A Camptothecin‐Grafted DNA Tetrahedron as a Precise Nanomedicine to Inhibit Tumor Growth

Abstract

Most chemotherapeutics are hydrophobic molecules and need to be converted into hydrophilic form before administration. Based on the excellent hydrophilicity and programmability of DNA, now, a general strategy to construct a precise drug‐containing DNA framework for cancer treatment is reported. In this novel drug delivery system, carbonethyl bromide‐modified camptothecin (CPT) is employed to directly react with phosphorothioate (PS) modified DNAs, resulting in the formation of chemotherapeutics‐grafted DNAs with a responsive disulfide linkage. By tuning the number and site of PS modifications on DNA strands, hydrophilicity of the obtained DNA‐drug conjugates (DDCs) can be regulated to retain their aqueous solubility and capability of molecular recognition. Subsequently, programmable DNA nanotechnology enables the self‐assembly of a precise drug‐containing tetrahedral framework with stimuli‐responsive feature and enhanced antitumor efficacy both in vitro and in vivo.

Tetrahedral DNA nanostructures for effective treatment of cancer: advances and prospects

“…Mosaic modification means that functionalized molecules or groups are embedded in the double helix structure of TDN by conjugation, such as SYBR Green I [ 25 ] and other dyes [ 24 ] for fluorescent labelling, or anticancer drugs [ 23 , 31 – 33 , 42 ], and etc. DOX inhibits tumor growth by inserting DNA double strands to interfere with macromolecular biosynthesis [ 65 ].…”

“…Meanwhile, experiments in vitro and in vivo showed that ANG-TDN could effectively cross the blood–brain barrier and precisely target U87MG human glioblastoma xenograft in nude mice. It had also been reported that siRNA or chemotherapy drugs can be loaded to TDN by cantilever modification [ 28 , 33 ], and that exchanging the hydrogen bonds of branched DNA structures for covalent bonds can further enhance TDN stability.…”

“…Therefore, multiple strategies were proposed for linking chemical compounds to DNA nanostructures with disulfide bonds. Zhang et al [ 33 ] reacted phosphorothioate-modified DNA with carbonyl bromide-modified camptothecin (CPT) to form disulfide bonds (Fig. 3 B).…”

“…The nanostructure could block EGFR signal transduction and exhibited excellent selectivity for cells with elevated EGFR expression, which exhibited significant anti-tumor activity without obvious systemic toxicity. In addition, drugs such as 5-fluorouracil, camptothecin and paclitaxel are loaded on TDN in different modified ways to achieve effective treatment of tumors [ 31 , 33 , 34 ]. The above-mentioned multifunctional DDS provides a new approach for tumor targeted chemotherapy and provides practical guidelines for enhancing reproducibility and reliability for the combined delivery of other functional components such as proteins.…”

Redox-sensitive lipophilic prodrugs: delivering unstable chemotherapeutant for improved cancer therapy

“…Such carboxylate CPT is mainly cleared by the kidneys and causes hemorrhagic cystitis and myelotoxicity, which caused the suspension of the clinical trials (Thomas et al., 2004). To address these challenges, strategies to overcome the aqueous insolubility and poor chemical instability of unmodified CPT remain a research hotspot in the recent scientific literatures (Alibolandi et al., 2017; Tian et al., 2017; Zhan et al., 2017; Li et al., 2018a; Dong et al., 2019; Zhang et al., 2019).…”