surgery. The former is sustaining the release of a small-molecule lipophilic drug, while the latter focusses on sustained siRNA delivery.

Modeling of drug release from bulk-degrading polymers.

This paper aims to provide a comprehensive review of the various models or simulations for predicting drug release from bulk-degrading systems. A brief description of bulk degradation processes and factors affecting the degradation rate, and consequently the release kinetics, is presented first. Next, several important classical models, often used as the basis for subsequent model development, are discussed. Both mathematical models and Monte-Carlo based simulations have been developed for controlled release from bulk-degrading systems. The mathematical models can be further subdivided into two categories. First, the diffusion-based models whose transport mechanism is mainly governed by diffusion, but with degradation-dependent diffusion coefficients. These are generally simpler and easier to use and are sufficient to illustrate mono-phasic release. Second, comprehensive models that combine diffusion with other theories such as erosion, drug dissolution and/or pore percolations. These models usually involve more complex equations but provide good matches for multi-phasic release profiles.

Evolution of a constitutional dynamic library driven by self-organisation of a helically folded molecular strand.

Conversion of macrocyclic imine entities into helical strands was achieved through three- and four-component exchange reactions within constitutionally dynamic libraries. The generation of sequences of the intrinsic helicity codon, based on the hydrazone-pyrimidine fragment obtained by condensation of pyrimidine dialdehyde A with pyrimidine bis-hydrazine B, shifted the equilibrium between all the possible macrocycles and strands towards the full expression (>98%) of helical product [A/B]. Furthermore, it was shown that chain folding accelerated the dynamic exchange reactions among the library members. Lastly, in four-component experiments (involving A, B, E and either C or D), even though the macrocyclic entities ([A/C], [B/E]; [A/D], [B/E]) were the kinetically preferred products, over time dialdehyde A relinquished its initial diamine partners C or D to opt for bis-hydrazine B, which allowed the preferential formation of the helically folded strand. The present results indicate that self-organisation pressure was able to drive the dynamic system towards the selective generation of the strand undergoing helical folding.

A novel model and experimental analysis of hydrophilic and hydrophobic agent release from biodegradable polymers.

Many factors affect the rate of drug release from biodegradable polymers. Here, we focus on investigating the effect of drug type on the degradation of P(DL)LGA 53/47 films and their ultimate release profiles. A freely water-soluble drug (metoclopramide monohydrochloride) exhibited an initial burst, whereas a water-insoluble drug (paclitaxel) exhibited an initial latent period with very little drug release. The onset of the second-stage release of the hydrophobic drug was delayed as compared with the hydrophilic drug. Overall, complete release of metoclopramide monohydrochloride was achieved much earlier than paclitaxel. In addition, the hydrophobic drug exhibited an extra stage of release when compared with the two-stage release for the hydrophilic drug. A novel model was developed to describe the underlying drug release mechanisms and kinetics. The model postulated that the total fraction of drug release from bulk-degrading polymer is a summation of three mechanisms: burst release, relaxation induced/drug-dissolution controlled release, and diffusional release. All the three steps are important for hydrophobic drugs. However, for hydrophilic drugs, burst and diffusional release steps are sufficient to account for the whole release process. The proposed model showed very good match with the experimental data.

Adjustable paclitaxel release kinetics and its efficacy to inhibit smooth muscle cells proliferation.

Despite the success of drug-eluting stents in the field of interventional cardiology, very little work has been reported on the role of drug (paclitaxel) release kinetics on smooth muscle cell proliferation. This paper demonstrates how paclitaxel release from degradable polymers was successfully tailored from fast release rate to moderate and slow by changing the matrix composition. Cell counting and proliferation assays were employed to investigate the efficacy of each type of release kinetics in preventing human coronary artery smooth muscle cells proliferation. The fast release kinetics presented excellent inhibition immediately but may affect the re-endothelialization process. In this study, the moderate release kinetics appeared to be the best choice to prevent cell proliferation with consequently less effect on re-endothelialization. The slow release kinetics showed little inhibition in the early days but may be beneficial in the long term as a result of its sustained release.

Modeling of drug release from biodegradable polymer blends.

Numerous mathematical models that predict drug release from degradable systems have been reported. Most of these models cater only to single step, diffusion-controlled release while a few attempt to describe bi-phasic release. All these models, however, are only applicable to drug release from single (unblended) degradable polymer systems. In this paper, we propose and test novel models for drug (notably paclitaxel) release from films made of neat poly (epsilon-caprolactone) PCL, neat poly (dl-lactide-co-glycolide) PLGA and their blends. The model developed for neat PCL consists of two terms: initial burst and diffusional release. On the other hand, a more complex model proposed for tri-phasic release from neat PLGA consists of burst release, degradative (relaxation-induced) drug dissolution release and diffusional release. Finally, this very first model to predict release from blend of PLGA and PCL was developed based on a heuristic approach. Drug distribution between PCL-rich and PLGA-rich phases is dictated by partition coefficient, and the overall fraction of drug release is a summation of drug released from the two phases. The proposed models exhibited good prediction of the experimental data.

Paclitaxel release from single and double-layered poly(DL-lactide-co-glycolide)/poly(L-lactide) film for biodegradable coronary stent application.

Our laboratory has been developing a completely biodegradable coronary stent which is made of bilayers of biodegradable polyesters. This article presents the preliminary work done to exploit the drug delivery potential of such a polymeric stent. An antiproliferative drug (paclitaxel) was added either only to the top layer or to both layers and the in vitro release profiles were monitored for up to 90 days. Within 90 days, the measured paclitaxel release was almost entirely from the P(DL)LGA layer. In general, the release profiles show three distinct stages: (a) extremely slow diffusional release, (b) accelerated diffusion-degradation release, and (c) saturation. Separate degradation studies (water absorption, molecular weight reduction, weight loss, and surface topography) were also conducted to better understand the observed release behavior.