Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system

Abstract

The combination of photodynamic therapy (PDT) with anti-tumor agents is a complimentary strategy to treat local cancers. We developed a unique photosensitizer (PS)-conjugated paclitaxel (PTX) prodrug in which a PS is excited by near-infrared wavelength light to site-specifically release PTX while generating singlet oxygen (SO) to effectively kill cancer cells with both PTX and SO. The aim of the present study was to identify the determinants influencing the combined efficacy of this light-activatable prodrug, especially the bystander killing effects from released PTX. Using PS-conjugated PTX as a model system, we developed a quantitative mathematical model describing the intracellular trafficking. Dynamics of the prodrug and the model predictions were verified with experimental data using human cancer cells in vitro. The sensitivity analysis suggested that parameters related to extracellular concentration of released PTX, prodrug uptake, target engagement, and target abundance are critical in determining the combined killing efficacy of the prodrug. We found that released PTX cytotoxicity was most sensitive to the retention time of the drug in extracellular space. Modulating drug internalization and conjugating the agents targeted to abundant receptors may provide a new strategy for maximizing the killing capacity of the far-red light-activatable prodrug system. These results provide guidance for the design of the PDT combination study in vivo and have implications for other stimuli-responsive drug delivery systems.

Prodrug strategies for targeted therapy triggered by reactive oxygen species

“…121,122 Coined "photo-unclick chemistry", the activation mechanism is identical to the one shown in Scheme 4. In a series of publications, [122][123][124][125][126][127][128][129][130] You and co-workers described photodynamic prodrugs containing the aminoacrylate linker and the tubulin polymerization inhibitor combretastatin A-4 (CA4). In combination with the pro-PS iodo-substituted 5IJ6)carboxyfluorescein diacetate (CF), the cascade, dual-activation photodynamic prodrug 63 was developed to facilitate easier handling under ambient light (Table 7).…”

“…Similar Pc-based constructs with the anticancer agent paclitaxel (PTX) were also synthesized showing the feasibility of using the linker with secondary alcohols and not only phenolics. 127,128,130 Recently, You and co-workers developed the mitochondriatargeting prodrug 67 based on an intermolecular prodrug/PS system. 132 The prodrug was assembled from CA4, an AA linker, and the targeting ligand Rhodamine B (RhB).…”

Sensors, Imaging Agents, and Theranostics to Help Understand and Treat Reactive Oxygen Species Related Diseases

“…Woo and co‐workers developed a prodrug of paclitaxel based on a silicon‐containing porphyrin macrocycle, which was activated by red light due to 1 O 2 production. The drug molecule was covalently linked to the silicon core and could be simply cleaved after oxidation.…”

Development of Prodrugs for PDT-Based Combination Therapy Using a Singlet-Oxygen-Sensitive Linker and Quantitative Systems Pharmacology

“…In our lab, we chose the Pc-(L-PTX) 2 (entry 8) prodrug to begin our in vitro investigation based on a QSP approach (Figure 9) [82]. We found that around 80% of our prodrug formed aggregates in medium, due to its high lipophilicity.…”

“…The model components describing the kinetic and dynamic processes of the released paclitaxel (PTX) (blue arrows) only apply to the cleavable Pc-(L-PTX)2 . Reproduced with permission from[82].…”