The ester bond as a universal linker has recently been applied in gene delivery systems owing to its efficient gene release by electrostatic repulsion after its cleavage. However, the ester bond is nonlabile and is difficult to cleave in cells. This work reports a method in which a secondary amine was introduced to the β-position of the ester bond to generate a hydrogen-bond cyclization (HBC) structure that can make the ester bond hydrolysis ultrafast. A series of molecules comprising ultrasensitive esters that can be activated by H2O2 were synthesized, and it was found that those able to form an HBC structure showed complete ester hydrolysis within 5 h in both water and phosphate-buffered saline solution, which was several times faster than other methods reported. Then, a series of amphiphilic poly(amidoamine) dendrimers were constructed, comprising the ultrasensitive ester groups for gene delivery; it was found that they could effectively release genes under quite a low concentration of H2O2 (<200 μm ) and transport them into the nucleus within 2 h in Hela cells with high safety. Their gene transfection efficiencies were higher than that of PEI25k. The results demonstrated that the hydrogen-bond-induced ultrasensitive esters could be powerfully applied to construct gene delivery systems. 相似文献
Molecular biology of mouse and chicken retroviruses had identified oncogenes and provided a revolutionary concept in understanding of cancers. A human retrovirus was established during 1980–1982 in linkage with a unique human leukemia, concurrently in Japan and USA. This review covers our efforts on the discovery of new retrovirus, Human T-cell Leukemia Virus Type 1 (HTLV-1), first introducing to a new class of retroviruses with a unique regulatory factors, Tax and Rex. Then it is followed by analyses of molecular interaction of the vial Tax with cellular machineries involved in the pathogenesis of Adult T-cell Leukemia (ATL). And then a probable mechanism of pathogenesis of ATL is proposed including recent findings on HBZ after our efforts. 相似文献
Human mesenchymal stem cells (MSCs) have emerged as attractive cellular vehicles
to deliver therapeutic genes for ex-vivo therapy of diverse diseases;
this is, in part, because they have the capability to migrate into tumor or
lesion sites. Previously, we showed that MSCs could be utilized to deliver a
bacterial cytosine deaminase (CD) suicide gene to brain tumors. Here we
assessed whether transduction with a retroviral vector encoding CD gene
altered the stem cell property of MSCs. MSCs were transduced at passage 1 and
cultivated up to passage 11. We found that proliferation and differentiation
potentials, chromosomal stability and surface antigenicity of MSCs were not
altered by retroviral transduction. The results indicate that retroviral vectors
can be safely utilized for delivery of suicide genes to MSCs for
ex-vivo therapy. We also found that a single retroviral
transduction was sufficient for sustainable expression up to passage 10. The
persistent expression of the transduced gene indicates that transduced MSCs
provide a tractable and manageable approach for potential use in allogeneic
transplantation. 相似文献
A series of nanoparticles is prepared via layer‐by‐layer assembly of oppositely charged, synthetic biocompatible polyamidoamine polymers as potential carriers. Particle size, surface charge and internal chain mobility are quantified as a function of the polymer type and number of layers. The effect of addition of surfactant is examined to simulate the effects of nanoparticle dissolution. The cyctotoxicity of these particles (in epithelia and murine cell lines) are orders of magnitude lower than polyethyleneimine controls. Stable nanoparticles may be prepared from mixtures of strongly, oppositely charged polymers, but less successfully from weakly charged polymers, and, given their acceptable toxicity characteristics, such modularly designed constructs show promise for drug and gene delivery.
A series of cholesterylated thiogalactosides L1–L6 the cell targeting ligands for gene delivery to hepatocytes, was synthesized. Related poly(ethylene glycol) chain was used as a bridge for the attachment of galactoside on one hydroxyl end, while the other hydroxyl end was linked with cholesterol. This design provided an effective entry for the synthesis of a poly(ethylene glycol) compound with the hepatocyte targeting. 相似文献
A hollow mesoporous silica nanoparticle (HMSNP) based drug/siRNA co‐delivery system was designed and fabricated, aiming at overcoming multidrug resistance (MDR) in cancer cells for targeted cancer therapy. The as‐prepared HMSNPs have perpendicular nanochannels connecting to the internal hollow cores, thereby facilitating drug loading and release. The extra volume of the hollow core enhances the drug loading capacity by two folds as compared with conventional mesoporous silica nanoparticles (MSNPs). Folic acid conjugated polyethyleneimine (PEI‐FA) was coated on the HMSNP surfaces under neutral conditions through electrostatic interactions between the partially charged amino groups of PEI‐FA and the phosphate groups on the HMSNP surfaces, blocking the mesopores and preventing the loaded drugs from leakage. Folic acid acts as the targeting ligand that enables the co‐delivery system to selectively bind with and enter into the target cancer cells. PEI‐FA‐coated HMSNPs show enhanced siRNA binding capability on account of electrostatic interactions between the amino groups of PEI‐FA and siRNA, as compared with that of MSNPs. The electrostatic interactions provide the feasibility of pH‐controlled release. In vitro pH‐responsive drug/siRNA co‐delivery experiments were conducted on HeLa cell lines with high folic acid receptor expression and MCF‐7 cell lines with low folic acid receptor expression for comparison, showing effective target delivery to the HeLa cells through folic acid receptor meditated cellular endocytosis. The pH‐responsive intracellular drug/siRNA release greatly minimizes the prerelease and possible side effects of the delivery system. By simultaneously delivering both doxorubicin (Dox) and siRNA against the Bcl‐2 protein into the HeLa cells, the expression of the anti‐apoptotic protein Bcl‐2 was successfully suppressed, leading to an enhanced therapeutic efficacy. Thus, the present multifunctional nanoparticles show promising potentials for controlled and targeted drug and gene co‐delivery in cancer treatment. 相似文献