Sequential Ultrasound-Triggered and Hypoxia-Sensitive Nanoprodrug for Cascade Amplification of Sonochemotherapy

Abstract

Hypoxia, the typical and conspicuous characteristic of most solid tumors, worsens the tumor invasiveness and metastasis. Here, we engineered a sequential ultrasound (US)/hypoxia-sensitive sonochemotherapeutic nanoprodrug by initially synthesizing the hypoxia-activated azo bond-containing camptothecin (CPT) prodrug (CPT2-Azo) and then immobilizing it into the mesopores of sonosensitizer-integrated metal organic frameworks (MOF NPs). Upon entering the hypoxic tumor microenvironment (TME), the structure of CPT2-Azo immobilized MOFs (denoted as MCA) was ruptured and the loaded nontoxic CPT2-Azo prodrug was released from the MOF NPs. Under US actuation, this sonochemotherapeutic nanoprodrug not only promoted sonosensitizer-mediated sonodynamic therapy (SDT) via the conversion of oxygen into cytotoxic reactive oxygen species (ROS) but also aggravated hypoxia in the TME by elevating oxygen consumption. The exacerbated hypoxia in turn served as a positive amplifier to boost the activation of CPT2-Azo, and the controllable release of toxic chemotherapeutic drug (CPT), and compensated the insufficient treatment efficacy of SDT. In vitro and in vivo evaluations confirmed that sequential SDT and tumor hypoxia-activated sonochemotherapy promoted the utmost of tumor hypoxia and thereby contributed to the augmented antitumor efficacy, resulting in conspicuous apoptotic cell death and noteworthy tumor suppression in vivo. Our work provides a distinctive insight into the exploitation of the hypoxia-activated sonochemotherapeutic nanoprodrug that utilizes the hypoxic condition in TME, a side effect of SDT, to initiate chemotherapy, thus causing a significantly augmented treatment outcome compared to conventional SDT.

NIR‐II Fluorescence Imaging‐Guided Oxygen Self‐Sufficient Nano‐Platform for Precise Enhanced Photodynamic Therapy

“…The antitumor activity of LSCaFPCe6 nanodrugs was initially investigated at a cellular level using the cell‐counting kit‐8 (CCK‐8) assay. [ 12 ] To demonstrate cell biocompatibility, the THLE‐3 and 293T cells were treated with different nanomaterials at different doses ( Figure A and Figure S13, Supporting Information). The cell survival rate was above 70% even after 48 h of co‐incubation with LSCaFPCe6 at a high concentration of 160 µg mL −1 .…”

Triarylboron‐Doped Acenethiophenes as Organic Sonosensitizers for Highly Efficient Sonodynamic Therapy with Low Phototoxicity

“…The fast development of novel minimally invasive or noninvasive therapeutic modalities has been considered as one of as more promising SDT candidates due to their well-defined molecular structures achieved by controlled synthetic modification and excellent biocompatibility. [18,19] At present, various organic sonosensitizers have been adopted for SDT, including porphyrin and their derivatives, [20][21][22][23][24] xanthenes, [25][26][27][28] some anticancer drugs, [29][30][31] and other small-molecule agents such as hypocrellin B, indocyanine green and IR780. [32][33][34][35] However, most organic sonosensitizers are derived from photosensitizers, and their potential phototoxicity issues hinder their further clinical translation.…”

A Unique Chemo-photodynamic Antitumor Approach to Suppress Hypoxia via Ultrathin Graphitic Carbon Nitride Nanosheets Supported a Platinum(IV) Prodrug

“…17 Besides, hypoxia results in an elevated level of regulatory transcription factors like hypoxia inducible factor 1α (HIF-1α) that plays a prominent part in tumorigenesis, angiogenesis, and resistance to therapy. 18,19 According to the reports, overexpression of HIF-1α exists in the majority of human cancers and is related to bad prognosis of patients, 20 which makes HIF-1α a valuable target for developing new anticancer drugs. At present, many studies have reported optimizing the materials themselves to improve the therapeutic efficiency by supplementing oxygen at the lesion site or aiming at the characteristics of the hypoxic microenvironment.…”

“…Generally, owing to the consumption of O 2 during PDT, tumor hypoxia is further aggravated, which leads to PDT resistance in the necrotic and hypoxic areas of solid tumors . Besides, hypoxia results in an elevated level of regulatory transcription factors like hypoxia inducible factor 1α (HIF-1α) that plays a prominent part in tumorigenesis, angiogenesis, and resistance to therapy. , According to the reports, overexpression of HIF-1α exists in the majority of human cancers and is related to bad prognosis of patients, which makes HIF-1α a valuable target for developing new anticancer drugs.…”