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

Abstract

Photodynamic therapy (PDT) has become an effective treatment for certain types of solid tumors. The combination of PDT with other therapies has been extensively investigated in recent years to improve its effectiveness and expand its applications. This focused review summarizes the development of a prodrug system in which anticancer drugs are activated locally at tumor sites during PDT treatment. The development of a singlet-oxygen-sensitive linker that can be conveniently conjugated to various drugs and efficiently cleaved to release intact drugs is recapitulated. The initial design of prodrugs, preliminary efficacy evaluation, pharmacokinetics study, and optimization using quantitative systems pharmacology is discussed. Current treatment optimization in animal models using physiologically based a pharmacokinetic (PBPK) modeling approach is also explored. prodrug specifically at the tumor site when PDT treatment is initiated. The drug provides a sustained and extended cell-killing effect, in addition to local damage produced by PDT. While there are a number of other reviews about prodrugs and PDT [9,16,[33][34][35][36][37][38], this case review summarizes the singlet-oxygen-activatable prodrug system developed in our lab, specifically focusing on development of our unique cleavable linker triggered by singlet oxygen, initial evaluation of photodynamic prodrugs utilizing the singlet-oxygen-sensitive linker, quantitative systems pharmacologic analysis, and current optimization aided by physiologically based pharmacokinetic modeling in animal models. Development of Singlet-Oxygen-Sensitive LinkerPhotocleavable bonds have long been investigated and used in numerous applications, such as in organic synthesis, drug delivery, and the study of intracellular biochemical processes (e.g., signaling pathways, gene expression) [39][40][41][42][43][44][45]. Light is a major component of PDT; however, the preferred wavelengths-to facilitate deeper penetration in tissue-are in the red and far-red regions, limiting the choices of linkers that are directly cleaved by such low-energy light [44][45][46][47]. In our prodrug system, we exploited a unique bond cleavage phenomenon mediated by singlet oxygen, which is generated during the PDT process, to overcome this problem. The cleavage mechanism is based on a well-known property of the double bond to participate in a [2+2] cycloaddition with singlet oxygen following decomposition to ultimately give carbonyl fragments via a dioxetane intermediate (Figure 1a) [48][49][50][51][52][53][54][55][56].

Multifunctional Molecular Therapeutic Agent for Targeted and Controlled Dual Chemo- and Photodynamic Therapy

“…Along with the production of singlet oxygen, it was expected that the aminoacrylate linker in 1 would be cleaved to release the CA4 moiety. 45 This on-demand drug release was monitored by reverse-phase high-performance liquid chromatography (HPLC) under different conditions. The retention times of free CA4 and 1 were first determined to be about 23 min and 34 min, respectively, monitored at 300 nm.…”

Targeted Chemoradiotherapy of Prostate Cancer Using Gold Nanoclusters with Protease Activatable Monomethyl Auristatin E

“…Other studies have used external trigger-responsive linkers to conjugate antitumor drugs to reduce toxicity caused by nonselective release. 50 Generally in clinical uses of antitumoral drugs, multiple doses at intervals will be utilized. Additionally, radiation doses are also given in multiple fractionations.…”

Conjugates of Porphyrinoid-Based Photosensitizers with Cytotoxic Drugs: Current Progress and Future Directions toward Selective Photodynamic Therapy

“…The folate-targeted conjugates 121 demonstrated significant selectivity for folate-positive cell lines, where they could be cleaved during irradiation , (Figure ). More detailed data concerning conjugates 118 , 119 , and 121 can be found in the recent review by You …”

“…More detailed data concerning conjugates 118, 119, and 121 can be found in the recent review by You. 179 Recently, Ng and colleagues reported the synthesis and evaluation of the more sophisticated 1 O 2 -cleavable conjugate 122 180 (Figure 28). Unlike compounds 118, 119, and 121, it is an activatable photosensitizer.…”