Light/glutathione-ignited nanobombs integrating azo and tetrasulfide bonds for multimodal therapy of colorectal cancer.

Reactive chemical bonds are associated with the generation of therapeutic radicals and gases under internal-external stimuli, which are highly attractive for cancer treatments. However, designing multifunctional nanostructures that incorporate multiple chemical bonds remains a significant challenge. Herein, novel core-shell nanobombs integrating azo (NN) and tetrasulfide bonds (SSSS) have been constructed with sensitive ignition by both near-infrared (NIR) laser and tumor microenvironments (TME) for treating colorectal tumors. The nanobombs (GNR/AIPH@MON@PVP, GAMP) were prepared by the in-situ growth of tetrasulfide-contained mesoporous organosilica nanoshell (MON) on gold nanorods (GNR) as the photothermal initiator, the load of azo compound (AIPH) as the radical producer and polymer modification. Upon NIR irradiation, the GNR core exhibits stable and high photothermal effects because of the passivation of the MON shell, leading to the thermal ablation of cancer cells. Simultaneously, the local hyperthermia ignites AIPH to release alkyl radicals to cause extensive oxidative stress without oxygen dependence. Moreover, the MON shell can be gradually decomposed in a reduced environment and release therapeutic H2S gas because of the cleavage of SSSS bonds by the glutathione (GSH) overexpressed in TME, causing mitochondrial injury. Owing to multifunctional functions, the GAMP significantly inhibits the growth rate of tumors upon NIR irradiation and achieves the highest efficacy among treatments. Therefore, this study presents activatable nanoagents containing multiple chemical bonds and provides insights into developing comprehensive antitumor strategies.

Design and synthesis of cancer-cell-membrane-camouflaged hemoporfin-Cu9S8 nanoagents for homotypic tumor-targeted photothermal-sonodynamic therapy.

Multimodal therapies have aroused great interest in tumor therapy due to their highly effective antitumor effect. However, immune clearance limits the practical application of nanoagents-based multimodal therapies. To solve this problem, we have designed hemoporfin-Cu9S8 hollow nanospheres camouflaged with the CT26 cell membrane (CCM) as a model of multifunctional agents, achieving homologous-targeted synergistic photothermal therapy (PTT) and sonodynamic therapy (SDT). Hollow Cu9S8 as photothermal agents and carriers have been obtained through sulfurizing cuprous oxide (Cu2O) nanoparticles through "Kirkendall effect", and they exhibit hollow nanospheres structure with a size of ∼200 nm. Then, Cu9S8 nanospheres could be used to load with hemoporfin sonosensitizers, and then hemoporfin-Cu9S8 nanospheres (abbreviated as H-Cu9S8) can be further surface-camouflaged with CCM. H-Cu9S8@CCM nanospheres exhibit a broad photoabsorption in the range of 700-1100 nm and high photothermal conversion efficiency of 39.8% under 1064 nm laser irradiation for subsequent PTT. In addition, under the excitation of ultrasound, the loaded hemoporfin could generate 1O2 for subsequent SDT. Especially, H-Cu9S8@CCM NPs are featured with biocompatibility and homologous targeting capacity. When intravenously (i.v.) injected into mice, H-Cu9S8@CCM NPs display a higher blood circulation half-life (3.17 h, 6.47 times) and tumor accumulation amount (18.75% ID/g, 1.94 times), compared to H-Cu9S8 NPs (0.49 h, 9.68% ID/g) without CCM. In addition, upon 1064 nm laser and ultrasound irradiation, H-Cu9S8@CCM NPs can inhibit tumor growth more efficiently due to high accumulation efficiency and synergistic PTT-SDT functions. Therefore, the present study provides some insight into the design of multifunctional efficient agents for homotypic tumor-targeted therapy.

Transforming a Sword into a Knife: Persistent Phototoxicity Inhibition and Alternative Therapeutical Activation of Highly-Photosensitive Phytochlorin.

The phototoxicity of photosensitizers (PSs) is a double-edged sword with one edge beneficial for destroying tumors while the other is detrimental to normal tissues, and the conventional "OFF-ON" strategy provides temporary inhibition so that phototoxicity would come sooner or later due to the inevitable retention and transformation of PSs in vivo. We herein put forward a strategy to convert "double-edged sword" PSs into "single-edged knife" ones with simultaneously persistent phototoxicity inhibition and alternative multiple therapeutical activation. The Chlorin e6 (Ce6) as the PS model directly assembles with Cu2+ ions into nanoscale frameworks (nFs) whose Cu2+-coordination includes both carboxyl groups and a porphyrin ring of Ce6 instead of Fe3+/Mn2+-coordination with only carboxyl groups. Compared to the high phototoxicity of Ce6, the nFs exhibit efficient energy transfer due to the dual-coordination of paramagnetic Cu2+ ions and the aggregation, achieving the persistent and high phototoxicity inhibition rate of >92%. Alternatively, the nFs not only activate a high photoacoustic contrast and near-infrared (NIR)-driven photothermal efficacy (3.5-fold that of free Ce6) due to the aggregation-enhanced nonradiative transition but also initiate tumor microenvironment modulation, structure disassembly, and chemodynamic effect by Cu2+ ions. Given these merits, the nFs achieve long-term biosecurity, no retina injury under sunlight, and a higher therapeutical output than the photodynamic effect of Ce6. This work presents a possibility of converting numerous highly phototoxic porphyrins into safe and efficient ones.