In Vivo Activation of Duocarmycin–Antibody
Conjugates by Near-Infrared Light
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Posted on 2017-04-26 - 05:19
Near-IR photocaging groups based
on the heptamethine cyanine scaffold
present the opportunity to visualize and then treat diseased tissue
with potent bioactive molecules. Here we describe fundamental chemical
studies that enable biological validation of this approach. Guided
by rational design, including computational analysis, we characterize
the impact of structural alterations on the cyanine uncaging reaction.
A modest change to the ethylenediamine linker (N,N′-dimethyl to N,N′-diethyl) leads to a bathochromic shift in the absorbance
maxima, while decreasing background hydrolysis. Building on these
structure–function relationship studies, we prepare antibody
conjugates that uncage a derivative of duocarmycin, a potent cytotoxic
natural product. The optimal conjugate, CyEt-Pan-Duo, undergoes small
molecule release with 780 nm light, exhibits activity in the picomolar
range, and demonstrates excellent light-to-dark selectivity. Mouse
xenograft studies illustrate that the construct can be imaged in vivo prior to uncaging with an external laser source.
Significant reduction in tumor burden is observed following a single
dose of conjugate and near-IR light. These studies define key chemical
principles that enable the identification of cyanine-based photocages
with enhanced properties for in vivo drug delivery.
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Nani, Roger
R.; Gorka, Alexander P.; Nagaya, Tadanobu; Yamamoto, Tsuyoshi; Ivanic, Joseph; Kobayashi, Hisataka; et al. (2017). In Vivo Activation of Duocarmycin–Antibody
Conjugates by Near-Infrared Light. ACS Publications. Collection. https://doi.org/10.1021/acscentsci.7b00026
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AUTHORS (7)
RN
Roger
R. Nani
AG
Alexander P. Gorka
TN
Tadanobu Nagaya
TY
Tsuyoshi Yamamoto
JI
Joseph Ivanic
HK
Hisataka Kobayashi
MS
Martin J. Schnermann
KEYWORDS
laser sourcebioactive moleculesnear-IR lightethylenediamine linkercyanine-based photocagestumor burdenbathochromic shiftmouse xenograft studieschemical principlesVivo ActivationSignificant reductionabsorbance maximavivo drug deliverymolecule releaselight-to-dark selectivitychemical studiesheptamethine cyanine scaffoldpicomolar rangeexhibits activitycyanine uncaging reaction780 nm lightNear-Infrared Light Near-IR photocaging groupsbackground hydrolysisantibody conjugates