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    MMP-2-Sensitive HA End-Conjugated Poly(amidoamine) Dendrimers via Click Reaction To Enhance Drug Penetration into Solid Tumor. Han Min,Huang-Fu Ming-Yi,Guo Wang-Wei,Guo Ning-Ning,Chen JieJian,Liu Hui-Na,Xie Zhi-Qi,Lin Meng-Ting,Wei Qi-Chun,Gao Jian-Qing ACS applied materials & interfaces Currently, the limited penetration of nanoparticles remains a major challenge for antitumor nanomedicine to penetrate into the tumor tissues. Herein, we propose a size-shrinkable drug delivery system based on a polysaccharide-modified dendrimer with tumor microenvironment responsiveness for the first time to our knowledge, which was formed by conjugating the terminal glucose of hyaluronic acid (HA) to the superficial amidogen of poly(amidoamine) (PAMAM), using a matrix metalloproteinase-2 (MMP-2)-cleavable peptide (PLGLAG) via click reaction. These nanoparticles had an initial size of ∼200 nm, but once deposited in the presence of MMP-2, they experienced a dramatic and fast size change and dissociated into their dendrimer building blocks (∼10 nm in diameter) because of cleavage of PLGLAG. This rapid size-shrinking characteristic not only promoted nanoparticle extravasation and accumulation in tumors benefited from the enhanced permeability and retention effect but also achieved faster nanoparticle diffusion and penetration. We have further conducted comparative studies of MMP-2-sensitive macromolecules (HA-pep-PAMAM) and MMP-2-insensitive macromolecules (HA-PAMAM) synthesized with a similar particle size, surface charge, and chemical composition and evaluated in both monolayer cells and multicellular spheroids. The results confirmed that the enzyme-responsive size shrink is an implementable strategy to enhance drug penetration and to improve therapeutic efficacy. Meanwhile, macromolecule-based nanoparticles with size-variable characteristics not only promote drug penetration, but they can also be used as gene delivery systems, suggesting great potential as nano-delivery systems. 10.1021/acsami.7b10098
    Dual pH-sensitive and UCST-type thermosensitive dendrimers: phenylalanine-modified polyamidoamine dendrimers with carboxyl termini. RSC advances Dendrimers are unique polymers with well-defined structures, and are useful as functional unimolecular nanoparticles. Previous reports have shown that polyamidoamine (PAMAM) dendrimers modified with hydrophobic molecules, such as amino-terminal phenylalanine (Phe), are thermosensitive at high pH. In the present study, we designed carboxyl-terminal Phe-modified PAMAM dendrimers that are thermosensitive under acidic conditions. We reacted an amino-terminal PAMAM dendrimer with various acid anhydrides, such as succinic anhydride, cyclohexanedicarboxylic anhydride, and phthalic anhydride, prior to the reaction with Phe. Interestingly, the amino-terminal Phe-modified PAMAM dendrimers exhibited LCST (lower critical solution temperature)-type thermosensitivity at approximately pH 7, but the carboxyl-terminal Phe-modified dendrimers exhibited UCST (upper critical solution temperature)-type thermosensitivity in acidic solutions. Temperature sensitivity was dependent on both pH and the anhydride modifier. We were able to separate rose bengal (a model compound) from aqueous solutions of the carboxyl-terminal Phe-modified dendrimer at low pH. 10.1039/c8ra05381b
    siRNA nanocarriers based on methacrylic acid copolymers. Felber Arnaud E,Castagner Bastien,Elsabahy Mahmoud,Deleavey Glen F,Damha Masad J,Leroux Jean-Christophe Journal of controlled release : official journal of the Controlled Release Society Poly(ethylene glycol)-b-poly(propyl methacrylate-co-methacrylic acid) (PEG-b-P(PrMA-co-MAA) can be complexed with poly(amido amine) (PAMAM) dendrimers and nucleic acids to form pH-responsive nanosized core-shell type polyion complex micelles (PICMs). These PICMs have the ability to lose their shell and release the PAMAM/nucleic acid core under mildly acidic conditions such as those encountered in the endosomal compartment. In this work, pH-sensitive PICMs composed of PEG-b-P(PrMA-co-MAA), different PAMAMs, and siRNAs were prepared and characterized. These micelles had mean diameters ranging from 50 to 100 nm depending on the structure of the polycationic component. In order to trigger PICM uptake by receptor-mediated endocytosis, the micelles were decorated with an antibody fragment directed against the transferrin receptor (anti-CD71). The targeting ligand was stably conjugated to a semi-telechelic amino-PEG-b-P(PrMA-co-MAA) via a maleimide/activated ester bifunctional linker, yielding up to 60%-80% functionalization of the maleimide groups. The cellular uptake of the micelles was assessed on human prostate cancer cells (PC-3) via flow cytometry. Native PICMs and micelles bearing a non-specific antibody fragment were taken up to the same extent with a low efficiency, whereas anti-CD71 Fab'-decorated PICMs exhibited significantly higher uptake. The capacity of the targeted, siRNA-loaded, PICMs to downregulate the expression of the Bcl-2 anti-apoptotic oncoprotein was investigated using the appropriate unmodified or 2'-modified (2'F-RNA and 2'F-ANA) siRNA sequence. Bcl-2 mRNA and protein levels were greatly reduced when the cells were transfected with anti-CD71 decorated PICMs. Optimal silencing was achieved with the chemically modified siRNA. These data suggest that combining optimized siRNA chemistry with an effective delivery system can potentiate the activity of siRNA, thereby potentially reducing the total dose of carrier required to achieve a pharmacological effect. 10.1016/j.jconrel.2010.12.012