Research Article: Focused Ultrasound‐Augmented Delivery of Biodegradable Multifunctional Nanoplatforms for Imaging‐Guided Brain Tumor Treatment

Date Published: January 10, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Meiying Wu, Wenting Chen, Yu Chen, Haixian Zhang, Chengbo Liu, Zhiting Deng, Zonghai Sheng, Jingqin Chen, Xin Liu, Fei Yan, Hairong Zheng.


The blood brain barrier is the main obstacle to delivering diagnostic and therapeutic agents to the diseased sites of brain. It is still of great challenge for the combined use of focused ultrasound (FUS) and theranostic nanotechnology to achieve noninvasive and localized delivery of chemotherapeutic drugs into orthotopic brain tumor. In this work, a unique theranostic nanoplatform for highly efficient photoacoustic imaging‐guided chemotherapy of brain tumor both in vitro and in vivo, which is based on the utilization of hollow mesoporous organosilica nanoparticles (HMONs) to integrate ultrasmall Cu2−xSe particles on the surface and doxorubicin inside the hollow interior, is synthesized. The developed multifunctional theranostic nanosystems exhibit tumor‐triggered programmed destruction due to the reducing microenvironment‐responsive cleavage of disulfide bonds that are incorporated into the framework of HMONs and linked between HMONs and Cu2−xSe, resulting in tumor‐specific biodegradation and on‐demand drug‐releasing behavior. Such tumor microenvironment‐responsive biodegradable and biocompatible theranostic nanosystems in combination with FUS provide a promising delivery nanoplatform with high performance for orthotopic brain tumor imaging and therapy.

Partial Text

Nanobiotechnology based on versatile organic and inorganic systems has contributed significantly to the fast development of drug delivery nanosystems for efficient cancer diagnosis and treatment. Compared with traditional organic nanosystems, biodegradable inorganic nanoplatforms have attracted widespread attention due to their intrinsic characteristics including multifunctionality, excellent biocompatibility, and relatively high stability in the body fluids, as well as controlled release of therapeutic agents from nanocarriers in the desired sites, especially in the tumor cells.1 Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor with a 5 year survival rate of less than 5%.2 Pathologically, glioblastoma diffusely infiltrates normal brain and resides behind a relatively impermeable blood‐brain barrier (BBB), causing the significant challenges for effective neurosurgical management and targeted delivery of chemotherapeutic drugs.3 The construction and localized delivery of cancer‐associated, stimuli‐driven biodegradable nanosystems for GBM theranostics (diagnosis and therapy) are of great significance for achieving the desirable theranostic outcome.

In summary, a highly efficient HCu theranostic nanoplatform has been successfully constructed for combating the brain tumor, which is based on the rational integration of organic–inorganic hybrid HMONs with ultrasmall Cu2−xSe nanoparticles on the surface. Especially, the disulfide bonds incorporated into the framework of HMONs and linked between HMONs and Cu2−xSe are physiologically active, which can be broken up in the reducing condition of TME, resulting in improved biodegradation and excretion of HCu nanosystems. The rapid biodegradation of HCu could promote anticancer drug release and enhance therapeutic efficacy. Importantly, excellent PA imaging contrast performance and tumor‐inhibition effect by concurrent use of HCu nanosystems and FUS‐BBB opening have been demonstrated in orthotopic brain tumor. Moreover, the obtained HCu nanosystems exhibit lowered hemolysis against red blood cells, negligible systematic toxicities, and high histocompatibility. Therefore, FUS‐mediated HCu delivery nanosystems are expected to provide new insight into TME‐related nanotechnology for the theranostics of orthotopic brain tumor.

Materials: Tetraethyl orthosilicate (TEOS), triethanolamine (TEA), hydrochloric acid (HCl, 37%), ethanol, and ammonia solution (25–28%) were purchased from Sinopharm Chemical Reagent Co. Cetyltrimethylammonium chloride (CTAC, 25 wt%), MPTMS, 2,2′‐dipyridyl disulfide (DPDS), and glutathione (GSH) were obtained from Sigma‐Aldrich. BTDS was bought from Lark Chemical Technology Co., Ltd. Cell counting Kit‐8 (CCK‐8) and phosphate buffer solution (PBS) was purchased from Beyotime Institute of Biotechnology. All chemicals were used as received without further purification, and their aqueous solutions were prepared using deionized water.

The authors declare no conflict of interest.




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