Additionally, this work was supported by Duke Cancer Institute (DCI) NCI Grant P30-CA014236 funding for the Duke Optical Molecular Imaging and Analysis Facility (in vivo imaging) and the Duke Light Microscopy Core Facility (confocal microscopy). Conflicts of Interest The authors declare no conflict of interest. Footnotes Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.. in size, aptamers are ideal for this type of drug targeting. Aptamer-highly toxic drug conjugates (ApTDCs) based on the E3 aptamer, selected on prostate cancer cells, target and inhibit prostate tumor growth in vivo. PDK1 inhibitor Here, we observe that E3 also broadly targets numerous other cancer types, apparently representing a universal aptamer for cancer targeting. Accordingly, ApTDCs formed by conjugation of E3 to the drugs monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF) efficiently target and kill a range of different cancer cells. Notably, this targeting extends to both patient-derived explant (PDX) cancer cell lines and tumors, with the E3 MMAE and MMAF conjugates inhibiting PDX cell growth in vitro and with the E3 aptamer targeting PDX colorectal tumors in vivo. = 3) or of control AF750-C36 (= 2) and imaged for PDK1 inhibitor NIR fluorescence. Shown are representative PDK1 inhibitor images from 48 h post-aptamer injection. 3. Discussion The clinical development of ADCs now represents one of the fastest-growing fields of cancer therapeutics (reviewed in [4,5]), with 5 ADCs gaining FDA approval since June of 2019 alone [6,7,8,9,10]. These therapeutics succeed by targeting and delivering highly toxic chemotherapy more directly to tumors, helping to prevent unwanted drug accumulation and toxicity in normal tissue. However, antibody development is an extensive process requiring not only antibody humanization but also difficult chemical conjugation, resulting in a heterogeneous drug product. Thus aptamers are emerging as ligands with an antibody-like affinity that can be used in place of antibodies to create targeted drug constructs. As aptamers are easily amenable to chemical synthesis and modification, they are chemical products and do not require Itgam the extensive optimization, such as humanization, that is required for biological drug products. Additionally, the small size of aptamers should aid in tumor penetration, a significant concern for ADCs, as studies have shown that less than 0.1% of an antibody is often even able to reach the tumor (reviewed in ). Only a few reports have appeared of aptamer conjugation to highly toxic agents, including two reports of aptamer conjugation to biological toxins ([33,34]). More recently, our labs as well as the Rossi lab, have demonstrated that aptamers can be conjugated to highly toxic chemotherapeutics to generate ApTDCs [12,13,14]. Only one of these ApTDCs, the E3 aptamer MMAF conjugate, has been tested in vivo . E3 was selected via positive-negative Cell-Internalization SELEX for internalization into prostate cancer and not normal prostate cells. ApTDCs formed by conjugating PDK1 inhibitor E3 to either MMAE or MMAF efficiently targeted and killed prostate cancer cells without affecting normal prostate cancer cells. Most significantly, AF750-E3 localized to prostate xenografts in mice and treatment with MMAF-E3 significantly inhibited prostate tumor growth and prolonged survival in mice. While E3 was selected for specificity to prostate cancer cells over normal prostate cells, we sought to determine whether E3 and E3 ApTDCs are solely selective for prostate cancer or whether they also target additional tumor types. Here, we demonstrate that PDK1 inhibitor the E3 aptamer targets across a broad range of human cancer types, showing an affinity for breast, pancreatic, lung, colorectal, cholangiocarcinoma, glioblastoma, neuroblastoma, leukemia, renal, and skin cancers. The E3 MMAE and MMAF drug conjugates also target and induce cell death across a range of these various cancer cell types. Most notably, E3 also targets.
Additionally, this work was supported by Duke Cancer Institute (DCI) NCI Grant P30-CA014236 funding for the Duke Optical Molecular Imaging and Analysis Facility (in vivo imaging) and the Duke Light Microscopy Core Facility (confocal microscopy)
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