An Emerging Molecular Design Approach to Heavy-Atom-Free Photosensitizers for Enhanced Photodynamic Therapy under Hypoxia
Authors: Gyoungmi Kim
Nahyun Kwon
Yubin Yim
Sangin Kim
Sungnam Park
Van-Nghia Nguyen
Sujie Qi
Juyoung Yoon
Journal: Journal of the American Chemical Society (2019)
Discipline: CHEMISTRY
Keywords: Photosensitizers; Reactive oxygen species; Thionaphthalimides; Singlet excited state; Triplet state
Affiliations: Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760, Republic of Korea, Department of Chemistry, Korea University, Seoul 02841, Republic of Korea

Abstract:  A novel strategy for designing highly efficient and activatable photosensitizers that can effectively generate reactive oxygen species (ROS) under both normoxia and hypoxia is proposed. Replacing both oxygen atoms in conventional naphthalimides (RNI-O) with sulfur atoms led to dramatic changes in the photophysical properties. The remarkable fluorescence quenching (ΦPL ≈ 0) of the resulting thionaphthalimides (RNI-S) suggested that the intersystem crossing from the singlet excited state to the reactive triplet state was enhanced by the sulfur substitution. Surprisingly, the singlet oxygen quantum yield of RNI-S gradually increased with increasing electron-donating ability of the 4-R substituents (MANI-S, ΦΔ ≈ 1.00, in air-saturated acetonitrile). Theoretical studies revealed that small singlet-triplet energy gaps and large spin-orbit coupling could be responsible for the efficient population of the triplet state of RNI-S. In particular, the ROS generation ability of MANI-S was suppressed under physiological conditions due to their self-assembly and was significantly recovered in cancer cells. More importantly, cellular experiments showed that MANI-S still produced a considerable amount of ROS even under severely hypoxic conditions (1% O2) through a type-I mechanism. 

Retracted: No

PubPeer comments:
 Fig 1.  A, CircUBAP2 was highly expressed in OC tissues compared with adjacent normal tissues. B, CircUBAP2 expression was significantly higher in OC with stage III-IV than stage I + II. ![file] One expects the upper and lower outlying extremes of the Normal-tissue distributions to be the same in 1A and 1B. Likewise, the lower outlying extremes of the early-stage OC distribution in 1B, and the upper outliers from the late-stage OC distribution, should match outliers of the Combined-tumor distribution in 1A. ![file] This is clearly not the case. , 
 Fig 3.  E, MicroRNA-144 lowly expressed in OC tissues than adjacent normal tissues. F, MicroRNA-144 expression gradually decreased with the disease progression, and presented the lowest level in OC tissues with stage III + IV ![file] One expects the upper and lower outlying extremes of the Normal-tissue distributions to be the same in 3E and 3F. Likewise, the higher outlying extremes of the early-stage OC distribution in 3F, and the lower outliers from the late-stage OC distribution, should match outliers of the Combined-tumor distribution in 3E. ![file] This is not the case. , 
 *[right]* Fig 2B from [Sheng et al (2019)] .  B, A negative correlation was found between the five-year survival rate of OC patients and circUBAP2 expression . *[left]* Fig 1D from [Zhao Huang (2019)] .  SNHG14 was highly expressed in ovarian cancer.... D, The five-year survival rate was analyzed . Remarkable similarities. ![file] , 
 Clockwise from upper left: a. Fig 1D from [Jiang et al (2019)] .  Lnc00908 was highly expressed in OC... Correlation between five-year survival rate of OC patients and lnc00908 expression . b. Fig 1D from [Zhao Huang (2019)] .  SNHG14 was highly expressed in ovarian cancer... The five-year survival rate was analyzed . **c. Fig 2B from [Sheng et al (2019)] .  CircUBAP2 promoted OC development... A negative correlation was found between the five-year survival rate of OC patients and circUBAP2 expression .** d. Fig 1D from [Sun Fan (2019)] .  Upregulation of SNHG12 in OC. ... The survival analysis demonstrated a worse prognosis in OC patients with high-level SNHG12 relative to those with low-level SNHG12 . ![file] Many similarities, most notably between b) and c), and between a) and d). --------------------------------------  A total of 24 OC patients treated in the Weifang Yidu Center Hospital from **2008 to 2016** were enrolled . The authors then followed patient survival for 6 years, i.e. through to **2014 to 2022**. ,