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Coordinating bioorthogonal reactions with two tumor-microenvironment-responsive nanovehicles for spatiotemporally controlled prodrug activation.

ABSTRACT: Precise activation of prodrugs in tumor tissues is critical to ensuring specific antitumor efficacy, meanwhile reducing the serious adverse effects. Here, a spatiotemporally controlled prodrug activation strategy was provided by integrating the inverse electron demand Diels-Alder (IEDDA) reaction with two tumor-microenvironment-responsive nanovehicles. The prodrug (Dox-TCO) and [4-(6-methyl-1,2,4,5-tetrazin-3-yl)phenyl]methanamine (Tz) were separately camouflaged into low pH and matrix metalloproteinase 2 (MMP-2) sensitive micellar nanoparticles. After systemic administration, only in the tumor tissues could both the nanovehicles dissociate via responding to two special tumor microenvironments, with Dox-TCO and Tz released and then immediately triggering the prodrug activation through the IEDDA reaction. The hierarchically regulated and locally confined Dox liberation led to dramatically decreased side-effects that were much lower than those of the clinical Doxorubicin Hydrochloride Liposomal Injection (Doxil), while the antitumor therapeutic effect was potent.

SUBMITTER: Zuo L

PROVIDER: S-EPMC8150104 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Coordinating bioorthogonal reactions with two tumor-microenvironment-responsive nanovehicles for spatiotemporally controlled prodrug activation.

Zuo Liping L Ding Jingjing J Li Changkun C Lin Feng F Chen Peng R PR Wang Peilin P Lu Guihong G Zhang Jinfeng J Huang Li-Li LL Xie Hai-Yan HY

Chemical science 20200113 8

Precise activation of prodrugs in tumor tissues is critical to ensuring specific antitumor efficacy, meanwhile reducing the serious adverse effects. Here, a spatiotemporally controlled prodrug activation strategy was provided by integrating the inverse electron demand Diels-Alder (IEDDA) reaction with two tumor-microenvironment-responsive nanovehicles. The prodrug (Dox-TCO) and [4-(6-methyl-1,2,4,5-tetrazin-3-yl)phenyl]methanamine (Tz) were separately camouflaged into low pH and matrix metallopr ...[more]

PMID: 34123305

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Project description:Non-toxic prodrugs have proved of great value in medicinal chemistry programmes for cancer, due to their ability to selectively deliver toxic components at tumour sites once they are activated by a localised mechanism. Since activation of the prodrug to afford the toxic drug is a prerequisite for success of the approach, much interest has focused on the localised chemical and enzymatic mechanisms for activating the prodrugs. Bioorthogonal chemistry has positively impacted this area by providing biocompatible reactions that enable on-demand prodrug activation and active drug release. However, to be effective, it is essential that one of the components of the bioorthogonal reaction is localised at the tumour, in order to initiate the on-demand and on-target activation of the prodrug. Polymers such as poly(ethylene glycol) (PEG) are known to target solid tumours by passive targeting via the enhanced permeability and retention (EPR) effect. In this paper, the feasibility of derivatising long PEG chains to afford bioorthogonal activators (PEG-azide and PEG-tetrazine) for prodrug activation via the Staudinger ligation and the tetrazine ligation reactions, respectively, is evaluated. The molecular weight of the PEG in the activator and the type of linkage in the prodrug moiety were shown to significantly affect the rate of prodrug activation and hence the rate of drug release. In vitro cytotoxicity studies on breast cancer cells (MCF-7 and MDA-MB-231) showed ∼68-76% restoration of the parent drug's cytotoxicity for the Staudinger ligation-based prodrug activation strategy, and 100% restoration of the parent drug's cytotoxicity for the tetrazine ligation-based prodrug activation strategy. Restoration of doxorubicin's ability to intercalate with DNA upon activation of the prodrug by the PEG-activators was also demonstrated via fluorescence spectroscopy. Moreover, conjugation of the tetrazine bioorthogonal activator to a 10 kDa PEG polymer improved its serum stability in comparison with other reported tetrazine activators that completely lose their stability in serum over the same period of time. The feasibility of the combined passive targeting/bioorthogonal prodrug activation approach has therefore been demonstrated using a range of prodrugs, activation mechanisms, and in vitro assays.

Project description:Click chemistry has proved a valuable tool in biocompatible hydrogel formation for 3D cell culture, owing to its bioorthogonal nature and high efficiency under physiological conditions. While traditional click reactions can be readily employed to create uniform functional materials about living cells, their spontaneity prohibits spatiotemporal control of material properties, thereby limiting their utility in recapitulating the dynamic heterogeneity characteristic of the in vivo microenvironment. Photopolymerization-based techniques gain this desired level of 4D programmability, but often at the expense of introducing propagating free radicals that are prone to non-specific reactions with biological systems. Here we present a strategy for bioorthogonal hydrogel formation and modification that does not rely on propagating free radicals, proceeding through oxime ligation moderated by a photocaged alkoxyamine. Upon mild near UV light exposure, the photocage is cleaved, liberating the alkoxyamine and permitting localized condensation with an aldehyde. Multi-arm crosslinkers, functionalized with either benzaldehydes or photocaged alkoxyamines, formed oxime-based hydrogels within minutes of light exposure in the presence of live cells. Polymerization rates and final mechanical properties of these gels could be systematically tuned by varying crosslinker concentrations, light intensity, aniline catalyst equivalents, and pH. Moreover, hydrogel geometry and final mechanical properties were controlled by the location and extent of UV exposure, respectively. Photomediated oxime ligation was then translated to the biochemical modification of hydrogels, where full-length proteins containing photocaged alkoxyamines were immobilized in user-defined regions exposed to UV light. The programmability afforded by photomediated oxime ligation can recapitulate dynamically anisotropic mechanical and biochemical aspects of the native extracellular matrix. Consequently, photopolymerized oxime-based hydrogels are expected to enable an enhanced understanding of cell-matrix interactions by serving as improved 4D cell culture platforms.

Dataset Information

Coordinating bioorthogonal reactions with two tumor-microenvironment-responsive nanovehicles for spatiotemporally controlled prodrug activation.

Publications

Coordinating bioorthogonal reactions with two tumor-microenvironment-responsive nanovehicles for spatiotemporally controlled prodrug activation.

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