Carrier‐Free Delivery of Precise Drug–Chemogene Conjugates for Synergistic Treatment of Drug‐Resistant Cancer

Abstract

Combinatorial antitumor therapies using different combinations of drugs and genes are emerging as promising ways to overcome drug resistance, which is a major cause for the failure of cancer treatment. However, dramatic pharmacokinetic differences of drugs greatly impede their combined use in cancer therapy, raising the demand for drug delivery systems (DDSs) for tumor treatment. By employing fluorescent dithiomaleimide (DTM) as a linker, we conjugate two paclitaxel (PTX) molecules with a floxuridine (FdU)‐integrated antisense oligonucleotide (termed chemogene) to form a drug–chemogene conjugate. This PTX–chemogene conjugate can self‐assemble into a spherical nucleic acid (SNA)‐like micellular nanoparticle as a carrier‐free DDS, which knocks down the expression of P‐glycoprotein and subsequently releases FdU and PTX to exert a synergistic antitumor effect and greatly inhibit tumor growth.

Nanoarchitectures to Deliver Nucleic Acid Drugs to Disease Sites

“…Polymeric wires and spheres were prepared by self‐assembly of oligodeoxynucleotides bearing cytosine‐phosphate‐guanosine (CpG) unit which shows high immunostimulatory activity [63] . Nanogels were also fabricated [64] .…”

Chemistries and applications of DNA-natural product conjugate

“…For example, P-glycoprotein or multidrug resistance protein (MDR1) overexpressed on cancer cells is one of the key issues affecting drug accumulation. To address this issue, Zhang and colleagues conjugated PTX onto a floxuridine (FdU)-integrated antisense oligonucleotide to develop synergistic chemo-gene therapy ( Zhu et al, 2020 ). They used fluorescent dithiomaleimde as a linker to form the conjugation, which further assembled into an SNA construct.…”

Enabling oligonucleotide-based therapeutics for non-liver disease targets

“…This "drug-integrated antisense" design allows for restoration of drug sensitivity in drug-resistant cancer cells by antisense gene More SNA-like More pacDNA-like regulation followed by chemotherapeutics release triggered by the nuclease degradation, resulting in the chronological and synergistic therapeutic effects. 128 With considerable developments around the SNA nanostructures, challenges remain for their application as a vector. A typical difficulty is that, even though the SNAs are taken up in large quantities by cells, they tend to be entrapped within the endo/lysosomal bodies following endocytosis, with only a fraction gaining access to the cytosol, hindering therapeutic efficacy.…”