Synthesis, Biological Evaluation, and in Vivo Imaging of the first Camptothecin–Fluorescein Conjugate

Abstract

The first synthesis and photophysical properties of a fluorecently labeled camptothecin derivative, namely, camptothecin-FI (CPT-FI), an antitumoral agent that targets topoisomerase I, are reported. The preparation of this fluorescent conjugate is based on a highly convergent and flexible approach which enables the rapid chemical modification of the AB ring system of this fragile pentacyclic alkaloid, aimed at introducing an anchoring point to graft the fluorophore. The selection of a fluorescein analogue as the reporter group has enabled us to get the first green-emitting CPT conjugate exhibiting valuable spectral properties and retaining biological properties of native CPT. Indeed, in biological models, i.e., glioma cell lines U87 and/or T98, the kinetics of cell endocytosis, as well as the efficacy of CPT-FI were compared to those of CPT. CPT-FI fluorescence was measured in the cytosolic compartment of T98 glioma cells from 5 min treatment and remained detectable until 48 h. As CPT, CPT-FI drastically inhibited glioma growth and cell cycle but exhibited a reduced affinity as compared to the native CPT. In vivo and ex vivo imaging studies of CPT-FI intratumoraly injected into a model of NIH-3T3 murine tumor xenografts in nude mice, showed accumulation around the injected site area, which is very promising to target tumors and follow biodistribution in vivo.

Systemic delivery of blood–brain barrier-targeted polymeric nanoparticles enhances delivery to brain tissue

“…Due to low overall uptake of NPs into the brain, NPs must have high drug loadings to be effective. CPT, which has been shown to be effective against glioma in vitro and in vivo (23, 53, 70, 71), was readily encapsulated in our PLA-HPG and PLA-HPG-Ad NPs; these particles exhibit sustained release and cytotoxicity in U87 cells (Figure 8A). In addition, in vivo retention was observed 24 h after a single IV dose (Figure 5C).…”

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

“…Theranostic prodrugs equipped with fluorophores as optical reporters have become attractive to monitor the drug delivery and release process since their fluorescence signals can be activated concomitantly with drug release. ,− It would be desirable to utilize near-infrared (NIR) fluorophores as the signaling subunit in prodrugs because NIR photons can deeply penetrate the skin and underlying tissue with minimal damage to the biological samples with low background interference. − To date, most of the fluorophores used for theranostic prodrugs, such as coumarin, 1,8-naphthalimide, , and xanthene, suffer from short wavelength emission. Therefore, the in vivo drug release performance could only be predicted indirectly via in vitro experiments.…”

A Glutathione (GSH)-Responsive Near-Infrared (NIR) Theranostic Prodrug for Cancer Therapy and Imaging

“…In theranostics, fluorophores are usually used as imaging reagents for monitoring the release of the drugs. However, fluorophores used for theranostic prodrugs, such as coumarin, BODIPY, 1,8-naphthalimide, and xanthene, , suffer from short wavelength emission that is not suitable for monitoring the drug release in vivo . Near-infrared (NIR) fluorophores with characteristics such as deep tissue penetration, minimal damage to the biological samples, and low background interference − are ideal candidate fluorophores for theranostics prodrug systems.…”