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Published on: November 7, 2013
Kinetic parameters for small-molecule drug delivery by covalent cell surface targeting
1Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720, USA.
Biochimica Et Biophysica Acta
|December 26, 2001
Summary
Researchers explored using unnatural sugar N-levulinoylmannosamine (ManLev) to modify cell surfaces with ketones. This enables targeted small-molecule drug delivery, matching antibody delivery efficiency for potential new therapies.
Area of Science:
- Biochemistry
- Chemical Biology
- Drug Delivery
Background:
- Metabolic engineering allows unnatural precursors to be processed by cells.
- Cell surface glycoconjugates can be modified with unnatural sugars.
- Ketone groups offer unique reactivity for chemical conjugation.
Purpose of the Study:
- To evaluate cell surface ketones as targets for covalent small-molecule drug delivery.
- To quantify ketone group incorporation and reactivity on cell surfaces.
- To model and compare small-molecule delivery via ketones to antibody-based delivery.
Main Methods:
- Incubation of human cells with N-levulinoylmannosamine (ManLev).
- Quantification of cell surface ketone groups using mathematical modeling and experimental validation.
- Determination of rate constants for conjugate formation, hydrolysis, and disappearance.
- Assessment of covalent bond formation with cell surface ketones.
Main Results:
- N-levulinoyl sialic acid (SiaLev) is formed and incorporated into cell surface glycoconjugates.
- The number of cell surface ketones correlates with ManLev concentration.
- Chemoselective reactions can deliver comparable numbers of molecules to antibodies.
- Mathematical model validated experimental findings on cell surface ketone reactivity.
Conclusions:
- Cell surface ketones, generated metabolically, serve as effective targets for small-molecule drug delivery.
- This approach offers a metabolically controlled system for targeted drug delivery.
- The efficiency of small-molecule delivery via ketones rivals that of antibody-based methods.
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