In Vivo and in Situ Tracking Cancer Chemotherapy by Highly Photostable NIR Fluorescent Theranostic Prodrug

Abstract

In vivo monitoring of the biodistribution and activation of prodrugs is urgently required. Near infrared (NIR) fluorescence-active fluorophores with excellent photostability are preferable for tracking drug release in vivo. Herein, we describe a NIR prodrug DCM-S-CPT and its polyethylene glycol-polylactic acid (PEG-PLA) loaded nanoparticles as a potent cancer therapy. We have conjugated a dicyanomethylene-4H-pyran derivative as the NIR fluorophore with camptothecin (CPT) as the anticancer drug using a disulfide linker. In vitro experiments verify that the high intracellular glutathione (GSH) concentrations in tumor cells cause cleavage of the disulfide linker, resulting in concomitantly the active drug CPT release and significant NIR fluorescence turn-on with large Stokes shift (200 nm). The NIR fluorescence of DCM-S-CPT at 665 nm with fast response to GSH can act as a direct off-on signal reporter for the GSH-activatable prodrug. Particularly, DCM-S-CPT possesses much better photostability than ICG, which is highly desirable for in situ fluorescence-tracking of cancer chemotherapy. DCM-S-CPT has been successfully utilized for in vivo and in situ tracking of drug release and cancer therapeutic efficacy in living animals by NIR fluorescence. DCM-S-CPT exhibits excellent tumor-activatable performance when intravenously injected into tumor-bearing nude mice, as well as specific cancer therapy with few side effects. DCM-S-CPT loaded in PEG-PLA nanoparticles shows even higher antitumor activity than free CPT, and is also retained longer in the plasma. The tumor-targeting ability and the specific drug release in tumors make DCM-S-CPT as a promising prodrug, providing significant advances toward deeper understanding and exploration of theranostic drug-delivery systems.

Fluorescent chemical probes for accurate tumor diagnosis and targeting therapy

“…Zhu and Guo et al developed novel activatable theranostics (69a and 69b) based on the dicyanomethylene-4H-pyran NIR fluorophore for in vivo and in situ monitoring of drug delivery and cancer chemotherapy in living animals. 207 The biologically abundant thiols in tumor cells triggered cleavage of the View Article Online disulfide linker, leading to the release of camptothecin and emission of NIR fluorescence. These theranostics showed similar cytotoxicity with significant in vitro antitumor activity against several cell lines including BCap-37, HepG2, MCF-7, HeLa, KB, and KB200.…”

Review on near-infrared heptamethine cyanine dyes as theranostic agents for tumor imaging, targeting, and photodynamic therapy

“…For example, the NIR prodrug dicyanomethylene-disulfidecamptothecin and its derivative, PEG-polylactic acid, when loaded in nanoparticles, emitted NIRF signals. 107,108 These NIR-encapsulated nanoparticles showed higher antitumor activity and longer retention in the plasma than free camptothecin. 108 Additionally, the excellent fluorescence intensity and photostability of DCM chromophores with a large Stokes shift makes the in vivo and in situ tracking of drug release and therapeutic efficacy in live animals possible.…”

“…108 Additionally, the excellent fluorescence intensity and photostability of DCM chromophores with a large Stokes shift makes the in vivo and in situ tracking of drug release and therapeutic efficacy in live animals possible. 108 …”

“…110 Finally, crucial evaluations of pharmacokinetics, pharmacodynamics, and toxicity of dyes and dye-drug conjugates are also needed in mouse and dog models before this group of novel compounds can be moved into the clinic for improved cancer diagnosis, prognosis and therapy. 108 Taking into account the complexity of targeted drug development, the development of diagnostic NIRF agents for tumor imaging should give the priority to the selection conducted in preclinical experimental models, where both the PDX mouse model and dog spontaneous tumor model are obviously convenient tools for preclinical tests.…”

A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy

“…The reduced products were prepared by in situ reduction of the respective disulfides using TCEP and used immediately (using the same agent and a similar method to that reported by Baud et al 35 ). (C) Proposed mechanisms for the release of SAHA: the first is direct cleavage of the ester linkage to generate the parent drug by intracellular esterases; the second involves reduction of the disulfide linkage and intramolecular cyclization; (a similar reaction mechanism has been reported by Zhang et al 55 and Wu et al 56 ) the third is the reduction of the disulfide linkage, followed by cleavage of ester linkage. Abbreviations: compd, compound; DMsO, dimethyl sulphoxide; eq, equivalent; gsh, glutathione; PBs, phosphate-buffered saline; hDac, histone deacetylase; Ic 50 , half maximal inhibitory concentration; TceP, tris(2-carboxyethyl)phosphine hydrochloride; h, hours.…”