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.
Highlights
Photodynamic therapy (PDT) is a clinically approved treatment for a number of local cancers or local precancerous conditions, e.g., cancer of the esophagus, Barrett’s esophagus, endobronchial cancer, and actinic keratosis, and is currently under investigation to treat many others, including cancers of the skin, brain, mouth, stomach, prostate, cervix, and vagina [1,2]
A major mechanism by which PDT eradicates tumors is by locally generating a reactive oxygen species, i.e., singlet oxygen, which causes cellular damage leading to cell death
We have been developing such prodrug systems in which the anticancer drug is released from the inert species were used for triggering drug release from stimuli-responsive drug-releasing systems [J.2C8l–in3.2M].edI.n20o1u9,r8l,a2b19,8we have been developing such prodrug systems in which the anticancer dr2uogf 1is9 released from the inert prodrug at the tumor site when PDT treatment is initiated
Summary
Photodynamic therapy (PDT) is a clinically approved treatment for a number of local cancers or local precancerous conditions, e.g., cancer of the esophagus, Barrett’s esophagus, endobronchial cancer, and actinic keratosis, and is currently under investigation to treat many others, including cancers of the skin, brain, mouth, stomach, prostate, cervix, and vagina [1,2]. EExxtetennddeeddcceelll-lk-kilillilninggeeffffeecctt ooff tthhee pprrooddrruugg--PPDDTT ssyysstteemm,, ccoommppaarreedd wwiitthh PPDDTT aalloonnee,, ddeemmoonnssttrraatteedd bbyyflfluuoorreesscceenncceelilviveececlel lilmimagaignign.g(a. The toxicity IC50s against MCF-7 cells was determined to be 173 nM (PDT-cleavable prodrug) and 916 nM (noncleavable mimetic), compared with around 7 nM for CA4. Significant cytotoxicity was observed for the noncleavable prodrug with illumination, demonstrating the highly potent PDT effect of silicon phthalocyanine (IC50 = 34 nM). AAnnttiittuummoorr eeffffeeccttss ooff tthhee CCMMPP--LL--CCAA44 pprrooddrruugg--PPDDTT ssyysstteemm. The cytotoxicity IC50 against colon 26 cell lines was determined to be 17, 27, 40, 45, and 49 nM for a PEG of 45, 18, 1, 0, and 18 units in length without the FA group, respectively (Table 1, entry 8). SSeelleeccttiivvee ttuummoorr ddaammaaggee wwiitthh mmiinniimmaall sskkiinn ddaammaaggee iinn aa bbrrooaadd iilllluummiinnaatteedd aarreeaa ooff mmiiccee ttrreeaatteedd wwiitthh aa ffoollaattee--rreecceeppttoorr--ttaarrggeetteedd aanndd nnoonnttaarrggeetteedd pprrooddrruugg. More systemic study for chronic toxicity remains to be performed
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