Robust polymer colloidal crystal photonic bandgap structures

New polymeric matrices are presented that embed organic colloidal crystalline arrays (CCA's) into mechanically stable photonic bandgap structures. We achieved these new matrices either by dispersing polystyrene CCA's with high molecular weight hydrophilic polymer [poly(ethylene glycol); (PEG)] or through in situ polymerization of hydrophilic monomers (acrylamide and acrylate functional PEG variants) about the CCA. CCA-dispersed PEG matrices exhibited strong red opalescence with a narrow peak at 614 nm and were sufficiently rigid to withstand repeated mechanical deformation. Visible photonic bandgaps also were observed from free-standing CCA composites with cross-linked poly(N, N-dimethylacrylamide) matrices. The results demonstrate the technological potential for robust organic photonic crystals

Discovery of a novel cabazitaxel nanoparticle-drug conjugate (CRLX522) with improved pharmacokinetic properties and anticancer effects using a β-cyclodextrin-PEG copolymer based delivery platform

Novel nanoparticle-drug conjugates (NDCs) containing diverse, clinically relevant anticancer drug payloads (docetaxel, cabazitaxel, and gemcitabine) were successfully generated and tested in drug discovery studies. The NDCs utilized structurally varied linkers that attached the drug payloads to a β-cyclodextrin-PEG copolymer to form self-assembled nanoparticles. In vitro release studies revealed a diversity of release rates driven by linker structure-activity relationships (SARs). Improved in vivo pharmacokinetics (PK) for the cabazitaxel (CBTX) NDCs with glycinate-containing (1c) and hexanoate-containing linkers (2c) were demonstrated, along with high and sustained tumor levels (>168 h of released drug in tumor tissues). This led to potent efficacy and survival in both taxane- and docetaxel-resistant in vivo anticancer mouse efficacy models. Overall, the CBTX-hexanoate NDC 2c (CRLX522), demonstrated optimal and improved in vivo PK (plasma and tumor) and efficacy profile versus those of the parent drug, and the results support the potential therapeutic use of CRLX522 as a new anticancer agent

Tumor Selective Silencing Using an RNAi-Conjugated Polymeric Nanopharmaceutical

Small interfering RNA (siRNA) therapeutics have potential advantages over traditional small molecule drugs such as high specificity and the ability to inhibit otherwise “undruggable” targets. However, siRNAs have short plasma half-lives <i>in vivo</i>, can induce a cytokine response, and show poor cellular uptake. Formulating siRNA into nanoparticles offers two advantages: enhanced siRNA stability against nuclease degradation beyond what chemical modification alone can provide; and improved site-specific delivery that takes advantage of the enhanced permeability and retention (EPR) effect. Existing delivery systems generally suffer from poor delivery to tumors. Here we describe the formation and biological activity of polymeric nanopharmaceuticals (PNPs) based on biocompatible and biodegradable poly­(lactic-<i>co</i>-glycolic acid) (PLGA) conjugated to siRNA via an intracellular cleavable disulfide linker (PLGA–siRNA). Additionally, these PNPs contain (1) PLGA conjugated to polyethylene glycol (PEG) for enhanced pharmacokinetics of the nanocarrier; (2) a cation for complexation of siRNA and charge compensation to avoid high negative zeta potential; and (3) neutral poly­(vinyl alcohol) (PVA) to stabilize the PNPs and support the PEG shell to prevent particle aggregation and protein adsorption. The biological data demonstrate that these PNPs achieve prolonged circulation, tumor accumulation that is uniform throughout the tumor, and prolonged tumor-specific knockdown. PNPs employed in this study had no effect on body weight, blood cell count, serum chemistry, or cytokine response at doses >10 times the effective dose. PNPs, therefore, constitute a promising solution for achieving durable siRNA delivery and gene silencing in tumors