Highly Bioactive SDF-1α Delivery from Low-Melting-Point, Biodegradable Polymer Microspheres.

Aliphatic polyester biodegradable microspheres have been extensively studied for controlled and minimally invasive in situ protein delivery. However, they are commonly characterized by protein denaturation via acidic polyester degradation products, whereas their supraphysiologic modulus contributes to the inflammatory response upon implantation. To address these limitations, low-melting-point poly(ε-caprolactone-co-glycolide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-glycolide) (PEG-(PCG)2) copolymers were prepared and characterized for their ability to release bioactive stromal-derived factor-1α (SDF-1α) as a representative therapeutic protein. The PEG molecular weight was chosen such that it would be crystalline at room temperature to promote easy handling of the microspheres, whereas the molecular weight and composition of the hydrophobic PCG blocks were adjusted to ensure the polymer was a viscous amorphous liquid at 37 °C. Microspheres prepared from the triblock copolymers completely degraded within 8 weeks in vitro with a minor decrease in microenvironmental pH. A prolonged release of SDF-1α was observed with its bioactivity highly retained after encapsulation and release.

Bioinspired Nanoparticulate Medical Glues for Minimally Invasive Tissue Repair.

Delivery of tissue glues through small-bore needles or trocars is critical for sealing holes, affixing medical devices, or attaching tissues together during minimally invasive surgeries. Inspired by the granule-packaged glue delivery system of sandcastle worms, a nanoparticulate formulation of a viscous hydrophobic light-activated adhesive based on poly(glycerol sebacate)-acrylate is developed. Negatively charged alginate is used to stabilize the nanoparticulate surface to significantly reduce its viscosity and to maximize injectability through small-bore needles. The nanoparticulate glues can be concentrated to ≈30 w/v% dispersions in water that remain localized following injection. With the trigger of a positively charged polymer (e.g., protamine), the nanoparticulate glues can quickly assemble into a viscous glue that exhibits rheological, mechanical, and adhesive properties resembling the native poly(glycerol sebacate)-acrylate based glues. This platform should be useful to enable the delivery of viscous glues to augment or replace sutures and staples during minimally invasive procedures.

Docetaxel conjugate nanoparticles that target α-smooth muscle actin-expressing stromal cells suppress breast cancer metastasis.

Docetaxel-conjugate nanoparticles, known as Cellax, were synthesized by covalently conjugating docetaxel and polyethylene glycol to acetylated carboxymethylcellulose via ester linkages, yielding a polymeric conjugate that self-assembled into 120 nm particles suitable for intravenous administration. In 4T1 and MDA-MB-231 orthotopic breast tumor models, Cellax therapy reduced α-smooth muscle actin (α-SMA) content by 82% and 70%, respectively, whereas native docetaxel and nab-paclitaxel (albumin-paclitaxel nanoparticle, Abraxane) exerted no significant antistromal activity. In Cellax-treated mice, tumor perfusion was increased by approximately 70-fold (FITC-lectin binding), tumor vascular permeability was enhanced by more than 30% (dynamic contrast-enhanced magnetic resonance imaging), tumor matrix was decreased by 2.5-fold (immunohistochemistry), and tumor interstitial fluid pressure was suppressed by approximately 3-fold after Cellax therapy compared with the control, native docetaxel, and nab-paclitaxel groups. The antistromal effect of Cellax treatment corresponded to a significantly enhanced antimetastatic effect: lung nodules were reduced by 7- to 24-fold by Cellax treatment, whereas native docetaxel and nab-paclitaxel treatments were ineffective. Studies of the 4T1 tumor showed that more than 85% of the Cellax nanoparticles were delivered to the α-SMA+ stroma. Significant tumor stromal depletion occurred within 16 hours (∼50% depletion) postinjection, and the α-SMA+ stroma population was almost undetectable (∼3%) by 1 week. The 4T1 tumor epithelial cell population was not significantly reduced in the week after Cellax injection. These data suggest that Cellax targets tumor stroma and performs more efficaciously than docetaxel and nab-paclitaxel.