Prodrug Activation Gated by a Molecular “OR” Logic Trigger

Amir, Roey J.; Popkov, Mikhail; Lerner, Richard A.; Barbas, Carlos F.; Shabat, Doron

doi:10.1002/anie.200500842

Cited by 143 publications

(79 citation statements)

References 18 publications

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“…To date, the triggers have included pH, catalytic antibody, and an amidase-in each case, the action of the stimulus serves to expose the nucleophile, which instantly causes the vector to self-destruct. [36,39] Most recently, the combination of these strategies has been used to generate a molecular OR logic gate, [40] wherein a drug-release readout can be generated by the action of either the catalytic antibody 38C2 or penicillin G amidase. Assays using the dualtriggered polymer-doxorubicin conjugates in leukemia cell lines resulted in dose-dependent growth inhibition and com- plete suppression of growth between 10-100 nM pro-drug concentration.…”

Section: Responsive Polymers In Drug Deliverymentioning

confidence: 99%

Responsive Polymers at the Biology/Materials Science Interface

2006

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Synthetic polymers can be prepared with features that combine many of the advantageous properties of natural materials, including environmental response. This Research News article considers the different types of response that can be ‘programmed in' to polymers and the applications that are developing as a consequence of the designed responses. In particular, we focus on two key applications at the biology/materials science interface: responsive drug delivery systems and ‘smart' surfaces for cell culture and regenerative medicine.

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Section: Responsive Polymers In Drug Deliverymentioning

confidence: 99%

Responsive Polymers at the Biology/Materials Science Interface

2006

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“…through a molecular "OR" logic trigger (a dual-input trigger activated by either one of two different enzymes). [14] Results and Discussion Molecular design of the dendritic system: To construct a dendritic architecture with signal-conducting activity similar to that of a neuron, we used a multitriggered self-immolative dendron [13] as a receiver and linked it through a short spacer to a single-triggered self-immolative dendron [3] that acts as an amplifier. In this design (shown schematically in Figure 2), a signal is received through activation of either of the triggers.…”

Section: Introductionmentioning

confidence: 99%

Receiver–Amplifier, Self‐Immolative Dendritic Device

Amir

Danieli

Shabat

2007

Chemistry A European J

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Self-immolative dendrimers disassemble through a domino-like chain fragmentation initiated by a single cleavage at the dendrimer core. We have designed and synthesized dendritic molecules that resemble dendritic architectures present in nature. The unique design allows a cleavage signal received by any one of the multiple triggers on one side of the dendrimer to be transferred convergently to a focal point. The signal is divergently amplified through to the other side of the dendrimer, reporter units are released, and fluorescence is emitted. During signal propagation, the dendritic molecule disassembles in a self-immolative manner into small fragments. These compounds are the longest dendritic system ever reported to disassemble through sequential self-immolative reactions. The synthesized dendritic molecules have an architecture and signal-conducting activity related to that of neurons.

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“…However, in recent years, there have been important advances toward finding practicality in molecular logic gates, such as, identification tags for small objects, 6 molecular keypad lock, 7 laboratory on molecule, 8 and pro-drug activation. 9 RNA-based logic devices were also shown to be promising in vitro, yielding fluorescent proteins, 10 or potentially important DNA antisense drug sequences as outputs. 11 In this Communication, we will put forward the idea that in essence, a comparison between the silicon-based digital electronics and "chemical" logic gates is mostly unfair, chemical logic systems are inherently more capable than they are given credit for, and the potential of the chemical logic gates is yet largely untapped.…”

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confidence: 99%

Thinking Outside the Silicon Box: Molecular AND Logic As an Additional Layer of Selectivity in Singlet Oxygen Generation for Photodynamic Therapy

2008

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Following a highly influential paper by de Silva, 1 there have been many reported examples of individual molecular logic gates, 2 and molecular equivalents of even more complex digital designs were presented in recent years, such as half adder, 3 half-subtractor 4 and multiplexer. 5 Nevertheless, the unresolved issues of individual addressability and input-output heterogeneity remain to be important handicaps, making molecular logic gates very difficult to integrate for the implementation of more advanced digital operations. However, in recent years, there have been important advances toward finding practicality in molecular logic gates, such as, identification tags for small objects, 6 molecular keypad lock, 7 laboratory on molecule, 8 and pro-drug activation. 9 RNA-based logic devices were also shown to be promising in vitro, yielding fluorescent proteins, 10 or potentially important DNA antisense drug sequences as outputs. 11 In this Communication, we will put forward the idea that in essence, a comparison between the silicon-based digital electronics and "chemical" logic gates is mostly unfair, chemical logic systems are inherently more capable than they are given credit for, and the potential of the chemical logic gates is yet largely untapped. The chemical logic gates and the biomolecules in living systems, including ourselves, speak the same language. It may be challenging to integrate two molecular logic gates; however, they can be easily integrated into the control processes of healthy or pathological biochemistry.Photodynamic therapy is a noninvasive methodology used for the treatment malignant tumors and age related macular degeneration. The treatment requires a combined application of red to near IR light and a sensitizer. The cytotoxic agent thus produced within the target region is singlet oxygen.A few years ago, O'Shea published 12 a report, where it was shown that singlet oxygen generation rate could be modulated by pH. This effect is directly related to PET efficiency; excited-state molecules can relax through a number of different pathways including two competing processes, intersystem crossing and photoinduced electron transfer. Blocking of PET process by protonation of the amine PET donor, shuts down one channel of deactivation, and thus enhances intersystem crossing efficiency and the rate of singlet oxygen generation.Recent works by Nagano 13 and us 14 have demonstrated that appropriately decorated bodipy 15 dyes can be very efficient generators for singlet oxygen, and thus act as satisfactory photodynamic agents. As a bonus, the dyes synthesized in our laboratory absorbed very strongly at 660 nm which is considered to be well within the therapeutic window of mammalian tissue. We are aware of the fact that PET process can be manipulated by a large variety of modulators other than pH: cations, anions, carbohydrates, phosphates, among others. 16 So, combining our earlier experience in molecular logic gates and rational design of photodynamic agents, we proposed a photodynamic therapy agent t...

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Prodrug Activation Gated by a Molecular “OR” Logic Trigger

Cited by 143 publications

References 18 publications

Responsive Polymers at the Biology/Materials Science Interface

Responsive Polymers at the Biology/Materials Science Interface

Receiver–Amplifier, Self‐Immolative Dendritic Device

Thinking Outside the Silicon Box: Molecular AND Logic As an Additional Layer of Selectivity in Singlet Oxygen Generation for Photodynamic Therapy

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