Low-Fouling Fluoropolymers for Bioconjugation and In†Vivo Tracking.

The conjugation of hydrophilic low-fouling polymers to therapeutic molecules and particles is an effective approach to improving their aqueous stability, solubility, and pharmacokinetics. Recent concerns over the immunogenicity of poly(ethylene glycol) has highlighted the importance of identifying alternative low fouling polymers. Now, a new class of synthetic water-soluble homo-fluoropolymers are reported with a sulfoxide side-chain structure. The incorporation of fluorine enables direct imaging of the homopolymer by 19 F MRI, negating the need for additional synthetic steps to attach an imaging moiety. These self-reporting fluoropolymers show outstanding imaging sensitivity and remarkable hydrophilicity, and as such are a new class of low-fouling polymer for bioconjugation and in vivo tracking.

Sustained-release ketamine-loaded lipid-particulate system: in vivo assessment in mice.

Ketamine is used as an analgesic adjuvant in patients with chronic cancer-related pain. However, ketamine's short half-life requires frequent dose administration. Our aim was to develop a sustained release formulation of ketamine with high loading and to evaluate the in vivo pharmacokinetics and biodistribution in mice. Here, ketamine hydrochloride sustained-release lipid particles (KSL) were developed using the thin-film hydration method. The mean (± SD) encapsulation efficiency (EE) and drug loading (DL) of KSL were 65.6 (± 1.7)% and 72.4 (± 0.5)% respectively, and the mean (± SD) size of the lipid particles and the polydispersity index were 738 (± 137) nm and 0.44 (± 0.02) respectively. The release period of KSL in pH 7.4 medium was 100% complete within 8 h in vitro but a sustained-release profile was observed for more than 5 days after intravenous injection in mice. Importantly, the KSL formulation resulted in a 27-fold increase in terminal half-life, a threefold increase in systemic exposure (AUC0-∞), and a threefold decrease in clearance compared with the corresponding pharmacokinetics for intravenous ketamine itself. Our findings demonstrate high encapsulation efficiency of ketamine in the sustained-release KSL formulation with prolonged release in mice after systemic dose administration despite 100% in vitro release within 8 h that requires future investigation.

Sustained-release ketamine-loaded nanoparticles fabricated by sequential nanoprecipitation.

Ketamine in sub-anaesthetic doses is an analgesic adjuvant with a morphine-sparing effect. Co-administration of a strong opioid with an analgesic adjuvant such as ketamine is a potential treatment option, especially for patients with cancer-related pain. A limitation of ketamine is its short in vivo elimination half-life. Hence, our aim was to develop biocompatible and biodegradable ketamine-loaded poly(ethylene glycol) (PEG)-block-poly(lactic-co-glycolic acid) (PLGA) nanoparticles for sustained release. Ketamine-encapsulated single polymer PEG-PLGA nanoparticles and double polymer PEG-PLGA/shellac (SH) nanoparticles with a high drug loading of 41.8% (drug weight/the total weight of drug-loaded nanoparticles) were prepared using a new sequential nanoprecipitation method. These drug-loaded nanoparticles exhibited a sustained-release profile for up to 21 days in vitro and for more than 5 days after intravenous injection in mice. Our study demonstrates that high drug loading and a sustained release profile can be achieved with ketamine-loaded PEG-PLGA nanoparticles prepared using this new nanoprecipitation method.

Release of bioactive peptides from polyurethane films in vitro and in vivo: Effect of polymer composition.

UNLABELLED: Thermoplastic polyurethanes (TPUs) are widely used in biomedical applications due to their excellent biocompatibility. Their role as matrices for the delivery of small molecule therapeutics has been widely reported. However, very little is known about the release of bioactive peptides from this class of polymers. Here, we report the release of linear and cyclic peptides from TPUs with different hard and soft segments. Solvent casting of the TPU at room temperature mixed with the different peptides resulted in reproducible efflux profiles with no evidence of drug degradation. Peptide release was dependent on the size as well as the composition of the TPU. Tecoflex 80A (T80A) showed more extensive release than ElastEon 5-325, which correlated with a degree of hydration. It was also shown that the composition of the medium influenced the rate and extent of peptide efflux. Blending the different TPUs allowed for better control of peptide efflux, especially the initial burst effect. Peptide-loaded TPU prolonged the plasma levels of the anti-inflammatory cyclic peptide PMX53, which normally has a plasma half-life of less than 30min. Using a blend of T80A and E5-325, therapeutic plasma levels of PMX53 were observed up to 9days following a single intraperitoneal implantation of the drug-loaded film. PMX53 released from the blended TPUs significantly inhibited B16-F10 melanoma tumor growth in mice demonstrating its bioactivity in vivo. This study provides important findings for TPU-based therapeutic peptide delivery that could improve the pharmacological utility of peptides as therapeutics. STATEMENT OF SIGNIFICANCE: Therapeutic peptides can be highly specific and potent pharmacological agents, but are poorly absorbed and rapidly degraded in the body. This can be overcome by using a matrix that protects the peptide in vivo and promotes its slow release so that a therapeutic effect can be achieved over days or weeks. Thermoplastic polyurethanes are a versatile family of polymers that are biocompatible and used for medical implants. Here, the release of several peptides from a range of polyurethanes was shown to depend on the type of polymer used in the polyurethane. This is the first study to examine polyurethane blends for peptide delivery and shows that the rate and extent of peptide release can be fine-tuned using different hard and soft segment mixtures in the polymer.