Nanosonosensitizer‐Augmented Sono‐Immunotherapy for Glioblastoma by Non‐Invasive Opening of the Blood–Brain Barrier

Abstract

The presence of blood-brain barrier (BBB) that limits effective penetration of therapeutics is the main reason for poor outcomes of glioblastoma (GBM) treatment. Ultrasound (US) combined with microbubbles (MBs) can precisely disrupt the tight junctions of brain endothelial cells, thus creating "acoustic pores" and non-invasive opening the BBB. Here, chitosan oligosaccharide (COS) is conjugated with a sonosensitizer protoporphyrin IX (PpIX) and an immune-enhancing adjuvant Poly(I:C) via electrostatic adsorption, and crosslinked with a tumor-targeting molecule hyaluronic acid (HA) affording nanosonosensitizers HA-Poly(I:C)/COS-PpIX (abbreviated as "HP/CP" NSs). HP/ CP NSs can target and penetrate GBMs, and trigger reactive oxygen species production upon US, simultaneously causing mitochondrial dysfunction and DNA damage. Tumor-associated antigens released by sonodynamic therapyinduced immunogenic cell death and loaded Poly(I:C) form an in situ vaccine together to potentiate antitumor immune responses. In orthotopic GBM mice models, the HP/CP+US treatments prolong mice survival, enhance cytotoxic T-lymphocytes infiltration, and activate peripheral immune circulation. Besides, HP/CP NSs possess favorable biosafety profiles. Collectively, this study sheds light on the application of HP/CP NSs for synergistic sonoimmunotherapy of GBMs after non-invasive opening of the BBB.

Ultrasound‐Sensitive Intelligent Nanosystems: A Promising Strategy for the Treatment of Neurological Diseases

“…In addition to their role in transporting therapeutic drugs across the BBB, the function of USINs as a treatment for PD was also explored. Kim and colleagues developed a novel therapeutic strategy for treating PD using piezoelectric material- Cur-NBs 1 MHz, 1 min PD mice [191] PD BTNP-pDA-BNN6 1.5 MHz, 462.4 W cm −2 , 1 min PD mice [193] PD C@BT 120 W cm −2 , 10 min PD zebrafish [167] AD NB (11a)-A and NB(11a)-R 1 MHz, 2 min AD mice [195] AD Qc@SNPs-MB 1000 kPa, 10 min AD mice [196] AD PX@OP@RVG 1 MHz, 3.0 W cm −2 , 3 min AD mice [120] Epilepsy Propofol-loaded nanoemulsions 1 MHz Epilepsy rats [200] GBM MDNPs 1 MHz, 0.5 W cm −2 , 5 min Orthotopic GBM mice [206] GBM HP/CP 1 MHz 1.5 W cm −2 , 2 min Orthotopic GBM mice [207] Neuromodulation BNNTs 20 W, 40 kHz, 5 s PC12 neurites [208] Neuromodulation BaTiO 3 1 MHz, 1.0 W cm −2 , 50% duty cycle, 3 min Cortical and hippocampal neurons from the rat embryo [209] Neuromodulation MoS 2 NS 2 MHz, 400 kPa, 1 000 000 cycles, 500 ms…”

“…In addition to combining SDT with chemotherapy to enhance antitumor effects, Guan et al combined the sonosensitizer PpIX with the immune adjuvant polyinosinicpolycytidylic acid (Poly(I:C)) (HP/CP NSs), to achieve enhanced SDT and immunotherapy for orthotopic GBM (Figure 15f). [207] HP/CP NSs could cross the BBB and generate ROS under ultrasound irradiation, leading to mitochondrial dysfunction and DNA damage (Figure 15g,h). Meanwhile, tumor immunogenic cell death was triggered by sonodynamic releases tumor-associated antigens, which can be combined with adjuvants to form in situ vaccines at tumor sites and enhance antitumor immune responses.…”

“…The tumor location is indicated by black circles. Reproduced with permission [207]. Copyright 2023, WILEY-VCH.…”

Boosting Sono-immunotherapy of Prostate Carcinoma through Amplifying Domino-Effect of Mitochondrial Oxidative Stress Using Biodegradable Cascade-Targeting Nanocomposites

“…With the advancement of nanomaterials and nanotechnology, a plethora of cancer treatment modalities have been developed to induce ICD and augment the body’s immune response capability, thereby achieving nanomaterial-mediated synergistic immunotherapy, including chemo-immunotherapy, radio-immunotherapy, photoimmunotherapy, sono-immunotherapy, and on the like. − Among them, sono-immunotherapy stands out as a reactive oxygen species (ROS)-mediated localized tumor therapeutic modality with the advantages of spatiotemporal control, minimal adverse effects, noninvasiveness, good biosafety, and high tissue penetration. − More importantly, the interaction of ultrasound (US) and sonosensitizers enables strict regulation of the production and accumulation of intracellular ROS, thus destroying the antioxidant defense (AOD) mechanism of tumor cells to induce ICD and further activate the tumor-specific immune response. Therefore, sono-immunotherapy is considered to be a promising antitumor strategy. , In recent years, various sonosensitive nanoplatforms have been developed and widely used in sono-immunotherapy. , However, these nano agents are faced with similar five-step “blood circulation-tumor accumulation-tumor penetration-tumor internalization-drug release (CAPIR) cascade” limitations of chemotherapy.…”

A Cancer Nanovaccine Based on an FeAl-Layered Double Hydroxide Framework for Reactive Oxygen Species-Augmented Metalloimmunotherapy

“…Therapeutic cancer vaccines are a type of immunotherapy that train the immune system to suppress tumor growth, recurrence, and metastasis. − Although a few general immunostimulants, such as sipuleucel-T (Provenge) and talimogene laherparepvec (T-VEC), have shown some clinical efficacy, the heterogeneity of individual tumors renders the effectiveness of general stimulants often far from optimal. , Thus, a more personalized strategy is to extract tumor-associated antigens (TAAs) from patients, engineer them ex vivo with adjuvants to form vaccines, and then reinfuse them back into patients to activate specific immune responses. However, this process can be quite time-consuming and costly and cause systemic toxicity. , As a potential alternative, in situ vaccines may be a more efficient and safer choice for use in patients. − Nanomaterials-based chemodynamic therapy, photothermal therapy, ion interference therapy, and chemotherapy have all been shown in mice models to stimulate tumors to release TAAs in situ to generate cancer nanovaccines, thereby avoiding the complicated process of preidentifying, isolating, and processing TAAs. − Therefore, the approach of transforming tumors into cancer nanovaccines has emerged as an attractive alternative that may make precision immunotherapy available to more patients with cancer. − …”