Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting, insufficient tumor cell internalization/bioavailability, and side effects, we developed a unique tumor-targeted micellar drug-delivery platform. Using paclitaxel as a model therapeutic, a nanopreparation composed of a matrix metalloproteinase 2 (MMP2)-sensitive self-assembly PEG 2000-paclitaxel conjugate (as a prodrug and MMP 2-sensitive moiety), transactivating transcriptional activator peptide-PEG1000-phosphoethanolamine (PE) (a cell-penetrating enhancer), and PEG1000-PE (a nanocarrier building block) was prepared. Several major drug delivery strategies, including self-assembly, PEGylation, the enhanced permeability and retention effect, stimulus sensitivity, a cell-penetrating moiety, and the concept of prodrug, were used in design of this nanoparticle in a collaborative manner. The nanopreparation allowed superior cell internalization, cytotoxicity, tumor targeting, and antitumor efficacy in vitro and in vivo over its nonsensitive counterpart, free paclitaxel and conventional micelles. This uniquely engineered nanoparticle has potential for effective intracellular delivery of drug into cancer cells.
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PMID:Enhanced anticancer activity of nanopreparation containing an MMP2-sensitive PEG-drug conjugate and cell-penetrating moiety. 2406 40

In this study, we described an "all-in-one" polymer-lipid conjugate (PEG2k-ppTAT-PEG1k-PE) that could self-assemble to matrix metalloproteinase 2 (MMP2)-sensitive multifunctional micelles. The assembled micelles had several key features, including a protective long chain poly(ethylene glycol) (PEG2k) (the outer shell), an MMP2-sensitive peptide linker (pp) (the tumor-targeting middle layer), a trans-activating transcriptional activator (TAT) peptide (the cell-penetrating middle layer), and a stable PEG1k-PE micelle for drug loading (the inner core). In the absence of MMP2, the PEG2k-ppTAT-PEG1k-PE micelles were intact and showed low bioactivity due to the surface-anchored PEG2k, whereas in the presence of MMP2, the pp was cleaved, resulting in the PEG2k deshielding and exposure of the previously hidden TAT for enhanced intracellular drug delivery. Even if completely cleaved by MMP2, the remaining PEG1k-PE micelles were stable and the micelles' particle size and drug release were not significantly influenced. The paclitaxel (PTX)-loaded PEG2k-ppTAT-PEG1k-PE micelles showed significant MMP2-dependent cellular uptake, tumor penetration, and anticancer activity in various cancer cells and three-dimensional multicellular spheroids. Because of the enhanced intracellular drug accumulation, these multifunctional micelles were able to sensitize the drug-resistant cancer cells and their spheroids to PTX treatments. Furthermore, in vivo tumor uptake and retention data indicated that the PEG2k-ppTAT-PEG1k-PE micelles could dramatically increase the residence time of their payloads in the tumor.
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PMID:Building Stable MMP2-Responsive Multifunctional Polymeric Micelles by an All-in-One Polymer-Lipid Conjugate for Tumor-Targeted Intracellular Drug Delivery. 2887 72