Synthesis and Evaluation of a Dipeptide–Drug Conjugate Library As Substrates for PEPT1

The oligopeptide transporter PEPT1 is considered as a valuable target for prodrug design, but its 3D structure and substrate specificity of PEPT1 are not fully understood. In this study, we designed a focused dipeptide conjugated azidothymidine (AZT) library and described a convenient and efficient solid phase synthesis scheme based on click chemistry. Over 60 candidate structures containing various dipeptide sequences were obtained with high purity, and screened in a PEPT1 overexpressing cell model for their abilities to compete with the known ligand cephalexin. Some of the compounds selected to have medium or high affinity were tested for their in vivo transport in a single-pass intestinal perfusion experiment. Results showed that the designed library contained some new structure features that have high affinities toward PEPT1 and could be further explored for their application in prodrug design and development

Characteristics of the studies included in this meta-analysis.

<p>WHO: World Health Organization; ADA: America Diabetes Association; NDDG: National Diabetes Data Group; NCEP-ATP III: National Cholesterol Education Program Adult Treatment Panel; IDF: International Diabetes Federation.</p

Hepatic Carcinoma Selective Nucleic Acid Nanovector Assembled by Endogenous Molecules Based on Modular Strategy

We rationally formulated a nucleic acid nanovector platform utilizing endogenous molecules in the following steps: nucleic acids are initially packed by a multifunctional peptide and a cationic liposome to form positively charged ternary complexes through electrostatic interaction; then the ternary complexes were coated with hyaluronic acid (HA) to form negatively charged quaternary nanocomplexes (Q-complexes). Among the components of Q-complexes, the multifunctional peptide was composed of a poly-16-arginine (R₁₆) and a hepatic tumor-targeted cell penetrating peptide (KRPT­MRFR­YTWN­PMK); the cationic lipid component included DOTAP and fusogenic lipid DOPE; the HA component shielded the cationic ternary complexes and actively targeted the CD44 overexpressed on the surface of tumor cells. Q-complexes have showed a relatively high stability in the medium, and HA component partially separated from the nanocomplexes after the Q-complexes bound to the cancer cells. The Q-complexes showed significantly enhanced nucleic acid delivery activity than the corresponding quaternary complexes containing R₁₆ and nonvisible cytotoxicity in SCMM-7721 cells. <i>In vivo</i>, a selected Q-complex HLP₁R specifically targeted and entered tumor cells without affecting normal tissues. Furthermore, HLP₁R wrapped survivin siRNA efficiently and silenced the targeting gene in the liver orthotropic transplantation tumor models and showed nontoxic <i>in vivo</i>. This study reveals that Q-complexes are reasonable and feasible gene therapeutic carriers