Localized In Vivo Activation of a Photoactivatable Doxorubicin Prodrug in Deep Tumor Tissue

Abstract

Sparing sensitive healthy tissue from chemotherapy exposure is a critical challenge in the treatment of cancer. The work described here demonstrates the localized in vivo photo-activation of a new chemotherapy prodrug of doxorubicin (DOX). The DOX prodrug (DOX-PCB) was 200 times less toxic to cells, but released pure DOX when exposed to 365 nm light delivered to the tumor tissue using a specialized fiber-optic LED system. This wavelength was chosen because it had good tissue penetration through a 1cm diameter tumor but had very low skin penetration, due to melanin absorption, preventing uncontrolled activation from outside sources. Pharmacokinetic studies showed DOX-PCB had an α circulation half-life of 10 min which is comparable to that of DOX at 20 min. DOX-PCB demonstrated resistance to metabolic cleavage ensuring that exposure to 365nm light was the main mode of in vivo activation. Tissue extractions from tumors exposed to 365 nm light in vivo showed the presence of DOX-PCB as well as activated DOX. The irradiated tumors had 6 times more DOX concentration than nearby control tumors. This in vivo proof of concept demonstrates the first preferential activation of a photocleavable prodrug in deep tumor tissue.

Chronic activation of the D156A point mutant of Channelrhodopsin-2 signals apoptotic cell death: the good and the bad

“…When one of the tumors in either flank reached ~5 mm in diameter, the 11-day treatment regime was immediately and individually started to guarantee a similar efficacy of illumination, as the light intensity is attenuated by tumor depth. 22, 23 ChR2(D156A) expression was induced in tumors of the ‘treated' and Ctrl Dox groups by replacing food pellets with doxycycline (200 mg/kg) containing pellets. Pulsed (1 s on - 10 s off) blue light illumination for 12 h per day over the 11-day treatment period was achieved by placing the cages of the ‘treated' and Ctrl Light groups into a custom-made LED-lining (Figure 6a).…”

“…Precise light delivery methods have been developed for photodynamic cancer therapy, and more recently, for optogenetics. 22 A second level of treatment specificity could be given by selective expression of ChR2 in cancer cells. Molecular tools for genetically targeted expression are under active investigations with some promising genetic tools arising, such as cancer cell-specific promoters 35, 36 and systemically deliverable viruses that efficiently target cancer cell surface proteins.…”

“…Four hundred seventy-nanometer light was shown to have an attenuance of 0.2 in tumor tissue over a 0.2 mm path length. 22 We therefore assumed the light intensity to reach saturating values for ChR2(D156A) activation to a tumor depth of minimally 5.8 mm 2 .…”

Development of a Tumor‐Specific Photoactivatable Doxorubicin Prodrug

“…In the highlighted study and a preceding one , Ibsen et al . developed a remarkable new DOX prodrug with high tumor specificity upon activation and minimal toxicity to normal tissue outside the activation area.…”

“…In the highlighted study (16) and a preceding one (17), Ibsen et al developed a remarkable new DOX prodrug with high tumor specificity upon activation and minimal toxicity to normal tissue outside the activation area. The prodrug, referred to as DOX-PCB, consists of a photocleavable o-nitrophenyl group (18) attached to the sugar amino group of DOX and conjugated to a biotinylated polyethylene glycol linker.…”