Dataset Information

Dual-channel NIR activatable theranostic prodrug for in vivo spatiotemporal tracking thiol-triggered chemotherapy.

ABSTRACT: Real-time tracking for where (W), when (W), and how (H) prodrugs are delivered and activated in vivo is a great challenge for prodrug development. Disulfide linkage-based prodrugs as well as their delivery systems have been studied extensively, but the WWH question in spatial and temporal (spatiotemporal) precision remains unanswered. Herein, we present a novel prodrug of camptothecin (CPT) linked to a near-infrared (NIR) cyanine dye via a disulfide linkage (Cy-S-CPT). The cleavage of the disulfide bond in Cy-S-CPT by endogenous glutathione (GSH) can activate the anti-cancer drug CPT and induce a remarkable fluorescence shift from 825 to 650 nm, thereby providing dual fluorescent channels to real-time track the prodrug biodistribution and activation in vivo. Impressively, the dual-channel NIR fluorescence bioimaging exhibits the pervasive drug distribution, i.e., the biodistribution of the intact prodrug was traced at the 825 nm-NIR fluorescence channel, whereas the activated drug was tracked at the 650 nm red fluorescence channel. In this way, we can overcome the blind spot in the metabolism kinetics of prodrugs in a certain organ or tissue. As demonstrated, the prodrug prompts activation in all the organs, particularly in the liver after an intravenous injection, and achieves predominant accumulation and activation in tumors at 24 h post injection. Cy-S-CPT loaded in PEG-PLA nanoparticles display significantly improved therapeutic efficacy and low side effects with respect to the clinical used drug CPT-11. As a consequence, the NIR spatiotemporal bioimaging in vivo with dual fluorescence channels allows the prodrug release profile to be extracted precisely, particularly in visualizing drug-released information from complex biological systems such as mice, thereby providing a unique opportunity to take insight into the relationship between theranosis and pharmacokinetics.

SUBMITTER: Ye M

PROVIDER: S-EPMC6018301 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Dual-channel NIR activatable theranostic prodrug for in vivo spatiotemporal tracking thiol-triggered chemotherapy.

Ye Mingzhou M Wang Xiaohang X Tang Jianbin J Guo Zhiqian Z Shen Youqing Y Tian He H Zhu Wei-Hong WH

Chemical science 20160428 8

Real-time tracking for where (W), when (W), and how (H) prodrugs are delivered and activated in vivo is a great challenge for prodrug development. Disulfide linkage-based prodrugs as well as their delivery systems have been studied extensively, but the WWH question in spatial and temporal (spatiotemporal) precision remains unanswered. Herein, we present a novel prodrug of camptothecin (CPT) linked to a near-infrared (NIR) cyanine dye via a disulfide linkage (Cy-S-CPT). The cleavage ...[more]

PMID: 30155145

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Project description:Fluorescence image-guided surgery combined with intraoperative therapeutic modalities has great potential for intraoperative detection of oncologic targets and eradication of unresectable cancer residues. Therefore, we have developed an activatable theranostic nanoplatform that can be used concurrently for two purposes: (1) tumor delineation with real-time near infrared (NIR) fluorescence signal during surgery, and (2) intraoperative targeted treatment to further eliminate unresected disease sites by non-toxic phototherapy. Methods: The developed nanoplatform is based on a single agent, silicon naphthalocyanine (SiNc), encapsulated in biodegradable PEG-PCL (poly (ethylene glycol)-b-poly(ɛ-caprolactone)) nanoparticles. It is engineered to be non-fluorescent initially via dense SiNc packing within the nanoparticle's hydrophobic core, with NIR fluorescence activation after accumulation at the tumor site. The activatable nanoplatform was evaluated in vitro and in two different murine cancer models, including an ovarian intraperitoneal metastasis-mimicking model. Furthermore, fluorescence image-guided surgery mediated by this nanoplatform was performed on the employed animal models using a Fluobeam® 800 imaging system. Finally, the phototherapeutic efficacy of the developed nanoplatform was demonstrated in vivo. Results: Our in vitro data suggest that the intracellular environment of cancer cells is capable of compromising the integrity of self-assembled nanoparticles and thus causes disruption of the tight dye packing inside the hydrophobic cores and activation of the NIR fluorescence. Animal studies demonstrated accumulation of activatable nanoparticles at the tumor site following systemic administration, as well as release and fluorescence recovery of SiNc from the polymeric carrier. It was also validated that the developed nanoparticles are compatible with the intraoperative imaging system Fluobeam® 800, and nanoparticle-mediated image-guided surgery provides successful resection of cancer tumors. Finally, in vivo studies revealed that combinatorial phototherapy mediated by the nanoparticles could efficiently eradicate chemoresistant ovarian cancer tumors. Conclusion: The revealed properties of the activatable nanoplatform make it highly promising for further application in clinical image-guided surgery and combined phototherapy, facilitating a potential translation to clinical studies.

Project description:Hypoxia (pO2 ? ~1.5%) is an important characteristic of tumor microenvironments that directly correlates with resistance against first-line therapies and tumor proliferation/infiltration. The ability to accurately identify hypoxic tumor cells/tissue could afford tailored therapeutic regimens for personalized treatment, development of more-effective therapies, and discerning the mechanisms underlying disease progression. Fluorogenic constructs identifying aforesaid cells/tissue operate by targeting the bioreductive activity of primarily nitroreductases (NTRs), but collectively present photophysical and/or physicochemical shortcomings that could limit effectiveness. To overcome these limitations, we present the rational design, development, and evaluation of the first activatable ultracompact xanthene core-based molecular probe (NO 2 -Rosol) for selectively imaging NTR activity that affords an "OFF-ON" near-infrared (NIR) fluorescence response (> 700 nm) alongside a remarkable Stokes shift (> 150 nm) via NTR activity-facilitated modulation to its energetics whose resultant interplay discontinues an intramolecular d-PET fluorescence-quenching mechanism transpiring between directly-linked electronically-uncoupled ?-systems comprising its components. DFT calculations guided selection of a suitable fluorogenic scaffold and nitroaromatic moiety candidate that when adjoined could (i) afford such photophysical response upon bioreduction by upregulated NTR activity in hypoxic tumor cells/tissue and (ii) employ a retention mechanism strategy that capitalizes on an inherent physical property of the NIR fluorogenic scaffold for achieving signal amplification. NO 2 -Rosol demonstrated 705 nm NIR fluorescence emission and 157 nm Stokes shift, selectivity for NTR over relevant bioanalytes, and a 28-/12-fold fluorescence enhancement in solution and between cells cultured under different oxic conditions, respectively. In establishing feasibility for NO 2 -Rosol to provide favorable contrast levels in solutio/vitro, we anticipate NO 2 -Rosol doing so in preclinical studies.

Dataset Information

Dual-channel NIR activatable theranostic prodrug for in vivo spatiotemporal tracking thiol-triggered chemotherapy.

Publications

Dual-channel NIR activatable theranostic prodrug for <i>in vivo</i> spatiotemporal tracking thiol-triggered chemotherapy.

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