Polymeric Photosensitizer Prodrugs for Photodynamic Therapy

Abstract

A targeting strategy based on the selective enzyme-mediated activation of polymeric photosensitizer prodrugs (PPP) within pathological tissue has led to the development of agents with the dual ability to detect and treat cancer. Herein, a detailed study of a simple model system for these prodrugs is described. We prepared "first-generation" PPP by directly tethering the photosensitizer (PS) pheophorbide a to poly-(L)-lysine via epsilon amide links and observed that by increasing the number of PS on a polymer chain, energy transfer between PS units improved leading to better quenching efficiency. Fragmentation of the PPP backbone by trypsin digestion gave rise to a pronounced fluorescence increase and to more efficient generation of reactive oxygen species upon light irradiation. In vitro tests using the T-24 bladder carcinoma cell line and ex vivo experiments using mouse intestines illustrated the remarkable and selective ability of these PPP to fluoresce and induce phototoxicity upon enzymatic activation. This work elucidated the basic physicochemical parameters, such as water solubility and quenching/activation behavior, required for the future elaboration of more adaptable "second-generation" PPP, in which the PS is tethered to a proteolytically stable polymer backbone via enzyme-specific peptide linkers. This polymer architecture offers great flexibility to tailor make the PPP to target any pathological tissue known to over-express a specific enzyme.

Quenching-induced deactivation of photosensitizer by nanoencapsulation to improve phototherapy of cancer

“…Thus, by increasing the encapsulation rate of Hy, we achieved an efficient deactivation of the PS. The underlying principle for treatment applications is the same as that for polymeric conjugates (Hamblin et al, 2001(Hamblin et al, , 2003Campo et al, 2007;Gabriel et al, 2007), in which higher degrees of substitution of the backbone by PSs result in higher 108.6 ± 13.6 The photoactivity was assessed by a MTT assay on the SKOV-3 cells after 1 h incubation with Hy-loaded NPs with increasing drug loading (Hy=0.05 g/mL) and irradiation at a light dose of 2.3 J/cm 2 . The fluorescence emission (F) of Hy-loaded NPs was measured in PBS at 640 nm after excitation at 590 nm.…”

“…Thus, the quenching is used as a beneficial process, silencing PS activity until the PS reaches its target. Deactivation may be obtained either by conjugation of several PS molecules, resulting in self-quenching, or a combination of PS and another quencher to different types of backbones, such as peptides, polymers, dendrimers, or DNA (Chen et al, 2004;Clo et al, 2006;Schneider et al, 2006;Campo et al, 2007;Gabriel et al, 2007;Zheng et al, 2007). These conjugates will then be activated specifically by diseased cells omitting the quenching, thus restoring photodynamic activity only at the desired target.…”

Selective Photodetection and Photodynamic Therapy for Prostate Cancer through Targeting of Proteolytic Activity

“…In this first-generation PPP, multiple copies of the photosensitizer are tethered to a protease-sensitive polymeric backbone (26,27). A major drawback of these compounds is their limited selectivity, as all proteases recognizing a Lys-Lys motif are able to activate them.…”

Polymer conjugates as therapeutics: future trends, challenges and opportunities

“…For example, PEG-zinc protoporphyrin (ZnPP) conjugate, a specific haem oxygenase (HO) inhibitor [115,116] , produces a tumour-selective suppression of HO activity, as well as an induction of apoptosis, possibly by increasing oxidative stress. Within the same line, polymeric photosensitiser prodrugs (PPP) with dual activity (detection and treatment) have also been synthesised by directly conjugating the photosensitiser pheophorbide to poly-L -lysine polymer [117] . As a final example on pro-apoptotic conjugates, it is important to mention a polymer-protein conjugate that targets cell death receptors, poly-1-vinylpyrrolidin-2-one (PVP)-tumour necrosis factor (TNF)-α , currently under preclinical development for sarcoma-180 [118] .…”