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Self-assembly of four generations of RNA dendrimers for drug shielding with controllable layer-by-layer release.

ABSTRACT: Chemical dendrimers have been shown to be a promising drug delivery platform due to their advantageous properties such as monodispersity, multivalency and branched structure. Taking advantage of self-assembly and its intrinsic negative charge, we used RNA as the building block for dendrimer construction to eliminate complex synthesis procedures and cationic charge-related toxicity. Oligo ribonucleotides produced by solid phase chemical synthesis allow the large-scale manufacture of homologous RNA dendrimers. Employing concepts from RNA nanotechnology enabled the controllable production of dendrimers with generations from G₁, G₂, G₃, to G₄ with layer-by-layer release capability. The conjugation of functional groups into individual RNA strands and the incorporation of functionalized RNA strands into the dendrimers at different sites have been reported. Anticancer drugs loaded into RNA dendrimers showed comparable cancer cell inhibition effect to free drugs. Encapsulation of cell binding ligands and hydrophobic drugs within the dendrimer significantly reduced the efficiency of cell binding and protein binding respectively, demonstrating the shielding effect of RNA dendrimers. The results imply a potential application of RNA dendrimer for delivery, shielding and controlled release of hydrophobic drugs in vivo.

SUBMITTER: Li X

PROVIDER: S-EPMC7448292 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mesoporous silica nanoparticles (MSNs) are promising solid supports for controlled anticancer drug delivery. Herein, we report biocompatible layer-by-layer (LbL) coated MSNs (LbL-MSNs) that are designed and crafted to release encapsulated anticancer drugs, e.g., doxorubicin hydrochloride (DOX), by changing the pH or by adding competitive agents. The LbL coating process comprises bis-aminated poly(glycerol methacrylate)s (BA-PGOHMAs) and cucurbit[7]uril (CB[7]), where CB[7] serves as a molecular bridge holding two different bis-aminated polymeric layers together by means of host-guest interactions. This integrated nanosystem is tuned to respond under specific acidic conditions or by adding adamantaneamine hydrochloride (AH), attributed to the competitive binding of hydronium ions or AH to CB[7] with BA-PGOHMAs. These LbL-MSN hybrids possess excellent biostability, negligible premature drug leakage at pH 7.4, and exceptional stimuli-responsive drug release performance. The pore sizes of the MSNs and bis-aminated compounds (different carbon numbers) of BA-PGOHMAs have been optimized to provide effective integrated nanosystems for the loading and release of DOX. Significantly, the operating pH for the controlled release of DOX matches the acidifying endosomal compartments of HeLa cancer cells, suggesting that these hybrid nanosystems are good candidates for autonomous anticancer drug nanocarriers actuated by intracellular pH changes without any invasive external stimuli. The successful cellular uptake and release of cargo, e.g., propidium iodide (PI), in human breast cancer cell line MDA-231 from PI-loaded LbL-MSNs have been confirmed by confocal laser scanning microscopy (CLSM), while the cytotoxicities of DOX-loaded LbL-MSNs have been quantified by the Cell Counting Kit-8 (CCK-8) viability assay against HeLa cell lines and fibroblast L929 cell lines. The uptake of DOX-loaded LbL-MSNs by macrophages can be efficiently reduced by adding biocompatible hydrophilic poly(ethylene glycol) or CB[7] without destroying the capping. In vivo tumor-growth inhibition experiments with BALB/c nude mice demonstrated a highly efficient tumor-growth inhibition rate of DOX-loaded LbL-MSNs, suggesting that the novel type of LbL-MSN materials hold great potentials in anticancer drug delivery.

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Self-assembly of four generations of RNA dendrimers for drug shielding with controllable layer-by-layer release.

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