Modularly Engineered Solid‐Phase Synthesis of Aptamer‐Functionalized Small Molecule Drugs for Targeted Cancer Therapy

Abstract

Biomarker‐guided anticancer strategy has evolved into one of the most reliable and efficient cancer treatment techniques. However, most targeted anticancer molecular platforms are constructed in liquid phase with multi‐step synthesis and complex purification. This work describes a general and modular solid‐phase synthesis strategy to engineer novel targeted anticancer therapeutics based on aptamer‐functionalized small molecule drugs (ASMD). Specifically, anticancer agent Combretastatin A4 (CA4) is transformed into a phosphoramidite module, and then is incorporated into aptamer Sgc8c via automated DNA synthesis technique to obtain intracellular phosphatase‐responsive Sgc8c‐CA4 conjugate (SC). In the rational design, SC retains excellent recognition ability and cytotoxicity against its target colorectal cancer cells. SC shows more efficient and safer therapy than CA4 both in vitro and in vivo. Moreover, the cellular events of SC are systematically visualized when they encounter the target cancer cells. The visualizing mechanism gives a clear picture of the anticancer function of targeted therapeutics against cancer cells. These results may pave the way for utilizing molecularly engineered ASMDs to develop more novel targeted cancer therapeutics for the treatment of different cancer types.

Mapping the gaps in chemical analysis for the characterisation of aptamer-target interactions

“…In the last 25 years, the number of publications dealing with aptamers and their applications has increased exponentially as shown in Figure 1. Nowadays aptamers are largely applied in therapeutics [6,9], diagnostics [10], drug delivery [11,12] and in sensing devices as biorecognition elements [13][14][15]. There were also developments in the selection process for aptamers and multiple variations exist, such as FluMag SELEX [16] which is nowadays the most commonly used one, capture-SELEX [17] developed specifically for small molecules and graphene oxide SELEX [18] that does not require immobilization of aptamer, or target, in contrast to other SELEX approaches.…”

Hierarchical Fabrication of DNA Wireframe Nanoarchitectures for Efficient Cancer Imaging and Targeted Therapy

“…To obtain single-stranded CA4-FS, the CA4 phosphoramidite group was prepared (Figures S1−S5) and then was incorporated into an Sgc8c aptamer via an automated DNA synthesizer (Figure S6, Table S1). 28,29 Both label-free and Cy5-labeled CA4-FS were verified by mass spectra (Figures S7 and S8). CA4 was attached to this CA4-FS via a cellular phosphoesterase-responsive phosphodiester bond, allowing intracellular phosphoesterase-triggered (not pHdependent, Figure S9) drug release when CA4-FS internalizes into target cancer cells.…”

“…CA4 was attached to this CA4-FS via a cellular phosphoesterase-responsive phosphodiester bond, allowing intracellular phosphoesterase-triggered (not pHdependent, Figure S9) drug release when CA4-FS internalizes into target cancer cells. 29,30 We next constructed a DNA octahedron through a hierarchical self-assembly strategy. By programmable annealing, six DNA tiles of four-way junction were constructed as a vertex of DNA octahedra.…”

Targeted Delivery Methods for Anticancer Drugs

“…Besides the binding ability to the cellular target, the spacer also increases the hydrophilicity of the conjugate [281,283]. Antibodies [284,285]) and aptamers [286], peptides [287,288] and low molecular weight compounds [289,290] can act as a targeting ligand. Although SMDCs do not exhibit an EPR effect and, therefore, do not passively accumulate in solid tumors, they nevertheless passively perfuse the cancer mass more thoroughly and faster than nanoparticles [282].…”