Stimuli-responsive,
on-demand release of drugs from drug-eluting
depots could transform the treatment of many local diseases, providing
intricate control over local dosing. However, conventional on-demand
drug release approaches rely on locally implanted drug depots, which
become spent over time and cannot be refilled or reused without invasive
procedures. New strategies to noninvasively refill drug-eluting depots
followed by on-demand release could transform clinical therapy. Here
we report an on-demand drug delivery paradigm that combines bioorthogonal
click chemistry to locally enrich protodrugs at a prelabeled site
and light-triggered drug release at the target tissue. This approach
begins with introduction of the targetable depot through local injection
of chemically reactive azide groups that anchor to the extracellular
matrix. The anchored azide groups then capture blood-circulating protodrugs
through bioorthogonal click chemistry. After local capture and retention,
active drugs can be released through external light irradiation. In
this report, a photoresponsive protodrug was constructed consisting
of the chemotherapeutic doxorubicin (Dox), conjugated to dibenzocyclooctyne
(DBCO) through a photocleavable ortho-nitrobenzyl linker. The protodrug
exhibited excellent on-demand light-triggered Dox release properties
and light-mediated in vitro cytotoxicity in U87 glioblastoma
cell lines. Furthermore, in a live animal setting, azide depots formed
in mice through intradermal injection of activated azide-NHS esters.
After i.v. administration, the protodrug was captured by the azide
depots with intricate local specificity, which could be increased
with multiple refills. Finally, doxorubicin could be released from
the depot upon light irradiation. Multiple rounds of depot refilling
and light-mediated release of active drug were accomplished, indicating
that this system has the potential for multiple rounds of treatment.
Taken together, these in vitro and in vivo proof of concept studies establish a novel method for in
vivo targeting and on-demand delivery of cytotoxic drugs
at target tissues.
Developing the next generation of cellular therapies will depend on fast, versatile, and efficient cellular reprogramming. Novel biomaterials will play a central role in this process by providing scaffolding and...
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