Leveraging intracellular ALDH1A1 activity for selective cancer stem-like cell labeling and targeted treatment via in vivo click reaction
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Published on: March 31, 2023
Yang Bo1, Jingyi Zhou1, Kaimin Cai1,2
1Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
Abstract:
Inhibition of overexpressed enzymes is among the most promising approaches for targeted cancer treatment. However, many cancer-expressed enzymes are "nonlethal," in that the inhibition of the enzymes' activity is insufficient to kill cancer cells. Conventional antibody-based therapeutics can mediate efficient treatment by targeting extracellular nonlethal targets but can hardly target intracellular enzymes. Herein, we report a cancer targeting and treatment strategy to utilize intracellular nonlethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound, AAMCHO [N-(3,4,6-triacetyl- N-azidoacetylmannosamine)-cis-2-ethyl-3-formylacrylamideglycoside], selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1. Notably, azide labeling is more efficient in identifying tumorigenic cell populations than endogenous markers such as CD44. A dibenzocyclooctyne (DBCO)-toxin conjugate, DBCO-MMAE (Monomethylauristatin E), could next target the labeled CSCs in vivo via bioorthogonal Click reaction to achieve excellent anticancer efficacy against a series of tumor models, including orthotopic xenograft, drug-resistant tumor, and lung metastasis with low toxicity. A 5/7 complete remission was observed after single-cycle treatment of an advanced triple-negative breast cancer xenograft (~500 mm3).
Insights
This study introduces a novel cancer treatment strategy targeting intracellular enzymes in cancer stem-like cells (CSCs). The approach uses selective labeling and Click chemistry for potent drug delivery, achieving significant tumor remission with low toxicity.
Area of Science:
- Biochemistry
- Oncology
- Drug Delivery
Background:
- Targeted cancer therapy often focuses on inhibiting overexpressed enzymes, but many are "nonlethal," requiring alternative strategies.
- Conventional antibody therapeutics struggle to target intracellular enzymes, limiting treatment options for certain cancers.
- Intracellular nonlethal enzymes present a therapeutic target if effective delivery mechanisms can be developed.
Purpose of the Study:
- To develop a novel cancer treatment strategy utilizing intracellular nonlethal enzymes.
- To enable targeted drug delivery to cancer stem-like cells (CSCs) using selective labeling and Click chemistry.
- To evaluate the efficacy and toxicity of this approach in various cancer models.
Main Methods:
- Designed a novel compound, AAMCHO, for selective labeling of cancer CSCs via aldehyde dehydrogenase 1A1 oxidation.
- Utilized bioorthogonal Click chemistry to link a toxin (DBCO-MMAE) to the labeled CSCs.
- Tested the therapeutic efficacy in orthotopic xenograft, drug-resistant, and lung metastasis tumor models.
Main Results:
- AAMCHO selectively labeled cancer CSCs in vitro and in vivo, outperforming CD44 as a marker.
- The Click chemistry-mediated drug delivery achieved excellent anticancer efficacy with low toxicity.
- Complete remission was observed in 5/7 advanced triple-negative breast cancer xenografts after a single treatment cycle.
Conclusions:
- The developed strategy effectively targets and treats cancer CSCs by leveraging intracellular enzymes.
- This approach offers a promising new avenue for cancer therapy, particularly for drug-resistant and metastatic cancers.
- The combination of selective labeling and Click chemistry-mediated drug delivery shows high therapeutic potential with minimal toxicity.
