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Abstract
<p class="first" id="d4231590e134">Deep penetration of nanomedicines to cancer cells
and tissues is a main obstacle to
conquering multidrug resistant (MDR) cancer. Here, we presented redox-responsive polyethyleneimine
(disulfide cross-linked PEI, PSP)/tetrahedral DNA (TDNs)/doxorubicin (DOX) nanocomplexes
(NCs), PSP/TDNs@DOX NCs, to accomplish tumor cell/tissue penetration for overcoming
MDR. The NCs can respond to glutathione and DNase I to disassociate and release DOX.
In vitro study revealed that the NCs (N/P = 30) with positive charge could be associated
to cell membranes and "dig holes" on them, evoking the membrane-breaking for enhanced
cellular internalization and bypassing endocytosis regardless of drug-resistant mechanism.
Transwell and 3D tumor models study established that NCs can efficiently depart from
cells through "holes leakage" and "infected" surrounding cells to penetrate into deep
tumor tissues. In vivo study showed that the PSP/TDNs@DOX NCs exhibited superior tumor
penetration and therapeutic efficiency in xenografted drug-resistant tumor mouse models
including human breast (MCF-7/R) and ovarian (SKOV3/R) cancer, which represent MDR
with characteristics of DOX efflux and impermeability, respectively.
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