Immobilization of horseradish peroxidase on metal-organic framework to imporve enzyme activity for enhanced chemodynamic therapy.

Bio-enzymes have the advantages of strong substrate specificity, high catalytic efficiency, and minimal toxic side effects, making them promising drugs in cancer therapy. However, the poor stability and cellular penetrability of uncoated protein in the physiological environment severely restricts the direct application of Bio-enzyme. To address it, we report a metal-organic framework (MOF), Hf-DBA (H2DBA, biphenyl carboxylic acid ligands). The morphology of the Hf-DBA was revealed by TEM and the diameter was in the range of 200 to 350 nm. Hf-DBA acted a carrier for intracellular delivery and protection of horseradish peroxidase (HRP). The prepared HRP@Hf-DBA can catalyze the excess H2O2 in the tumor cells to generation of •OH for chemodynamic therapy (CDT). Compared with free HRP, the catalytic activity of HRP@Hf-DBA is significantly improved, and the optimal catalytic conditions are explored. The catalytic stability of HRP@Hf-DBA remained above 70% after 12 cycles of catalysis. After treatment with HRP@Hf-DBA, the apoptosis rates of A549 and Hela cells was 71.64%, and 76.86%. The results in vitro show that HRP@Hf-DBA can effectively inhibit the growth of tumor cells through enhanced CDT.

New Xanthene Dyes with NIR-II Emission Beyond 1200 nm for Efficient Tumor Angiography and Photothermal Therapy.

Fluorescence (FL) bioimaging in the second near-infrared window (NIR-II, 1000-1700 nm) provides improved imaging quality and high resolution for diagnosis of deep-seated tumors. However, integrating FL bioimaging and photothermal therapy (PTT) in a single photoactive molecule exhibits a great challenge because a dramatic increase of PTT in the NIR-II window benefitting from the nonradiative decay will sacrifice the fluorescence brightness that is unfavorable for FL bioimaging. Therefore, balancing the radiative decay and nonradiative decay is an effective and rational design strategy. Herein, four NIR-II xanthene dyes (CL1-CL4) are synthesized with maximal emission beyond 1200 nm under 1064 nm excitation. CL4 exhibits the largest fluorescence quantum yield and a significant fluorescence enhancement after complexation with fetal bovine serum (FBS). As-prepared CL4/FBS has a maximal emission of 1235 nm and a high photothermal conversion efficiency of 36% under 1064 nm excitation. Bright and refined tumor vessels with a fine resolution of 0.23 mm can be clearly distinguished by CL4/FBS. In vivo studies show that a balanced utilization of fluorescence and photothermy in the NIR-II window is successfully achieved with superior biocompatibility. This efficient strategy provides promising avenue for precise theranostics of deep tumors.

A novel hypocrellin-based assembly for sonodynamic therapy against glioblastoma.

The non-invasive treatment of glioblastoma (GBM) is of great significance and can greatly reduce the complications of craniotomy. Sonodynamic therapy (SDT) is an emerging tumor therapeutic strategy that overcomes some fatal flaws of photodynamic therapy (PDT). Different from PDT, SDT has deep tissue penetration and can be applied in the non-invasive treatment of deep-seated tumors. However, effective sonosensitizers that can be used for SDT of GBM are still very rare. Herein, we have prepared a suitable assembly based on a hypocrellin derivative (CTHB) with good biocompatibility. Excitedly, the hypocrellin-based assembly (CTHB NPs) can effectively produce reactive oxygen species under ultrasound stimulation. The inherent fluorescence and photoacoustic imaging characteristics of the CTHB NPs are conducive to the precise positioning of the tumors. It has been proved both in subcutaneous and in intracranial tumor models that CTHB NPs can be used as an effective sonosensitizer to inhibit tumor growth under ultrasound irradiation. This hypocrellin-based assembly has a good clinical prospect in the non-invasive treatment of GBM.

Amphiphilic Diketopyrrolopyrrole Derivatives for Efficient Near-Infrared Fluorescence Imaging and Photothermal Therapy.

The design and synthesis of single-molecule amphiphilic and multifunctional phototherapeutic agents are important to cancer diagnosis and therapy. In this work, we developed three amphiphilic diketopyrrolopyrrole derivatives (TPADPP, DTPADPP, and TPADDPP) with different donor-acceptor structures and poly(ethylene glycol) side chains. The corresponding nanoparticles (NPs) were obtained via a self-assembly from three amphiphilic DPP derivatives and used as smart phototherapeutic agents for tumor diagnosis and treatment. The three amphiphilic DPP NPs exhibited near-infrared (NIR) emissions and good biocompatibility. Thus, they could be used as fluorescence (FL) imaging agents for guided therapy. DTPADPP NPs and TPADDPP NPs also displayed excellent photothermal performance and high accumulation in the tumor. Owing to these beneficial features, the DTPADPP NPs and TPADDPP NPs synthesized herein are suitable for NIR FL imaging and effective photothermal therapy against the tumor in vivo.

Multifunctional sonosensitizers in sonodynamic cancer therapy.

Phototherapy, including photodynamic therapy and photothermal therapy, has the potential to treat several types of cancer. However, to be an effective anticancer treatment, it has to overcome limitations, such as low penetration depth, low target specificity, and resistance conferred by the local tumor microenvironment. As a non-invasive technique, low-intensity ultrasound has been widely used in clinical diagnosis as it exhibits deeper penetration into the body compared to light. Recently, sonodynamic therapy (SDT), a combination of low-intensity ultrasound with a chemotherapeutic agent (sonosensitizer), has been explored as a promising alternative for cancer therapy. As all known cancer treatments such as chemotherapy, photodynamic therapy, photothermal therapy, immunotherapy, and drug delivery have been advanced independently enough to complement others substantially, the combination of these therapeutic modalities with SDT is opportune. This review article highlights the recent advances in SDT in terms of sonosensitizers and their formulations and anticancer therapeutic efficacy. Also discussed is the potential of SDT in combination with other modalities to address unmet needs in precision medicine.

Organic Dye Nanoparticles with a Special D-π-A Structure for Photoacoustic Imaging and Photothermal Therapy.

FTC dye with a D-π-A structure showed outstanding stability, high extinction coefficient, and good photothermal performance. Thus, nanoparticles based on FTC dye were first fabricated by a nanoprecipitation method for photothermal therapy (PTT) which was guided by photoacoustic imaging (PAI). The prepared FTC NPs showed a photothermal conversion efficiency of ∼52.71%, good photoacoustic performance, and excellent stability in in vitro experiments. Moreover, FTC NPs showed good performance in tumor ablation under a 635 nm laser irradiation and low cytotoxicity to the mice model without laser treatment. Histopathological analysis further confirmed that FTC NPs did not harm the major organs of mice. Given the abovementioned features, FTC NPs have great potential to be effective phototheranostic materials for PAI and PTT.

Hypocrellin-Based Multifunctional Phototheranostic Agent for NIR-Triggered Targeted Chemo/Photodynamic/Photothermal Synergistic Therapy against Glioblastoma.

A huge challenge exists in the diagnosis and treatment of malignant glioblastoma (GBM) due to the presence of the blood-brain barrier (BBB). Herein, a multifunctional phototheranostic agent is designed on the basis of an octadecane-modified temozolomide (TMZ-C18) for chemotherapy, a dicysteamine-modified hypocrellin derivative (DCHB) as a natural-origin photosensitizer with a singlet oxygen (1O2) quantum yield of 0.51, and a cyclic peptide (cRGD) as a targeting unit against glioblastoma. Co-encapsulated DCHB and TMZ-C18 assembly with cRGD decoration, referred to as DTRGD NPs, shows a wide absorption at the NIR region peaked at 703 nm, an NIR emission peak at 720 nm, good photostability, high photothermal conversion efficiency (33%), and effective degradation of TMZ-C18. More importantly, DTRGD NPs can efficiently break through the blood-brain barrier and enrich in the orthotopic glioblastoma. The treatment of subcutaneous U87MG tumor beard mice demonstrates that DTRGD NPs present remarkable anticancer efficiency and the targeted chemo/photodynamic/photothermal synergistic therapy can be achieved with almost no toxicity. This multifunctional phototheranostic agent shows great potential for the diagnosis and treatment of glioblastoma.

Natural-Origin Hypocrellin-HSA Assembly for Highly Efficient NIR Light-Responsive Phototheranostics against Hypoxic Tumors.

Tumor hypoxia severely limits the therapeutic efficacy of solid tumors in photodynamic therapy. One strategy is to develop photosensitizers with simultaneously high efficiency in photodynamic (PDT) and photothermal therapies (PTT) in a single natural-origin phototheranostic agent to overcome this problem. However, less attention has been paid to the natural-origin phototheranostic agent with high PDT and PTT efficiencies even though they have negligible side effects and are environmentally sustainable in comparison with many reported phototheranostic agents. In addition, almost all clinical applied photosensitizers are of natural origin so far. Herein, we synthesized a natural product-based hypocrellin derivative (AETHB), with a high singlet oxygen quantum yield of 0.64 as an efficient photosensitizer different from commercially available porphyrin-based photosensitizers. AETHB is further assembled with human serum albumin to construct nanoparticles (HSA-AETHB NPs) with a high photothermal conversion efficiency (more than 50%). As-prepared HSA-AETHB NPs have shown good water solubility and biocompatibility, pH and light stability, wide absorption (400-750 nm), and NIR emission centered at 710 nm. More importantly, HSA-AETHB NPs can be applied for fluorescent/photoacoustic dual-mode imaging and simultaneously highly efficient PDT/PTT in hypoxic solid tumors. Therefore, this natural-origin multifunctional phototheranostic agent is showing very promising for effective, precise, and safe cancer therapy in clinical applications.