Drug‐grafted DNA as a novel chemogene for targeted combinatorial cancer therapy

Abstract

Combinatorial therapy based on chemotherapeutic drugs and gene agents to achieve synergistic antitumor effects has emerged as a new direction for cancer treatment. However, simple and efficient co‐delivery of those two drug categories remains a key challenge in this hot area owing to their substantially different pharmacodynamics, impeding the translational potentials of combinatorial approaches. To address this issue, herein we propose a simple strategy to site‐specifically graft camptothecins (CPTs, a representative chemodrug) onto a DNA with dual functional segments, including an AS1411 aptamer sequence to target the cancer cell and a BCL‐2 antisense sequence to down‐regulate the anti‐apoptotic gene. The obtained DNA‐drug conjugate possesses precise chemical composition, controllable drug loading ratio, and responsive disulfide linkage, which can serve as a novel type of chemogene for combinatorial cancer therapy. In both in vitro and in vivo evaluations, our CPT‐bearing chemogene exhibit the targeted co‐delivery of chemo and gene agents to tumor site, efficient BCL‐2 gene knockdown, and strong induced apoptosis of cancer cells, together leading into an enhanced antitumor efficacy. With simple and precise structure as well as facile synthetic procedure, the new chemogene may turn into a promising drug formulation for combinatorial antitumor treatment.

Nanoarchitectures to Deliver Nucleic Acid Drugs to Disease Sites

“…"Aptamers" are often also categorized as a member of nucleic acid drugs, although these oligonucleotides directly bind to disease-causing proteins and modulate their functions for therapy. [43,44] Frequently, they are also employed as pilot molecules to deliver drugs to target disease sites, as described below in this account. [45][46][47][48][49] They are single-stranded DNA (or RNA), which bind a designated compound (or a part of large assembly) strongly and selectively as naturally occurring antibodies.…”

Recent Advances in Nanoparticle-Based Co-Delivery Systems for Cancer Therapy

“…Combining chemotherapeutic drugs with additional therapeutic genes, such as nucleic acids, is another promising option for a co-delivery system. This co-delivery system can also be referred to as gene therapy [ 40 , 95 , 128 , 138 ]. The latter is defined as releasing external normal genes into target cells to counterweigh faulty and aberrant genes.…”

An orthogonally activatable CRISPR-Cas13d nanoprodrug to reverse chemoresistance for enhanced chemo-photodynamic therapy

“…Also, increasing the drug uptake by prodrug strategies or combination with nanocarriers is also a promising option for overcoming MDR. [14][15][16] In particular, many efforts have been made towards the generation of combinatorial chemo-and gene-therapeutics from various gene regulation tools such as antisense oligonucleotides, 17,18 RNAi, 19,20 and CRISPR-Cas9, 8,9 leading to maximum synergistic activity for reversing chemoresistance. Inspired by these promising achievements, we therefore believe that combining a Cas13d gene editing system with chemotherapy would be an effective approach to treat drug-resistant cancers.…”