Abstract
BackgroundThough the combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) appears to be very attractive in cancer treatment, hypoxia and overproduced glutathione (GSH) in the tumor microenvironment (TME) limit their efficacy for further application.ResultsIn this work, a smart hypoxia-irrelevant free radical nanogenerator (AIPH/PDA@CuS/ZIF-8, denoted as APCZ) was synthesized in situ via coating copper sulphide (CuS)-embedded zeolitic imidazolate framework-8 (ZIF-8) on the free radical initiator 2,2′-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH)-loaded polydopamine (PDA). APCZ showed promising GSH-depleting ability and near-infrared (NIR)-II photothermal performance for combined cancer therapy. Once internalized by 4T1 cells, the outer ZIF-8 was rapidly degraded to trigger the release of CuS nanoparticles (NPs), which could react with local GSH and sequentially hydrogen peroxide (H2O2) to form hydroxyl radical (·OH) for CDT. More importantly, the hyperthermia generated by APCZ upon 1064 nm laser excitation not only permitted NIR-II photothermal therapy (PTT) and promoted CDT, but also triggered the decomposition of AIPH to give toxic alkyl radical (·R) for oxygen-independent PDT. Besides, the PDA together with CuS greatly decreased the GSH level and resulted in significantly enhanced PDT/CDT in both normoxic and hypoxic conditions. The tumors could be completely eradicated after 14 days of treatment due to the prominent therapeutic effects of PTT/PDT/CDT. Additionally, the feasibility of APCZ as a photoacoustic (PA) imaging contrast agent was also demonstrated.ConclusionsThe novel APCZ could realize the cooperative amplification effect of free radicals-based therapies by NIR-II light excitation and GSH consumption, and act as a contrast agent to improve PA imaging, holding tremendous potential for efficient diagnosis and treatment of deep-seated and hypoxic tumors.Graphic abstract
Highlights
Though the combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) appears to be very attractive in cancer treatment, hypoxia and overproduced glutathione (GSH) in the tumor microenviron‐ ment (TME) limit their efficacy for further application
PDA was first used to load AIPH after 6 h of polymerization to obtain AIPH-loaded PDA (AP), which could further be functionalized with Zn2+ ions and Copper sulphide (CuS); aqueous 2-MIM solution was added to induce the formation of zeolitic imidazolate framework-8 (ZIF-8) layer with simultaneous embedment of CuS
The CuS embedded in the ZIF-8 can endow remarkably enhanced NIR-II absorption for photothermal therapy (PTT) as well as GSH-depleting capability for the APCZ to provide free radicals-mediated therapies
Summary
Though the combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) appears to be very attractive in cancer treatment, hypoxia and overproduced glutathione (GSH) in the tumor microenviron‐ ment (TME) limit their efficacy for further application. Zhang et al J Nanobiotechnol (2021) 19:265 conventional PDT agents are usually activated by shorter wavelength lasers which are known to have only limited tissue penetration [4,5,6]. In view of these considerations, the use of free radical initiator, 2,2′-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH), has become a research hotspot as it allows the prompt production of toxic alkyl radical (·R) upon thermal stimulation and without the need of oxygen molecules [7, 8]. Upon exposure to near-infrared (NIR) light, the PTAs rapidly convert the photo energy to hyperthermia for both photothermal therapy (PTT) and thermal decomposition of AIPH to give ·R for oxygen-independent PDT [9,10,11,12]
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