Hypoxia-Triggered Self-Assembly of Ultrasmall Iron Oxide Nanoparticles to Amplify the Imaging Signal of a Tumor.

Hypoxia is a common phenomenon among most solid tumors that significantly influences tumor response toward chemo- and radiotherapy. Understanding the distribution and extent of tumor hypoxia in patients will be very important to provide personalized therapies in the clinic. Without sufficient vessels, however, traditional contrast agents for clinical imaging techniques will have difficulty in accumulating in the hypoxic region of solid tumors, thus challenging the detection of hypoxia in vivo. To overcome this problem, herein we develop a novel hypoxia imaging probe, consisting of a hypoxia-triggered self-assembling ultrasmall iron oxide (UIO) nanoparticle and assembly-responding fluorescence dyes (NBD), to provide dual-mode imaging in vivo. In this strategy, we have employed nitroimidazole derivatives as the hypoxia-sensitive moiety to construct intermolecular cross-linking of UIO nanoparticles under hypoxia, which irreversibly form larger nanoparticle assemblies. The hypoxia-triggered performance of UIO self-assembly not only amplifies its T2-weighted MRI signal but also promotes the fluorescence intensity of NBD through its emerging hydrophobic environment incorporated into self-assemblies. In vivo results further confirm that our hypoxic imaging probe can display a prompt MRI signal for the tumor interior region, and its signal enhancement performs a long-term effective feature and gradually reaches 3.69 times amplification. Simultaneously, this probe also exhibits obvious green fluorescence in the hypoxic region of tumor sections. Accordingly, we also have developed a MRI difference value method to visualize the 3D distribution and describe the extent of the hypoxic tumor region within the whole bodies of mice. Due to its notable efficiency of penetration and accumulation inside a hypoxic tumor, our hypoxia imaging probe could also be considered as a potential candidate as a versatile platform for hypoxia-targeted drug delivery, and meanwhile its hypoxia-related therapeutic efficacy can be monitored.

New power of self-assembling carbonic anhydrase inhibitor: Short peptide-constructed nanofibers inspire hypoxic cancer therapy.

Carbonic anhydrase (CA) IX overexpresses exclusively on cell membranes of hypoxic tumors, regulating the acidic tumor microenvironment. Small molecules of CA inhibitor modified with short peptide successfully achieve CA IX-targeted self-assembly that localizes CA inhibitors on hypoxic cancer cell surfaces and enhances their inhibition efficacy and selectivity. CA IX-related endocytosis also promotes selective intracellular uptake of these nanofibers under hypoxia, in which nanofiber structures increase in size with decreasing pH. This effect subsequently causes intracellular acid vesicle damage and blocks protective autophagy. The versatility of tunable nanostructures responding to cell milieu impressively provokes selective toxicities and provides strategic therapy for hypoxic tumors. Moreover, in vivo tests demonstrate considerable antimetastatic and antiangiogenesis effects in breast tumors, and particularly remarkable enhancement of antitumor efficacy in doxorubicin administration. With its biocompatible components and distinctive hypoxia therapies, this nanomaterial advances current chemotherapy, providing a new direction for hypoxic cancer therapy.

Dopamine Delivery via pH-Sensitive Nanoparticles for Tumor Blood Vessel Normalization and an Improved Effect of Cancer Chemotherapeutic Drugs.

Tumor blood vessels have been reported to be abnormal in both structure and function compared with those in normal tissues, leading to a hostile microenvironment and inadequate antitumor drug delivery. Dopamine, a chemical messenger, is proven to inhibit angiogenesis and improve tumor vessel normalization. Here, a mesoporous silicon nanoparticle (MSN) is constructed that is responsive to the weakly acidic pH of the tumor extracellular matrix for steady delivery and tumor-localized release of dopamine. Then MSNs are functionalized with amine conjugated phenylboronicacid molecules, and dopamine is loaded by reacting with phenylboronic acid. In a weakly acidic environment, MSNs intelligently release dopamine due to the hydrolysis of boronic-ester bond between dopamine and phenylboronic acid, resulting in an evident inhibition of vascular endothelial cell migration and tubule formation. It is shown that loading of dopamine into the functional MSNs significantly prolong the circulatory half-life of this small molecule. After intravenous injection to tumor bearing mice, this nanoformulation induce tumor blood vessel normalization, thereby improving the antitumor chemotherapeutic efficacy of doxorubicin. This study demonstrates that the pH-responsive MSN offers great potential for delivery of dopamine in vivo and the normalization of tumor vessels by dopamine can provide an auxiliary treatment for cancer chemotherapeutic drugs.