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Azide-modified cell surfaces are engineered biological targets created through the incorporation of azide (N3) functional groups into cell surface molecules, typically glycans or proteins. This modification is achieved via metabolic glycoengineering, where cells utilize synthetic azido-sugar precursors, or through the localized delivery of azide-labeled polymers [1][2]. These azide groups serve as unique, non-natural chemical handles that are biologically inert but highly reactive toward specific complementary functional groups, such as strained alkynes (e.g., DBCO), through bioorthogonal click chemistry [3]. In therapeutic applications like the Click Activated Protodrugs Against Cancer (CAPAC) platform, these modified surfaces act as a docking site to capture and activate systemically administered protodrugs specifically at the tumor site [4]. This mechanism allows for the localized release of potent cytotoxic agents, such as doxorubicin, thereby maximizing therapeutic efficacy while minimizing systemic side effects [5]. The approach is primarily being investigated in oncology to improve the therapeutic index of chemotherapy by decoupling drug activation from natural biological processes [4].
Bioorthogonal click chemistry (specifically Strain-Promoted Azide-Alkyne Cycloaddition or SPAAC)
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