Implantable biomaterial based on click chemistry for targeting small molecules

Oneto, José M. Mejía; Gupta, Munish C.; Leach, J. Kent; Lee, Mark; Sutcliffe, Julie L.

doi:10.1016/j.actbio.2014.08.019

Cited by 27 publications

(28 citation statements)

References 46 publications

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“…Efficient targeting by the two small molecules to their respective disease sites was observed (Figure 4). Although targeting of hydrogels has been previously demonstrated,10b herein we demonstrate gel homing within an animal model of ischemia. Additionally, we show repeated homing to the gel site over a period of one month and the ability to segregate two different molecules through the use of two orthogonal chemistry systems.…”

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confidence: 65%

In Vivo Targeting through Click Chemistry

et al. 2015

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Targeting small molecules to diseased tissues as therapy or diagnosis is a significant challenge in drug delivery. Drug‐eluting devices implanted during invasive surgery allow the controlled presentation of drugs at the disease site, but cannot be modified once the surgery is complete. We demonstrate that bioorthogonal click chemistry can be used to target circulating small molecules to hydrogels resident intramuscularly in diseased tissues. We also demonstrate that small molecules can be repeatedly targeted to the diseased area over the course of at least one month. Finally, two bioorthogonal reactions were used to segregate two small molecules injected as a mixture to two separate locations in a mouse disease model. These results demonstrate that click chemistry can be used for pharmacological drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug‐eluting vascular grafts and stents.

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confidence: 65%

In Vivo Targeting through Click Chemistry

et al. 2015

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“…Since our original description of the flow photoisomerization protocol, it has been employed by a number of groups for trans ‐cyclooctene synthesis with applications that include radiochemistry, cellular imaging, drug delivery and materials science . There have also been a number of modifications to the flow procedure that have been introduced.…”

Section: Figurementioning

confidence: 99%

Flow Photochemical Syntheses of trans‐Cyclooctenes and trans‐Cycloheptenes Driven by Metal Complexation

Pigga

Fox

2019

Israel Journal of Chemistry

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trans-Cyclooctenes and trans-cycloheptenes have long been the subject of physical organic study, but the broader application had been limited by synthetic accessibility. This account describes the development of a general, flow photochemical method for the preparative synthesis of trans-cycloalkene derivatives. Here, photoisomerization takes place in a closed-loop flow reactor where the reaction mixture is continuously cycled through Ag(I) on silicagel. Selective complexation of the trans-isomer by Ag(I) during flow drives an otherwise unfavorable isomeric ratio toward the transisomer. Analogous photoreactions under batch-conditions are low yielding, and flow chemistry is necessary in order to obtain trans-cycloalkenes in preparatively useful yields. The applications of the method to bioorthogonal chemistry and stereospecific transannulation chemistry are described.The unusual reactivity and well-defined chiral structure of trans-cycloalkenes has made them attractive targets for synthesis for nearly 70 years. [1][2][3] For example, trans-cyclooctene possesses planar chirality and displays a high barrier to racemization (E a = 35.6 kcal/mol), [4] and the most stable "crown" conformer has an alternating sequence of equatorial and axial hydrogens that is akin to chair cyclohexane. [5][6] The double bond of trans-cyclooctene is twisted severely in the crown conformation, [7] and as a consequence the HOMO of trans-cyclooctene is relatively high in energy. [8] trans-Cycloheptene also has a rigid structure with a distorted alkene. [7] The double bonds of medium-ring trans-alkenes are twisted. [7] trans-Cycloalkenes display unusual reactivity in HOMOalkene controlled cycloaddition reactions with dienes, [9] 1,3dipoles [8] and ketenes. [10] Strained trans-cycloalkenes also serve as ligands for transition metals. [11][12][13][14][15][16] This reactivity profile has made trans-cycloalkanes interesting targets for applications in synthesis and biology.The broadest applications of trans-cycloalkenes are in the field of bioorthogonal chemistry. The inverse-electron demand Diels-Alder reaction between tetrazines and strained alkenes has a rich history in physical organic and synthetic chemistry (Figure 1). [17][18][19] In 2008, three groups described the bioorthogonal reactions of tetrazines with strained alkenes. [20][21][22] The variant introduced by our group that used trans-cyclooctene is marked by exceptionally rapid kinetics, with rate constants that can exceed 10 6 M À 1 s À 1 in the fastest cases. [23][24] With the advances including the development of fluorogenic tetrazines [25] and reactions in live cells [26] and animals, [27] the tetrazine ligation has become a widely used tool for applications that span chemical biology, biomedical imaging, and materials science. [28][29][30][31][32][33][34][35][36][37] This account describes the development of general, flow photochemical methods for the preparative synthesis of transcycloalkene derivatives and enabled applications in synthesis and bioorthogonal chemistry. Selectiv...

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“…In 2014, we demonstrated the proof-of-concept and feasibility of the technology in an animal model. 2 In 2016, we showed the enhanced safety and sustained anti-tumor responses using this technology in a mouse fibrosarcoma model with a single tumor 3 . Here, we discuss the effects of SQ3370, the lead asset of the CAPAC Platform, in a dual-tumor mouse model.…”

Section: Introductionmentioning

confidence: 99%

“…The reaction between tetrazines and trans-cyclooctene (TCO) is one of the most efficient click reactions reported to date, with demonstrated utility in animal models systems. [2][3][4][5][6][7][8][9] Tetrazine and TCO react irreversibly and specifically in vivo with a high thermodynamic driving force, with minimal interaction with the surrounding biological mileu. 10,11 The CAPAC Platform uses a tetrazine-modified biopolymer injected at the tumor that can capture a systemically circulating TCO-modified protodrug TM , to precisely release the active drug at the tumor.…”

Section: Introductionmentioning

confidence: 99%

SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected & Non-injected Lesions

Srinivasan¹,

Yee²,

et al. 2020

Preprint

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While systemic immuno-oncology therapies have shown remarkable success, only a limited subset of patients benefit from them. Our Click Activated Protodrugs Against Cancer (CAPAC™) Platform is a click chemistry-based approach that activates cancer drugs at a specific tumor with minimal systemic toxicity. CAPAC Platform is agnostic to tumor characteristics that can vary across patients and hence applicable to several types of tumors. We describe the benefits of SQ3370 (lead candidate of CAPAC) to achieve systemic anti-tumor responses in mice bearing two tumors. SQ3370 consists of a biopolymer, injected in a single lesion, followed by systemic doses of an attenuated protodrug of doxorubicin (Dox). SQ3370 was well-tolerated at 5.9-times the maximum dose of conventional Dox, increased survival by 63% and induced a systemic anti- tumor response against injected and non-injected lesions. The sustained anti-tumor response also correlated with immune activation measured at both lesions. SQ3370 could potentially benefit patients with micro-metastatic lesions.

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Implantable biomaterial based on click chemistry for targeting small molecules

Cited by 27 publications

References 46 publications

In Vivo Targeting through Click Chemistry

In Vivo Targeting through Click Chemistry

Flow Photochemical Syntheses of trans‐Cyclooctenes and trans‐Cycloheptenes Driven by Metal Complexation

SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected & Non-injected Lesions

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