Boosting Photothermal Theranostics via TICT andMolecular Motions for Photohyperthermia Therapy of Muscle-Invasive Bladder Cancer

Sheng Zeng, Heqi Gao, Chuang Li, Shaoqiang Xing, Zhaoliang Xu, Qian Liu,* Guangxue Feng,* and Dan Ding*

 1. The development of photothermal agents with high photothermal conversion efficiency (PCE) can help to reduce drug and laser dosage, but still remains a big challenge. Herein, a novel approach is reported to design photothermal agents with high PCE values by promoting nonradiative heat generation processes through the cooperation of twisted intramolecular charge transfer (TICT) and molecular motions. Within the designed molecule 2DMTT-BBTD, the tetraphenylethenes act as molecular rotors, the long alkyl chain grafted thiophene helps to twist the molecular geometry to facilitate TICT state formation and preserve molecular motions in aggregate, while the strong electron-withdrawing BBTD unit enhances TICT effect. 2DMTT-BBTD exhibits NIR-absorption and a high PCE value of 74.8% under 808 nm laser irradiation. Gambogic acid (GA) which surmounts tumor cell thermotolerance by inhibiting heat shock protein 90 (HSP90) expression is coloaded into the nanoparticles, RGD peptide is further introduced to the nanoparticle surface to improve tumor accumulation. The resultant nanoparticles facilitate the effective low-temperature hyperthermia therapy of muscle-invasive bladder cancer (MIBC) with minimal damage to surrounding heathy tissues. This work delivers a new design concept for development of highly efficient photothermal agents, which also provides a safer approach for noninvasive treatment of MIBC and other malignant tumors.

Introduction
Cancer represents one of the biggest pub- lic health threats to human beings, whose morbidity and mortality have been increas- ing during the past decades.[1] Great ef- forts have been made to fight against can- cers over decades.[2–5] Among these ma- lignant tumors, urinary bladder cancer, especially muscle-invasive bladder cancer (MIBC) remains to be big challenges of clin- ical treatment.[6] The heterogeneous and complex tissue environment of MIBC usu- ally result in high recurrence and metas- tasis for traditional intravesical therapy or transurethral resection of the bladder tu- mor, which often proceeds to the stage of bladder radical cystectomy to com- pletely remove bladder.[7–9] Bladder rad- ical cystectomy combined with neoadju- vant chemotherapy is the most adopted treatment approach for MIBC, but it suf- fers from high trauma, high surgery risk, and urination changes, which causes phys- ical burden and anxiety for patients, and the 5-year overall survival rate is still far beyond satisfactory.[10] In this regard, novel noninvasive therapeutic approaches

S. Zeng, Q. Liu Department of Urology

Tianjin First Central Hospital Tianjin 300192, China
E-mail: [email protected]
H. Gao, D. Ding
Frontiers Science Center for Cell Responses
State Key Laboratory of Medicinal Chemical Biology Key Laboratory of Bioactive Materials
Ministry of Education
and College of Life Sciences Nankai University
Tianjin 300071, China
E-mail: [email protected]
C. Li, S. Xing, Z. Xu Department of Urology First Central Clinical College Tianjin Medical University Tianjin 300052, China
G. Feng
AIE Institute
State Key Laboratory of Luminescent Materials and Devices Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates
School of Materials Science and Engineering South China University of Technology Guangzhou 510640, China
E-mail: [email protected]

The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adhm.202101063
DOI: 10.1002/adhm.202101063

that could preserving patient’s native bladder while removing MIBC and prolongating survival rate are highly desired.Photothermal therapy (PTT) that transfers absorbed photons into localized heat to ablate tumor tissues represents a promising therapeutic modality with high spatial and temporal control.[11–13] Possessing the advantages of low toxicity, easy operation, low cost, and minimal invasiveness, PTT has attracted great inter- est in recent years.[14–16] An ideal PTT agent should have a near-infrared (NIR) absorption and a high photothermal conver- sion efficiency (PCE) to improve the phototreatment depth and efficacy.[ 17–19] According to Jablonski diagram, the photothermy is realized by the nonradiative energy dissipation from excited state to ground state for organic agents.[20,21] In light of this, many approaches to inhibit other dissipation pathways have been reported for PTT agents, such as introducing strong