Zinc peroxide-based nanotheranostic platform with endogenous hydrogen peroxide/oxygen generation for enhanced photodynamic-chemo therapy of tumors.

Nanotheranostic platforms, which can respond to tumor microenvironments (TME, such as low pH and hypoxia), are immensely appealing for photodynamic therapy (PDT). However, hypoxia in solid tumors harms the treatment outcome of PDT which depends on oxygen molecules to generate cytotoxic singlet oxygen (1O2). Herein, we report the design of TME-responsive smart nanotheranostic platform (DOX/ZnO2@Zr-Ce6/Pt/PEG) which can generate endogenously hydrogen peroxide (H2O2) and oxygen (O2) to alleviate hypoxia for improving photodynamic-chemo combination therapy of tumors. DOX/ZnO2@Zr-Ce6/Pt/PEG nanocomposite was prepared by the synthesis of ZnO2 nanoparticles, in-situ assembly of Zr-Ce6 as typical metal-organic framework (MOF) on ZnO2 surface, in-situ reduction of Pt nanozymes, amphiphilic lipids surface coating and then doxorubicin (DOX) loading. DOX/ZnO2@Zr-Ce6/Pt/PEG nanocomposite exhibits average sizes of ∼78 nm and possesses a good loading capacity (48.8 %) for DOX. When DOX/ZnO2@Zr-Ce6/Pt/PEG dispersions are intratumorally injected into mice, the weak acidic TEM induces the decomposition of ZnO2 core to generate endogenously H2O2, then Pt nanozymes catalyze H2O2 to produce O2 for alleviating tumor hypoxia. Upon laser (630 nm) irradiation, the Zr-Ce6 component in DOX/ZnO2@Zr-Ce6/Pt/PEG can produce cytotoxic 1O2, and 1O2 generation rate can be enhanced by 2.94 times due to the cascaded generation of endogenous H2O2/O2. Furthermore, the generated O2 can suppress the expression of hypoxia-inducible factor α, and further enable tumor cells to become more sensitive to chemotherapy, thereby leading to an increased effectiveness of chemotherapy treatment. The photodynamic-chemo combination therapy from DOX/ZnO2@Zr-Ce6/Pt/PEG nanoplatform exhibits remarkable tumor growth inhibition compared to chemotherapy or PDT. Thus, the present study is a good demonstration of a TME-responsive nanoplatform in a multimodal approach for cancer therapy.

Tricetin suppresses the cell migration and BMP-6 expression through p38 signaling pathways in human retinal pigment epithelium cells.

Proliferative vitreoretinopathy (PVR) is a visual-threatening disease, which cause from the migration of retinal pigment epithelium (RPE). Tricetin, a family of flavonoids, can inhibit the metastasis of several cancers. Herein, we aim to evaluate the possible effect of tricetin on inhibiting ARPE-19 cells migration. The Boyden chamber assay, wound healing assay, RNA sequencing, and Western blot analysis were applied in our experiment. The results revealed that tricetin inhibited the cell migration abilities of ARPE-19 cells. Moreover, using RNA sequencing technology, we revealed that tricetin repressed bone morphogenetic protein-6 (BMP-6) gene expressions in ARPE-19 cells. Overexpression of BMP-6 resulted in significant restoration of cell migration capabilities of tricetin-treated ARPE-19 cells. Furthermore, tricetin suppressed the phosphorylation of the p38 signaling pathway. Moreover, blocking the p38 pathway also inhibits BMP-6 expression and migration in the ARPE-19 cells. In conclusion, this study revealed that tricetin inhibits the ARPE-19 cell migration mainly via the suppression of BMP-6 expression and p38 signaling pathway.

Dressing and undressing MOF nanophotosensitizers to manipulate phototoxicity for precise therapy of tumors.

Photodynamic therapy (PDT) is a clinically approved treatment for tumors, and it relies on the phototoxicity of photosensitizers by producing reactive oxygen species (ROS) to destroy cancer cells under light irradiation. However, such phototoxicity is a double-edged sword, which is also harmful to normal tissues. To manipulate phototoxicity and improve the therapy effect, herein we have proposed a dressing-undressing strategy for de-activating and re-activating therapy functions of photosensitizer nanoparticles. One kind of metal organic framework (PCN-224), which is composed of Zr(IV) cation and tetrakis (4-carboxyphenyl) porphyrin (TCPP), has been prepared as a model of photosensitizer, and it has size of ∼70 nm. These PCN-224 nanoparticles are subsequently coated with a mesoporous organic silica (MOS) shell containing tetrasulfide bonds (-S-S-S-S-), realizing the dressing of PCN-224. MOS shell has the thickness of ∼20 nm and thus can block 1O2 (diffusion distance: <10 nm), deactivating the phototoxicity and preventing the damage to skin and eyes. Furthermore, PCN-224@MOS can be used to load chemotherapy drug (DOX·HCl). When PCN-224@MOS-DOX are mixed with glutathione (GSH), MOS shell with -S-S-S-S- bonds can be reduced by GSH and then be decomposed, which results in the undressing and then confers the exposure of PCN-224 with good PDT function as well as the release of DOX. When PCN-224@MOS-DOX dispersion is injected into the mice and accumulated in the tumor, endogenous GSH also confers the undressing of PCN-224@MOS-DOX, realizing the in-situ activation of PDT and chemotherapy for tumor. Therefore, the present study not only demonstrates a general dressing-undressing strategy for manipulating phototoxicity of photosensitizers, but also provide some insights for precise therapy of tumors without side-effects. STATEMENT OF SIGNIFICANCE: Photosensitizers can generate reactive oxygen species (ROS) under light radiation to destroy cancer cells. However, this phototoxicity is a double-edged sword and also harmful to normal tissues such as the skin and eyes. To control phototoxicity and improve therapeutic efficacy, we prepared a PCN-224@MOS-DOX nanoplatform and proposed a dressing and undressing strategy to deactivate and reactivate the therapeutic function of the photosensitizer nanoparticles. The MOS shell can block the diffusion of 1O2, eliminate phototoxicity, and prevent damage to the skin and eyes. When injected into mice and accumulated in tumors, PCN-224@MOS-DOX dispersions are endowed with an endogenous GSH-driven undressing effect, achieving in situ activation of PDT and tumor chemotherapy.

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.

Phytic acid-Cu2+ framework/Cu2-xS nanocomposites with heat-shock protein down-modulation ability for enhanced multimodal combination therapy.

Mild-temperature photothermal therapy (mPTT) has shown some advantages over traditional photothermal therapy, such as reducing the damage to surrounding healthy tissues and minimizing side effects. Nevertheless, cancer cells can easily repair damage caused by mild hyperthermia due to heat shock proteins (HSPs). Thus, it is imperative to maximize the mPTT efficiency by down-regulating HSPs overexpression and combining other cancer treatments. Herein, we report the synthesis of phytic acid (PA)-Cu2+ framework/copper sulfide (Cu2-xS) nanocomposites (abbreviated as PA-Cu/Cu2-xS NPs) as the novel therapeutic platform that can down-regulate HSPs overexpression for enhanced multimodal mPTT/chemodynamic therapy (CDT)/chemotherapy. PA-Cu/Cu2-xS NPs were prepared through self-assembly and in-situ vulcanization strategy, resulting in irregular-shaped particles with an approximate size of 100 nm. PA-Cu/Cu2-xS NPs display a plasmon effect from Cu2-xS, which enhances near-infrared (NIR) absorption and possesses excellent photothermal conversion efficiency (41.7%). Moreover, PA-Cu/Cu2-xS NPs exhibit Fenton-like reaction activity resulting from the Cu ions for CDT, and the reaction activity can be further improved 1.3 times due to mild hyperthermia during mPTT. Furthermore, the generated hydroxyl radical (•OH) can effectively decrease HSPs level to enhance mPTT. PA-Cu/Cu2-xS NPs can also serve as a drug delivery system, and they are capable of loading doxorubicin (DOX) with a loading ability (20.7%). Combining mPTT/CDT/chemotherapy exhibits significant inhibition of tumor growth. This approach can serve as a basis for designing more exquisite platforms that combine mPTT with other therapies to achieve more effective cancer treatment.

The roles of phospholipase C-ß related signals in the proliferation, metastasis and angiogenesis of malignant tumors, and the corresponding protective measures.

PLC-ß is widely distributed in eukaryotic cells and is the key enzyme in phosphatidylinositol signal transduction pathway. The cellular functions regulated by its four subtypes (PLC-ß1, PLC-ß2, PLC-ß3, PLC-ß4) play an important role in maintaining homeostasis of organism. PLC-ß and its related signals can promote or inhibit the occurrence and development of cancer by affecting the growth, differentiation and metastasis of cells, while targeted intervention of PLC-ß1-PI3K-AKT, PLC-ß2/CD133, CXCR2-NHERF1-PLC-ß3, Gαq-PLC-ß4-PKC-MAPK and so on can provide new strategies for the precise prevention and treatment of malignant tumors. This paper reviews the mechanism of PLC-ß in various tumor cells from four aspects: proliferation and differentiation, invasion and metastasis, angiogenesis and protective measures.

Construction of PEGylated chlorin e6@CuS-Pt theranostic nanoplatforms for nanozymes-enhanced photodynamic-photothermal therapy.

Multifunctional nanoagents with photodynamic therapy (PDT) and photothermal therapy (PTT) functions have shown great promise for cancer treatment, while the design and synthesis of efficient nanoagents remain a challenge. To realize nanozyme-enhanced PDT-PTT combined therapy, herein we have synthesized the Ce6@CuS-Pt/PEG nanoplatforms as a model of efficient nanoagents. Hollow CuS nanospheres with an average diameter of âˆ¼ 200 nm are first synthesized through vulcanization using Cu2O as the precursor. Subsequently, CuS nanospheres are surface-decorated with Pt nanoparticles (NPs) as nanozyme via an in-situ reduction route, followed by modifying the DSPE-PEG5000 and loading the photosensitizer Chlorin e6 (Ce6). The obtained Ce6@CuS-Pt/PEG NPs exhibit high photothermal conversion efficiency (43.08%), good singlet oxygen (1O2) generation ability, and good physiological stability. In addition, Ce6@CuS-Pt/PEG NPs show good catalytic performance due to the presence of Pt nanozyme, which can effectively convert H2O2 to O2 and significantly enhance the production of cytotoxic 1O2. When Ce6@CuS-Pt/PEG NPs dispersion is injected into mice, the tumors can be wholly suppressed owing to nanozyme-enhanced PDT-PTT combined therapy, providing better therapeutic effects compared to single-mode phototherapy. Thus, the present Ce6@CuS-Pt/PEG NPs can act as an efficient multifunctional nanoplatform for tumor therapy.

Efficient sonodynamic ablation of deep-seated tumors via cancer-cell-membrane camouflaged biocompatible nanosonosensitizers.

Ultrasound (US)-triggered therapies are promising in cancer treatments, and their effectiveness can be enhanced through the proper camouflage of sonosensitizers. Herein, we have constructed cancer cell membrane (CCM)-camouflaged sonosensitizers for homotypic tumor-targeted sonodynamic therapy (SDT). The camouflaged sonosensitizers have been prepared by encapsulating hemoporfin molecules in poly(lactic acid) polymers (H@PLA) and extruding with CCM from Colon Tumor 26 (CT26) cells, forming the H@PLA@CCM. Under excitation with US, the hemoporfin encapsulated in H@PLA@CCM can convert O2 into cytotoxic 1O2, which exerts an efficient sonodynamic effect. The H@PLA@CCM nanoparticles show enhanced cellular internalization to CT26 cells compared to H@PLA, and they also can be more efficiently engulfed by CT26 cells than by mouse breast cancer cells, due to the homologous targeting ability of CT26 CCM. After the intravenous injection, the blood circulation half-life of H@PLA@CCM is determined to be 3.23 h which is 4.3-time that of H@PLA. With high biosafety, homogeneous targeting ability, and sonodynamic effect, the combination of H@PLA@CCM and US irradiation has induced significant apoptosis and necrosis of tumor cells through the efficient SDT, achieving the strongest inhibition rate of tumors among other groups. This study provides insights into designing efficient and targeted cancer therapies using CCM-camouflaged sonosensitizers.

Efficacy and Safety of Concurrent Chemoradiotherapy Combined with Nimotuzumab in Elderly Patients with Esophageal Squamous Cell Carcinoma: A Prospective Real-world Pragmatic Study.

BACKGROUND: Concurrent or definitive chemoradiotherapy is the standard treatment of locally advanced esophageal squamous cell carcinoma (ESCC). Elderly patients could not tolerate the standard concurrent chemotherapy and were treated with radiotherapy because of weak physical status and multiple comorbidities. OBJECTIVE: The efficacy and safety profile of concurrent (chemo) radiotherapy combined with nimotuzumab in elderly patients with ESCC were investigated. METHODS: Eligible elderly (≥70 years) patients with locally advanced ESCC were enrolled in this prospective, real-world pragmatic study and received concurrent chemoradiotherapy or radiotherapy combined with nimotuzumab. The primary endpoint was overall survival (OS). Secondary endpoints were objective response rate, disease control rate, progression-free survival (PFS), and adverse drug reactions. RESULTS: Fifty-three elderly patients were enrolled. Thirty-two (60.4%) were treated with radiotherapy combined with nimotuzumab (RT+N), and 21 (39.6%) with concurrent chemoradiotherapy combined with nimotuzumab (CRT+N). The median age was 75.8 years. Fourteen (56.0%) patients achieved a partial response, and 11 (44.0%) patients achieved stable disease at 3 months. The median follow-up duration was 24.4 (95%CI, 21.6-26.7) months. Median OS (mOS) was 27.0 (95%CI, 14.8-48.4) months. Median PFS (mPFS) was 22.6 (95%CI, 12.4-not reached) months. Higher mPFS (not reached vs. 12.0 months; p=0.022) and mOS (48.4 vs. 15.3 months; p=0.009) were observed in the CRT+N group compared with the RT+N group. Most adverse reactions were grade 1-2 (46, 86.8%). CONCLUSIONS: Concurrent chemoradiotherapy or radiotherapy combined with nimotuzumab was safe and well-tolerated in elderly patients with locally advanced ESCC. ESCC patients treated with CRT+N could live longer.

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.

Metal-Free Far-Red Light-Driven Photolysis via Triplet Fusion to Enhance Checkpoint Blockade Immunotherapy.

Metal-free long-wavelength light-driven prodrug photoactivation is highly desirable for applications such as neuromodulation, drug delivery, and cancer therapy. Herein, via triplet fusion, we report on the far-red light-driven photo-release of an anti-cancer drug by coupling the boron-dipyrromethene (BODIPY)-based photosensitizer with a photocleavable perylene-based anti-cancer drug. Notably, this metal-free triplet fusion photolysis (TFP) strategy can be further advanced by incorporating an additional functional dopant, i.e. an immunotherapy medicine inhibiting the indoleamine 2,3-dioxygenase (IDO), with the far-red responsive triplet fusion pair in an air-stable nanoparticle. With this IDO inhibitor-assisted TFP system we observed efficient inhibition of primary and distant tumors in a mouse model at record-low excitation power, compared to other photo-assisted immunotherapy approaches. This metal-free TFP strategy will spur advancement in photonics and biophotonics fields.

Temperature-adaptive hydrogel optical waveguide with soft tissue-affinity for thermal regulated interventional photomedicine.

Photomedicine has gained great attention due to its nontoxicity, good selectivity and small trauma. However, owing to the limited penetration of light and difficult monitoring of the photo-media therapies, it is challenging to apply photomedical treatment in deep tissue as they may damage normal tissues. Herein, a thermal regulated interventional photomedicine based on a temperature-adaptive hydrogel fiber-based optical waveguide (THFOW) is proposed, capable of eliminating deeply seated tumor cells while lowering risks of overtemperature (causes the death of healthy cells around the tumor). The THFOW is fabricated by an integrated homogeneous-dynamic-crosslinking-spinning method, and shows a remarkable soft tissue-affinity (low cytotoxicity, swelling stability, and soft tissue-like Young's modulus). Moreover, the THFOW shows an excellent light propagation property with different wavenumbers (especially -0.32 dB cm-1 with 915 nm laser light), and temperature-gated light propagation effect. The THFOW and relevant therapeutic strategy offer a promising application for intelligent photomedicine in deep issue.

Prognostic value of circulating tumour DNA during post-radiotherapy surveillance in locally advanced esophageal squamous cell carcinoma.

BACKGROUND: The potential of circulating tumour DNA (ctDNA) as a reliable biomarker for relapse/metastasis early detection and prognosis in esophageal squamous cell carcinoma (ESCC) after radiotherapy/chemoradiotherapy (RT/CRT) initiation requires comprehensive investigation. METHODS: Treatment-naive locally advanced ESCC patients with available baseline plasma samples were prospectively enrolled from November 2018 to January 2020. RT/CRT was delivered with a simultaneous integrated boost of radiation dose. Serial plasma samples were collected at baseline (T0 ), week 4 of RT/CRT (T1 ), 1-3 (T2 ) and 3-6 months post-RT/CRT (T3 ). ctDNA was analysed using next-generation sequencing of 474 cancer-relevant genes. RESULTS: A total of 128 plasma samples from 40 eligible patients were analysed (median age: 64 [range: 40-78], 88% males, 95% stage III/IV), and the median follow-up time was 20.6 months (range: 12.2-33.3). During the post-RT/CRT surveillance including 36 patients, radiological progression was observed in 16 patients, and 69% (11/16) had detectable post-RT/CRT ctDNA prior to radiological progression, with a median lead time of 4.4 months compared with radiological imaging. ctDNA positivity at T1 (hazard ratio, HR: 3.60, 95% confidence interval, CI: 1.30-10.01) or T2 (HR: 5.45, 95% CI: 1.72-17.26) indicated inferior progression-free survival (PFS). ctDNA clearance between T0 -T1 (HR: 0.31, 95% CI: 0.08-1.13) or T0 -T2 (HR: 0.11; 95% CI: 0.02-0.61) was associated with relatively favourable PFS. Similar results were obtained when focusing on patients without esophagectomy after RT/CRT. Notably, detectable ctDNA at T1 was a potential indicator of high local recurrence risks (HR: 4.43, 95% CI: 1.31-15.04). CONCLUSIONS: ctDNA was identified as a robust biomarker for early detection of disease progression and post-RT/CRT prognosis stratification in ESCC. Detectable ctDNA at week 4 of RT/CRT might indicate higher local recurrence risks, implying the potential clinical utility of ctDNA tests in guiding post-RT/CRT treatments for locoregional control in ESCC.

Application of symptom-based mind mapping combined with PBL teaching method in emergency trauma standardized resident training in MDT model.

Explore the feasibility and effectiveness of accepting mind mapping combined with problem-based learning (PBL) teaching method in the standardized training of emergency surgery residents in the multi-disciplinary team (MDT) model of emergency trauma. Eighty-nine doctors under training who rotated in the Department of Emergency Surgery of the First Affiliated Hospital of Anhui Medical University from January 2021 to January 2022 were selected as the study subjects, and randomly divided into a group receiving mind mapping combined with PBL teaching and a group receiving traditional lecture-based learning teaching. Mini-clinical evaluation exercise (Mini-CEX), direct observation of procedural skills (DOPS), teaching adherence, and satisfaction assessments were completed at the time of discharge from the department. There were no significant differences between the observation and control group trainees in terms of gender, age, education, and entry grades. Both groups of doctors were better able to participate in their respective teaching modes and made significant progress. The participants in the observation group had significantly higher Mini-CEX, DOPS, and teaching satisfaction scores than the control group (P < .05). Under the MDT model of emergency trauma, the combination of mind mapping and PBL teaching can improve the comprehensive clinical ability of the trainees more than participating in the traditional lecture-based learning teaching, which is worth promoting and implementing in the clinical standardized training.

Multifunctional hemoporfin-Cu9S8-MnO2 for magnetic resonance imaging-guided catalytically-assisted photothermal-sonodynamic therapies.

Integrated theranostic nanoplatforms with multi-model imaging and therapeutic functions are attracting great attention in cancer treatments, while the design and preparation of such nanoplatforms remain an open challenge. Herein, we report hemoporfin@Cu9S8@MnO2 nanoparticles (H@Cu9S8@MnO2 NPs) as multifunctional nanoplatforms for magnetic resonance imaging-guided catalytically-assisted photothermal-sonodynamic therapies of tumors. Cu9S8 hollow spherical nanoparticles were firstly prepared by in-situ vulcanization of Cu2O, and the growth of MnO2 shell was realized by the reduction of manganese permanganate, where the hollow structure of Cu9S8 could be used to load hemoporfin sonosensitizer. Cu9S8@MnO2 nanoparticles with diameters of âˆ¼ 130 nm exhibit increased photoabsorption in near-infrared (NIR) region (680-1100 nm) due to the plasmonic effect of Cu9S8, and the photothermal conversion efficiency is determined to be 32.5% under 1064 nm laser irradiation. Furthermore, MnO2 shells can mimic catalase to trigger the decomposition of endogenous H2O2 into O2 with a significant O2 elevation (14.7 mg L-1) within 8 min and then promote the production of 1O2 via sonodynamic effect of hemoporfin. Meanwhile, MnO2 shells provide the T1-weight magnetic resonance (MR) imaging function. When H@Cu9S8@MnO2 NPs solution is administered to the mice, the tumor growth can be effectively inhibited due to catalytically-assisted synergetic photothermal-sonodynamic therapies which have superior therapeutic effect compared to mono-model therapy alone. Thus, H@Cu9S8@MnO2 NPs present a promising strategy for the development of integrated theranostic nanoplatforms with multi-model imaging and therapy functions.

Nanoscale Hf-hematoporphyrin frameworks for synergetic sonodynamic/radiation therapy of deep-seated tumors.

Most of tumors are located in deep-depth of animals, and the therapy of deep-seated tumors remains a severe challenge due to the performance reduction of promising technologies including phototherapy. To solve the problem, herein we have developed a hafnium-hemoporfin frameworks (HfHFs) as multifunctional theranostic nanoplatforms for synergetic sonodynamic therapy (SDT) and radiation therapy (RT) of deep-seated tumors. HfHFs are constructed by a sonication-assisted assembly route with hematoporphyrin monomethyl ether (HMME) sonosensitizer molecules as bridging linkers and Hf4+ as metal nodes. The resulting HfHFs sample is composed of spherical nanoparticles with size of 90-130 nm, and then surface-modified with DSPE-PEG to improve the water-dispersity. Under ultrasound (US) irradiation, HMME ligands in HfHFs can be motivated to produce singlet oxygen (1O2) due to sonodynamic effect. When the HfHFs sample is exposed by X-ray, the high atomic-number Hf4+ in the HfHFs can effectively absorb X-ray to increase RT effect by producing hydroxyl radicals (•OH). When HfHFs dispersion is intravenously injected in the tumor-bearing mice, the tumor can be monitored by CT imaging. Moreover, the deep-seated tumors coated by tissue barriers can be suppressed effectively by the synergistic SDT and RT, which is better than that of SDT or RT alone. Therefore, HfHFs can be employed as a novel nanoagent for the SDT-RT of deep-seated tumors.

Dynamic Effects of Endo-Exogenous Stimulations on Enzyme-Activatable Polymeric Nanosystems with Photo-Sono-Chemo Synergy.

Activatable polymeric nanosystems have attracted great interest, and their interactions with endo-exogenous stimulations are highly vital for therapeutic efficacy, which urgently needs systematic study. Herein we focus on systematically investigating these interactions on an enzyme-nanosystem model, the tumor-overexpressed hyaluronidase (HAase) and the doxorubicin-loaded hyaluronic-acid-porphyrin nanoassemblies (DOX@HPNAs), to augment photo-sono-chemo therapies. The HAase degrades the HPNAs in acidic solution at a higher rate than that in neutral solution, which leads to structure disassembly at the nano level, chain cleavage at the molecular level, and strong radiative recovery at the energy level. Upon excitation with light and ultrasound, the enzymatically degraded sample produces ∼2.5 times more singlet oxygen than the HPNAs because of the absence of aggregation-induced quenching and 1O2 migration limitation. The nanosystem can be activated by trimodal stimulations (acidity, ultrasound, and HAase), exerting the controllable release behavior and high release content. Moreover, the nanosystem exhibits synergistic effects among efficient photodynamic therapy, high tissue-penetrating sonodynamic therapy, and lasting chemotherapy, which induces significant necrosis and apoptosis of cancer cells. With high compatibility, tumor-targeting ability, and fluorescent-imaging-guided capability, the nanosystem achieves the highest inhibition rate of malignant tumors than the single or dual-modal therapies. Thus, the enzyme-activatable nanosystem enables the therapeutic synergy and also provides insights to develop other polymeric nanosystems.

On-demand assembly of polymeric nanoparticles for longer-blood-circulation and disassembly in tumor for boosting sonodynamic therapy.

Sonodynamic therapy (SDT) is one of the promising strategies for tumor therapy, but its application is usually hindered by fast clearance in blood-circulation, abnormal tumor microenvironment, and inefficient generation of reactive oxygen species. To solve these problems, we proposed an on-demand assembly-disassembly strategy, where the assembly is favorable for longer-blood-circulation and then the disassembly in tumor is favorable for boosting SDT. Hematoporphyrin monomethyl ether (HMME) as the model of organic sonosensitizers were conjugated with hyaluronic acid (HA). Then HA-HMME was mixed with catalase (CAT) and assembled into polymeric nanoparticles (CAT@HA-HMME NPs) with size of ∼80 nm. CAT@HA-HMME NPs exhibit good biocompatibility and a longer blood half-time (t1/2 = 4.17 h) which is obviously longer than that (∼0.82 h) of HMME molecules. After HA receptor-mediated endocytosis of cancer cells, CAT@HA-HMME NPs can be cleaved by endogenous hyaluronidase, resulting in the on-demand disassembly in tumor to release HA-HMME molecules and CAT. The CAT catalyzes the endogenous H2O2 into O2 to relieve the hypoxic microenvironment, and the released HA-HMME exhibits a higher ROS generation ability, greatly boosting SDT for the inhibition of tumor growth. Therefore, the on-demand assembly-disassembly strategy may provide some insight in the design and development of nanoagents for tumor therapy.

Nanoscale hematoporphrin-based frameworks for photo-sono synergistic cancer therapy via utilizing Al(III) as metal nodes rather than heavy metals.

Nanoscale metal-organic frameworks composed of heavy metal ions (such as Fe3+ and Cu2+) as metal nodes have been utilized for cancer therapy, but they suffer from serious quenching in fluorescence and photo-sono sensitization due to their paramagnetism and unsaturated 3d orbitals. To solve these problems, we synthesize nanoscale hematoporphrin-based frameworks with Al3+ ions as metal nodes (AlHFs) rather than heavy metals and achieve enhanced photo-sono therapy of malignant tumors. The hydrophilic AlHFs are prepared by first assembling hematoporphrin molecules and Al(III) trimers via covalent coordination and then surface-modifying them with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol) (DSPE-PEG) molecules. Under excitation with 660 nm light or ultrasound, AlHFs-PEG can produce 3.6-fold or 2.8-fold more 1O2 species than the as-synthesized nanoscale Fe-hematoporphrin frameworks (FeHFs) because the Al3+ ions without 3d orbitals are not beneficial for energy transfer, while Fe3+ ions with unsaturated 3d orbitals and paramagnetism can cause significant energy transfer. AlHFs-PEG exhibits high biocompatibility and can be engulfed by cells to produce intracellular 1O2 for efficient destruction of cells. With the high biosafety and the photo-sono sensitization, the growth rate of tumors in mice with the AlHFs-PEG injection is significantly inhibited upon exposure to both light and ultrasound, showing higher therapeutic efficacy than photodynamic therapy or sonodynamic therapy alone. Therefore, the present work not only presents the preparation of AlHFs-PEG for tumor photo-sono therapy but also provides some insights for developing nanoscale frameworks with light metal ions as metal nodes.

Multifunctional Doxorubicin@Hollow-Cu9S8 nanoplatforms for Photothermally-Augmented Chemodynamic-Chemo therapy.

Multimodal therapy has attracted increasing interests in tumor treatment due to its high anti-cancer efficacy, and the key is to develop multifunctional nanoagents. The classic multifunctional nanoagents are made up of expensive and complex components, leading to limited practical applications. To solve these problems, we have developed the polyethylene glycol (PEG) coated hollow Cu9S8 nanoparticles (H-Cu9S8/PEG NPs), whose H-Cu9S8 component exhibits the photothermal effect for near-infrared (NIR) photothermal therapy (PTT), the Fenton-like catalytic activity for chemodynamic therapy (CDT), and the drug-loading capacity for chemotherapy. The H-Cu9S8/PEG NPs with a diameter of âˆ¼ 100 nm have been synthesized by sulfurizing cuprous oxide (Cu2O) nanoparticles through "Kirkendall effect", and they exhibit high photothermal conversion efficiency of 40.9%. Meanwhile, the H-Cu9S8/PEG NPs are capable of a Fenton-like reaction, which can be augmented by 2 times under the NIR irradiation. The hollow structure gives the H-Cu9S8/PEG high doxorubicin (DOX) loading capacity (21.1%), and then the DOX release can be further improved by pH and photothermal effect. When the DOX@H-Cu9S8/PEG dispersions are injected into the tumor-bearing mice, the tumor growth can be efficiently inhibited due to the synergistic effect of photothermally-augmented CDT-chemo therapy. Therefore, the DOX@H-Cu9S8/PEG can serve as a multifunctional nanoplatform for photothermally-augmented CDT-chemo treatment of malignant tumors.