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Novel CD123-aptamer-originated targeted drug trains for selectively delivering cytotoxic agent to tumor cells in acute myeloid leukemia theranostics.

ABSTRACT: Since conventional chemotherapy for acute myeloid leukemia (AML) has its limitations, a theranostic platform with targeted and efficient drug transport is in demand. In this study, we developed the first CD123 (AML tumor marker) aptamers and designed a novel CD123-aptamer-mediated targeted drug train (TDT) with effective, economical, biocompatible and high drug-loading capacity. These two CD123 aptamers (termed as ZW25 and CY30, respectively) can bind to a CD123 peptide epitope and CD123 + AML cells with high specificities and KD of 29.41 nM and 15.38 nM, respectively, while has minimal cross reactivities to albumin, IgG and trypsin. Further, TDT is self-assembled from two short primers by ligand-modified ZW25 that acted as initiation position for elongation, while intercalated by doxorubicin (Dox). TDT is capable of transporting high capacity of Dox to CD123 + cells and retains the efficacy of Dox, while significantly reducing drug uptake and eased toxicity to CD123- cells in vitro (p < .01). Moreover, TDT can ease Dox cytoxicity to normal tissues, prolong survivals and inhibit tumor growth of mouse xenograft tumor model in vivo. These suggest that CD123 aptamer and CD123 aptamer-mediated targeted drug delivery system may have potential applications for selective delivery cytotoxic agents to CD123-expressing tumors in AML theranostics.

SUBMITTER: Wu H

PROVIDER: S-EPMC8241133 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Insufficient penetration of therapeutic agents into tumor tissues results in inadequate drug distribution and lower intracellular concentration of drugs, leading to the increase of drug resistance and resultant failure of cancer treatment. Targeted drug delivery to solid tumors followed by complete drug penetration and durable retention will significantly improve clinical outcomes of cancer therapy. Monoclonal antibodies have been commonly used in clinic for cancer treatment, but their limitation of penetrating into tumor tissues still remains because of their large size. Aptamers, as "chemical antibodies", are 15-20 times smaller than antibodies. To explore whether aptamers are superior to antibodies in terms of tumor penetration, we carried out the first comprehensive study to compare the performance of an EpCAM aptamer with an EpCAM antibody in theranostic applications. Penetration and retention were studied in in vitro three-dimensional tumorspheres, in vivo live animal imaging and mouse colorectal cancer xenograft model. We found that the EpCAM aptamer can not only effectively penetrate into the tumorsphere cores but can also be retained by tumor sphere cells for at least 24 h, while limited tumor penetration by EpCAM antibody was observed after 4 h incubation. As observed from in vivo live animal imaging, EpCAM aptamers displayed a maximum tumor uptake at around 10 min followed by a rapid clearance after 80 min, while the signal of peak uptake and disappearance of antibody appeared at 3 h and 6 h after intravenous injection, respectively. The signal of PEGylated EpCAM aptamers in xenograft tumors was sustained for 26 h, which was 4.3-fold longer than that of the EpCAM antibody. Consistently, there were 1.67-fold and 6.6-fold higher accumulation of PEGylated aptamer in xenograft tumors than that of antibody, at 3 h and 24 h after intravenous administration, respectively. In addition, the aptamer achieved at least a 4-time better tumor penetration in xenograft tumors than that of the antibody at a 200 μm distances from the blood vessels 3 h after intravenous injection. Taken together, these data indicate that aptmers are superior to antibodies in cancer theranostics due to their better tumor penetration, more homogeneous distribution and longer retention in tumor sites. Thus, aptamers are promising agents for targeted tumor therapeutics and molecular imaging.

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Novel CD123-aptamer-originated targeted drug trains for selectively delivering cytotoxic agent to tumor cells in acute myeloid leukemia theranostics.

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