Mitochondria-Targeted and Ultrasound-Activated Nanodroplets for Enhanced Deep-Penetration Sonodynamic Cancer Therapy. Zhang Liang,Yi Hengjing,Song Jiao,Huang Ju,Yang Ke,Tan Bin,Wang Dong,Yang Nanlan,Wang Zhigang,Li Xingsheng ACS applied materials & interfaces Sonodynamic therapy (SDT), a promising alternative for cancer therapy, utilizes a sonosensitizer combined with ultrasound (US) irradiation to damage tumor cells/tissues for therapeutic purposes. The ability of sonosensitizers to specifically accumulate in tumor cells/tissues could greatly influence their therapeutic efficiency. In this work, we report the use of US-activated sonosensitizer (IR780)-based nanodroplets (IR780-NDs) for SDT, which provide numerous benefits for killing cancer cells compared with traditional methods. For instance, IR780-NDs showed effective surface-to-core diffusion both in vitro and in vivo. In the presence of US, the acoustic droplet vaporization (ADV) effect significantly assisted the conveyance of IR780-NDs from the circulatory system to tumor regions, and the acoustic wave force also increased the penetration depth within tumor tissues. Furthermore, IR780-NDs possesses mitochondrial targeting capabilities, which improves the precision and accuracy of SDT delivery. During the in vitro assessment, the overproduction of reactive oxygen species (ROS) was observed following mitochondrial targeting, which rendered cancer cells more susceptible to ROS-induced apoptosis. Additionally, IR780-ND is a suitable candidate for photoacoustic and fluorescence imaging and can also enhance US imaging because of the ADV-generated bubbles, which provides the potential for SDT guidance and monitoring. Therefore, with combined modalities, IR780-NDs can be a promising theranostics nanoplatform for cancer therapy. 10.1021/acsami.8b21968
    Size-Modulable Nanoprobe for High-Performance Ultrasound Imaging and Drug Delivery against Cancer. Zhang Lu,Yin Tinghui,Li Bo,Zheng Rongqin,Qiu Chen,Lam Kit S,Zhang Qi,Shuai Xintao ACS nano Among medical imaging modalities available in the clinic, ultrasonography is the most convenient, inexpensive, ionizing-radiation-free, and most common. Micrometer-size perfluorocarbon bubbles have been used as efficient contrast for intravascular ultrasonography, but they are too big for tumor penetration. Nanodroplets (250-1000 nm) encapsulating both perfluorocarbon and drug have been used as an ultrasound-triggered release drug delivery platform against cancer, but they are generally not useful as a tumor imaging agent. The present study aims to develop a type of pH-sensitive, polymersome-based, perfluorocarbon encapsulated ultrasonographic nanoprobe, capable of maintaining at 178 nm during circulation and increasing to 437 nm at the acidic tumor microenvironment. Its small size allowed efficient tumor uptake. At the tumor site, the nanoparticle swells, resulting in lowering of the vaporization threshold for the perfluorocarbon, efficient conversion of nanoprobes to echogenic nano/microbubbles for ultrasonic imaging, and eventual release of doxorubicin from the theranostic nanoprobe for deep tissue chemotherapy, triggered by irradiation with low-frequency ultrasound. 10.1021/acsnano.8b00076
    Fluorinated Chitosan To Enhance Transmucosal Delivery of Sonosensitizer-Conjugated Catalase for Sonodynamic Bladder Cancer Treatment Post-intravesical Instillation. Li Guangzhi,Wang Shupeng,Deng Dashi,Xiao Zhisheng,Dong Ziliang,Wang Zhiping,Lei Qifang,Gao Shan,Huang Guixiao,Zhang Enpu,Zeng Guohua,Wen Zhong,Wu Song,Liu Zhuang ACS nano Sonodynamic therapy (SDT) is a noninvasive ultrasound-triggered therapeutic strategy for site-specific treatment of tumors with great depth penetration. The design of nano-sonosensitizers suitable for SDT treatment of bladder cancer (BCa) post-intravesical instillation has not yet been reported. Herein, a transmucosal oxygen-self-production SDT nanoplatform is developed to achieve highly efficient SDT against BCa. In this system, fluorinated chitosan (FCS) is synthesized as a highly effective nontoxic transmucosal delivery carrier to assemble with -tetra(4-carboxyphenyl)porphine-conjugated catalase (CAT-TCPP). The formed CAT-TCPP/FCS nanoparticles after intravesical instillation into the bladder cavity exhibit excellent transmucosal and intratumoral penetration capacities and could efficiently relieve hypoxia in tumor tissues by the catalase-catalyzed O generation from tumor endogenous HO to further improve the therapeutic efficacy of SDT to ablate orthotopic bladder tumors under ultrasound. Our work presents a nano-sonosensitizer formulation with FCS to enhance transmucosal delivery and intratumoral diffusion and CAT to improve tumor oxygenation, promising for instillation-based SDT to treat bladder tumors without the concern of systemic toxicity. 10.1021/acsnano.9b06689
    Controlled and Tunable Loading and Release of Vesicles by Using Gigahertz Acoustics. Lu Yao,de Vries Wilke C,Overeem Nico J,Duan Xuexin,Zhang Hongxiang,Zhang Hao,Pang Wei,Ravoo Bart Jan,Huskens Jurriaan Angewandte Chemie (International ed. in English) Controllable exchange of molecules between the interior and the external environment of vesicles is critical in drug delivery and micro/nano-reactors. While many approaches exist to trigger release from vesicles, controlled loading remains a challenge. Herein, we show that gigahertz acoustic streaming generated by a nanoelectromechanical resonator can control the loading and release of cargo into and from vesicles. Polymer-shelled vesicles showed loading and release of molecules both in solution and on a solid substrate. We observed deformation of individual giant unilamellar vesicles and propose that the shear stress generated by gigahertz acoustic streaming induces the formation of transient nanopores, with diameters on the order of 100 nm, in the vesicle membranes. This provides a non-invasive method to control material exchange across membranes of different types of vesicles, which could allow site-specific release of therapeutics and controlled loading into cells, as well as tunable microreactors. 10.1002/anie.201810181
    Concurrent Drug Unplugging and Permeabilization of Polyprodrug-Gated Crosslinked Vesicles for Cancer Combination Chemotherapy. Hu Xianglong,Zhai Shaodong,Liu Guhuan,Xing Da,Liang Haojun,Liu Shiyong Advanced materials (Deerfield Beach, Fla.) Combination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains a considerable challenge to achieve synchronized release of both types of drugs due to distinct encapsulation mechanisms; premature release of water-soluble cargos from unstable liposomes and ruptured vesicles is also a major concern. Herein, the fabrication of physiologically stable polyprodrug-gated crosslinked vesicles (GCVs) via the self-assembly of camptothecin (CPT) polyprodrug amphiphiles and in situ bilayer crosslinking through traceless sol-gel reaction is reported. Polyprodrug-GCVs possess high CPT loading (>30 wt%) and minimized leakage of encapsulated hydrophilic doxorubicin (DOX) hydrochloride due to the suppressed permeability of crosslinked membrane, exhibiting extended blood circulation (t > 13 h) with caged cytotoxicity in physiological circulation. Upon cellular uptake by cancer cells, cytosolic reductive milieu-triggered CPT unplugging from vesicle bilayers is demonstrated to generate hydrophilic mesh channels and make the membrane highly permeable. Concurrently, it will promote DOX corelease from hydrophilic lumen (≈36-fold increase). The reduction-activated combination chemotherapeutic potency based on polyprodrug-GCVs is confirmed by both in vitro and in vivo explorations. 10.1002/adma.201706307
    Antitumor Activity of a Unique Polymer That Incorporates a Fluorescent Self-Assembled Metallacycle. Yu Guocan,Zhang Mingming,Saha Manik Lal,Mao Zhengwei,Chen Jin,Yao Yong,Zhou Zijian,Liu Yijing,Gao Changyou,Huang Feihe,Chen Xiaoyuan,Stang Peter J Journal of the American Chemical Society Despite the well-known anticancer activity of mono- and multinuclear platinum complexes, studies of the antitumor performances of platinum-based supramolecular coordination complexes are rare. Herein, we report on the synthesis of a four-armed amphiphilic copolymer, Pt-PAZMB-b-POEGMA, containing a metallacycle M, in which the tetraphenylethene derivative acts as an aggregation-induced emissive fluorescent probe for live cell imaging and the 3,6-bis[trans-Pt(PEt)]phenanthrene (PhenPt) is an anticancer drug. This copolymer was further self-assembled into nanoparticles of different sizes and vesicles depending upon the experimental conditions. The impacts of the morphology and size of the assemblies on their endocytic pathways, uptake rates, internalization amounts, and cytotoxicities were investigated. The self-assemblies were further employed to encapsulate doxorubicin (DOX) to achieve a synergistic anticancer effect. Controlled drug release was also realized via amphiphilicity changes and was driven by a glutathione-induced cascade elimination reaction. The DOX-loaded nanoparticles of around 50 nm in size exhibited an excellent antitumor performance as well as a low systemic toxicity, due to an enhanced permeability and retention effect. 10.1021/jacs.7b09224