The ability to control chemical functionality is an exciting feature of modern polymer science that enables precise design of drug delivery systems. Ring-opening polymerization of functional monomers has emerged as a versatile method to prepare clinically translatable degradable polyesters.1 A variety of functional groups have been introduced into lactones; however, the direct polymerization of tertiary amine functionalized cyclic esters has remained elusive. We report a strategy that enabled the rapid synthesis of >130 lipocationic polyesters directly from functional monomers without protecting groups. These polymers are highly effective for siRNA delivery at low doses in vitro and in vivo.

Conventional chemotherapeutics nonselectively kill all rapidly dividing cells, which produces numerous side effects. To address this challenge, we report the discovery of functional polyesters that are capable of delivering siRNA drugs selectively to lung cancer cells and not to normal lung cells. Selective polyplex nanoparticles (NPs) were identified by high-throughput library screening on a unique pair of matched cancer/normal cell lines obtained from a single patient. Selective NPs promoted rapid endocytosis into HCC4017 cancer cells, but were arrested at the membrane of HBEC30-KT normal cells during the initial transfection period. When injected into tumor xenografts in mice, cancer-selective NPs were retained in tumors for over 1 wk, whereas nonselective NPs were cleared within hours. This translated to improved siRNA-mediated cancer cell apoptosis and significant suppression of tumor growth. Selective NPs were also able to mediate gene silencing in xenograft and orthotopic tumors via i.v. injection or aerosol inhalation, respectively. Importantly, this work highlights that different cells respond differentially to the same drug carrier, an important factor that should be considered in the design and evaluation of all NP carriers. Because no targeting ligands are required, these functional polyester NPs provide an exciting alternative approach for selective drug delivery to tumor cells that may improve efficacy and reduce adverse side effects of cancer therapies.

Dysregulated pH has been recognized as a universal tumor microenvironment signature that can delineate tumors from normal tissues. Existing fluorescent probes that activate in response to pH are hindered by either fast clearance (in the case of small molecules) or high liver background emission (in the case of large particles). There remains a need to design water-soluble, long circulating, pH-responsive nanoprobes with high tumor-to-liver contrast. Herein, we report a modular chemical strategy to create acidic pH-sensitive and water-soluble fluorescent probes for high in vivo tumor detection and minimal liver activation. A combination of a modified Knoevenagel reaction and PEGylation yielded a series of NIR BODIPY fluorophores with tunable pKas, high quantum yield, and optimal orbital energies to enable photoinduced electron transfer (PeT) activation in response to pH. After intravenous administration, Probe 5c localized to tumors and provided excellent tumor-to-liver contrast (apparent T/L = 3) because it minimally activates in the liver. This phenomenon was further confirmed by direct ex vivo imaging experiments on harvested organs. Because no targeting ligands were required, we believe that this report introduces a versatile strategy to directly synthesize soluble probes with broad potential utility including fluorescence-based image-guided surgery, cancer diagnosis, and theranostic nanomedicine.

We report a bioinspired upconversion (UC) system using a cellulose template, in which an aggregated platinum(II)-tetraphenylporphyrin (PtTPP) sensitizer is able to excite Rhodamine B as an emitter, enabling near-infrared (NIR)-to-orange wavelength conversions. The comodified cellulose was observed to undergo J aggregation of PtTPP in DMSO solution, as indicated by broad, weak absorption bands in the NIR region of the absorption spectrum. Excitation of these NIR J aggregation peaks of PtTPP led to efficient UC emission in the orange wavelength region. These materials were shown to exhibit UC properties in biological settings both in vitro and in vivo, demonstrating utility of UC for tumor imaging.

Donor-acceptor semiconducting polymers containing benzodithiophene with decyl phenylethynyl substituents have been synthesized. Density functional calculations on the polymers' band gaps and frontier orbitals energies provide reasonable agreement with cyclic voltammetry, photoelectron spectroscopy, and UV-vis absorption measurements. V C 2011