Inhibition of cell proliferation through an ATP-responsive co-delivery system of doxorubicin and Bcl-2 siRNA

Abstract

Herein, DNA duplex was constructed through the hybridization of adenosine triphosphate (ATP)-responsive aptamer and its cDNA in which GC-rich motif could be used to load doxorubicin (DOX), and then, cationic polymer PEI25K was used as a carrier to simultaneously condense DOX-Duplex and Bcl-2 siRNA to prepare the ternary nanocomplex polyethylenimine (PEI)/DOX-Duplex/siRNA. The ATP concentration gradient between the cytosol and extracellular environment could achieve the stable loading of DOX in duplex and the rapid drug release in an ATP-responsive manner. Using human prostate tumor cell line PC-3 as a model, an obvious induction of cell proliferation could be detected with a cell viability of 53.3%, which was stronger than single cargo delivery, indicating the synergistic effect between these two components. The enhanced anti-proliferative effect of ternary nanocomplex could be attributed to the improved induction of cell apoptosis in a mitochondria-mediated pathway and cell-cycle arrest at the G2 phase. Overall, the ATP-responsive nanocarrier for co-delivering DOX and Bcl-2 siRNA has been demonstrated to be a smart delivery system with favorable anti-proliferative effect, especially for solving the multidrug resistance of tumors.

Tumor microenvironment responsive drug delivery systems

“…Unique physical and chemical features of ATP aptamers include rich “GC” pairs and negatively charged surfaces, allowing multiple attachment of anticancer agents and cationic polymers. This provides new insight for development of co-delivery systems [135 , 136] . DOX and siRNA co-delivery system was reported.…”

“…ATP aptamers can bind with single strand nucleotides forming DNA duplex via complementary base pairing. The DNA duplex has been incorporated into various drug carriers, such as poly(ethylenimine) (PEI) [135 , 136] , MSNPs [137] , MOFs [138] , nanogel [139] , liposome [140] , nanosheet [141 , 142] , microcapsules [143] , [144] , [145] , and etc.…”

Virus‐inspired and mimetic designs in non‐viral gene delivery

“…To date, three categories have been employed to fabricate these delivery systems: (i) PBA moieties that can bind to diol‐containing molecules (i.e. ATP); (ii) single‐stranded DNA aptamers that specifically bind ATP; and (iii) enzymes that consume ATP as a source of energy . Among them, systems based on PBA that can form a reversible ester linkage with cis ‐diol molecule are mainly reported …”

<p>A chemoenzymatically synthesized cholesterol-g-poly(amine-co-ester)-mediated <em>p53</em> gene delivery for achieving antitumor efficacy in prostate cancer</p>

“…Besides the selection of therapeutic genes, the construction of gene carriers with high transfection efficiency and low cytotoxicity is another issue to be addressed in cancer gene therapy. 12,13 To date, cationic polymers such as poly(ethylenimine), polyamidoamine dendrimer, poly(Llysine), and their derivatives have been successfully applied in p53 gene delivery. [14][15][16][17][18][19][20][21] Apart from these cationic polymers, copolyester poly(amine-co-ester)s containing tertiary amino substituents have also been widely employed as gene vectors owing to their unique features such as high transfection efficiency, favorable biocompatibility and biodegradability, and ease of production.…”