Transmembrane (TMEM)-176A and 176B proteins belong to the MS4A family of proteins whose function in the immune system remains unclear. TMEM176A transcripts were previously shown to be elevated in liver cancer or kidney tissue with proteinuria, while marked changes in TMEM176B transcripts have been found in tolerated tissue allografts and neoplastic fibroblasts. To study the functional relationship between human TMEM176A and 176B and their putative link to cancer, we used polymerase chain reaction and biochemical assays. Here, we show that TMEM176A and 176B are widely expressed in all human tissues examined. Co-immunoprecipitation of heterologously expressed TMEM176A and 176B revealed direct physical interaction. To determine the relevance of such interaction to cancer pathology, we analyzed biopsied tissue samples from a variety of normal and cancer tissues. Our data reveal that human TMEM176A and 176B protein levels are significantly elevated in lymphoma, but not in normal tissues. The protein levels of TMEM176A are also significantly increased in lung carcinoma. Finally, analysis of the protein expression ratio of TMEM176A over 176B showed significant differences between normal and cancer tissues of the breast, lymph, skin, and liver, which indicates that both TMEM proteins could be potential useful markers for certain human cancers.

In this report, a redox- and pH-sensitive poly­(β-amino ester)-grafted disulfide methylene oxide poly­(ethylene glycol) (PAE-g-DSMPEG) was synthesized, and it showed not only a sharp pH-dependent assembly–disassembly transition but also a quick shell shading in a high concentration of reducing agent by Michael addition polymerization. 1H NMR, dynamic light scattering, and transition electron microscopy were combined to characterize the redox- and pH-responsiveness in various triggered conditions. The hydrophobic drug doxorubicin (DOX) was used as the model drug to investigate the encapsulation and delivery ability of polymeric micelles, in both in vitro and in vivo experiments. Notably, antitumor experiments in tumor-bearing mice showed that DOX-loaded polymeric micelles effectively enhanced the therapeutic efficacy in comparison to free-DOX. These results were further confirmed by histopathological examinations. Taken together, the results suggested that PAE-g-DSMPEG could be a potential hydrophobic drug delivery vehicle.

In this work, pH-responsive polypeptide-based nanogels are reported as potential drug delivery systems. By the formation of pH-sensitive benzoic imine bonds, pH-responsive nanogels are constructed using hydrophilic methoxy poly(ethylene glycol)- b-poly[ N-[ N-(2-aminoethyl)-2-aminoethyl]-l-glutamate] (MPEG- b-PNLG) and hydrophobic terephthalaldehyde (TPA) as a cross-linker. At pH 7.4, MPEG- b-PNLG nanogels exhibit high stabilities with hydrophobic inner cores, which allow encapsulation of hydrophobic therapeutic agents. Under tumoral acidic environments (pH ∼6.4), the cleavage of benzoic imine bonds induces the destruction of MPEG- b-PNLG nanogels and leads to rapid release of their payloads. The formation and pH sensitivity of the nanogels are investigated by dynamic light scattering. These nanogels exhibit excellent stabilities in the presence of salt or against dilution. The globular morphologies of the nanogels are confirmed using transmission electron microscopy. Doxorubicin is used as a model drug to evaluate drug encapsulation and release. Finally, the anticancer activities of the drug-encapsulated nanogels are assessed in vitro.

No abstract

As an effective and safe strategy to overcome the limits of therapeutic nucleic acid or adenovirus (Ad) vectors for in vivo application, various technologies to modify the surface of vectors with nonimmunogenic/biocompatible polymers have been emerging in the field of gene therapy. However, the transfection efficacy of the polymer to transfer genetic materials is still relatively weak. To develop more advanced and effective polymers to deliver not only Ad vectors, but also nucleic acids, 6 biocompatible polymers were newly designed and synthesized to different sizes (2k, 3.4k, or 5k) of poly(ethylene) glycol (PEG) and different numbers of amine groups (2 or 5) based on methoxy poly(ethylene glycol)-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl]-l-glutamate (PNLG). We characterized size distribution and surface charge of 6 PNLGs after complexation with either nucleic acid or Ad. Among all 6 PNLGs, the 5 amine group PNLG showed the strongest efficacy in delivering nucleic acid as well as Ad vectors. Interestingly, cellular uptake results showed higher uptake ability in Ad complexed with 2 amine group PNLG than Ad/5 amine group PNLG, suggesting that the size of Ad/PNLGs is more essential than the surface charge for cellular uptake in polymers with charges greater than 30 mV. Moreover, the endosome escape ability of Ad/PNLGs increased depending on the number of amine groups, but decreased by PEG size. Cancer cell killing efficacy and immune response studies of oncolytic Ad/PNLGs showed 5 amine group PNLG to be a more effective and safe carrier for delivering Ad. Overall, these studies provide new insights into the functional mechanism of polymer-based approaches to either nucleic acid or Ad/nanocomplex. Furthermore, the identified ideal biocompatible PNLG polymer formulation (5 amine/2k PEG for nucleic acid, 5 amine/5k PEG for Ad) demonstrated high transduction efficiency as well as therapeutic value (efficacy and safety) and thus has strong potential for in vivo therapeutic use in the future.