Single‐Triggered Trimeric Prodrugs

Haba, Keren; Popkov, Mikhail; Shamis, Marina; Lerner, Richard A.; Barbas, Carlos F.; Shabat, Doron

doi:10.1002/anie.200461657

Cited by 156 publications

(123 citation statements)

References 14 publications

(11 reference statements)

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“…Earlier, several prodrugs of dox, 6, including prodoxs 7-8 ( Fig. 4A), were prepared and evaluated (6,7,21). On treatment with a catalytic amount of 38C2, all prodoxs were activated.…”

Section: Resultsmentioning

confidence: 99%

“…The excellent retro-aldolase activity (2, 3) of Abs 38C2 (4) and 93F3 (5) has allowed us to design, synthesize, and evaluate prodrugs of various chemotherapeutic agents that can be activated by retro-aldol reactions (6)(7)(8)(9)(10). In a syngeneic mouse model of neuroblastoma, systemic administration of an etoposide prodrug and intratumor injection of Ab 38C2 inhibited tumor growth (11).…”

mentioning

confidence: 99%

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Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation

Abraham

Guo

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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An obstacle in the utilization of catalytic Abs for selective prodrug activation in cancer therapy has been systemic tumor targeting. Here we report the generation of catalytic Abs that effectively target tumor cells with undiminished prodrug activation capability. Ab conjugates were prepared by covalent conjugation of an integrin ␣v␤3-targeting antagonist to catalytic Ab 38C2 through either sulfide groups of cysteine residues generated by reduction of the disulfide bridges in the hinge region or surface lysine residues not involved in the catalytic activity. Using flow cytometry, the Ab conjugates were shown to bind efficiently to integrin ␣v␤3-expressing human breast cancer cells. The Ab conjugates also retained the retro-aldol activity of their parental catalytic Ab 38C2, as measured by methodol and doxorubicin (dox) prodrug activation. Complementing these Ab conjugates, an evolved set of dox prodrugs was designed and synthesized. Dox prodrugs that showed higher stability and lower toxicity were evaluated both in the presence and absence of the integrin ␣v␤3-targeting 38C2 conjugates for cell-killing efficacy by using human breast cancer cells. Our study reveals that cell targeting and prodrug activation capabilities can be efficiently combined for selective chemotherapy with novel dox prodrugs.aldolase Ab ͉ Ab conjugate ͉ doxorubicin ͉ integrin ␣v␤3

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“…Earlier, several prodrugs of dox, 6, including prodoxs 7-8 ( Fig. 4A), were prepared and evaluated (6,7,21). On treatment with a catalytic amount of 38C2, all prodoxs were activated.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation

Abraham

Guo

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…9b,c,i From the above examples, it is clear that homoselenacalixarenes possess the intrinsic potential to complex metal cations. The binding potential of the novel macrocycles was initially evaluated using homoselenacalix [4] (22) as off-white solids in high yields (Scheme 5). ESI-MS analysis showed an intense peak at m/z 1184, which corresponds to the monomer of the [Ag-4] + ionic species in agreement with the existence of a 1 : 1 complex in solution.…”

Section: Metallosupramolecular Chemistrymentioning

confidence: 99%

Homoselenacalix[4]arenes: synthetic exploration and metallosupramolecular chemistry

et al. 2012

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Homoselenacalix [4]arenes were synthesized by a [2 + 2] reductive coupling protocol favouring the cyclotetramers. The inner and outer-rim decoration was varied and a bicyclic derivative was prepared by a similar one-pot procedure. Conformational analysis in solution and the solid state showed noticeable differences between the homoselenacalix[4]arenes and the analogous homothiacalix[4]arenes and provided insight into the metal binding potential of the Se-bridged macrocycles. The homoselenacalix[4]-arenes were found to bind Ag(I). Complexation was visualized in the solid state and different packing networks were formed depending on the counter ions applied.

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“…They facilitated the release of DOX or MTX from the dendrimers enzymatically degraded in tumor cells. In addition, Shabat et al demonstrated the synthesis of a trimeric pro-drug, which contains three anticancer drugs (such as DOX, etoposide, and camptothecin) linked to certain enzymatic substrates [91]. After the enzymatic degradation of substrates by the catalytic antibody 38C2 in human MOLT-3 leukemia cells, three anticancer drugs were simultaneously released.…”

Section: Enzyme-activating Systemsmentioning

confidence: 99%

Intelligent Polymeric Nanocarriers Responding to Physical or Biological Signals: A New Paradigm of Cytosolic Drug Delivery for Tumor Treatment

Lee

Baik

et al. 2010

Polymers

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Abstract:The physicochemical properties of stimuli-responsive polymers change with physical or biological signals, such as pH, enzyme concentrations, and temperature. These polymers have attracted considerable attention in the field of drug delivery. The drug carrier system, which was revolutionized by the introduction of these polymers, has recently provided a new paradigm of maximizing the therapeutic activity of drugs. This review highlights recent studies regarding stimuli-responsive drug carriers tailor-made for effective cytosolic drug delivery, with particular emphasis on tumor treatment.

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Single‐Triggered Trimeric Prodrugs

Cited by 156 publications

References 14 publications

Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation

Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation

Homoselenacalix[4]arenes: synthetic exploration and metallosupramolecular chemistry

Intelligent Polymeric Nanocarriers Responding to Physical or Biological Signals: A New Paradigm of Cytosolic Drug Delivery for Tumor Treatment

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