Biomimetic Nanosonosensitizers Combined with Noninvasive Ultrasound Actuation to Reverse Drug Resistance and Sonodynamic-Enhanced Chemotherapy against Orthotopic Glioblastoma

Abstract

Glioblastoma (GBM) is the most devastating brain tumor and highly resistant to conventional chemotherapy. Herein, we introduce biomimetic nanosonosensitizer systems (MDNPs) combined with noninvasive ultrasound (US) actuation for orthotopic GBM-targeted delivery and sonodynamic-enhanced chemotherapy. MDNPs were fabricated with biodegradable and pH-sensitive polyglutamic acid (PGA) and the chemotherapeutic agent and sonosensitizer doxorubicin (DOX), camouflaged with human GBM U87 cell membranes. MDNPs presented homologous targeting accumulation and in vivo long-term circulation ability. They effectively passed through the blood−brain barrier (BBB) under US assistance and reached the orthotopic GBM site. MDNPs exhibited controllable US-elicited sonodynamic effect by generation of reactive oxygen species (ROS). ROS not only induced cancer cell apoptosis but also downregulated drug-resistance-related factors to disrupt chemoresistance and increase sensitivity to chemotherapy. The in vivo study of orthotopic GBM treatments further proved that MDNPs exhibited US-augmented synergistic antitumor efficacy and strongly prolonged the survival rate of mice. The use of low-dose DOX and the safety of US enabled repeated treatment (4 times) without obvious cardiotoxicity. This effective and safe US-enhanced chemotherapy strategy with the advantages of noninvasive brain delivery and high drug sensitivity holds great promise for deep-seated and drug-resistant tumors.

Nanoparticles Mediated the Diagnosis and Therapy of Glioblastoma: Bypass or Cross the Blood–Brain Barrier

“…With poor degradation and clearance of drugs [37][38][39] Tight junction modulation Feasibly permit paracellular drug transport Nonspecific and nonselective strategy [42][43][44][45][46][47][48][49][50] Extra stimuli-mediated transport administration of drugs into the skull as a new approach for bypassing the BBB (Figure 7). They used a 3D printing technique and designed a specific intracalvaiosseous administration device (ICO device), which was suitable for the mouse skull.…”

“…Another study by Chen et al involved the preparation of a biomimetic nanosonosensitizer nanosystem coated with membrane-DOX nanoparticles (MDNPs) (Figure 12B). [50] MDNPs with homologous targeting ability effectively cross the BBB with ultrasound (US) assistance and reach the orthotopic glioblastoma. MDNPs entered the glioblastoma cells and released DOX in the endo/lysosome.…”

ROS-Triggered Self-Assembled Nanoparticles Based on a Chemo-Sonodynamic Combinational Therapy Strategy for the Noninvasive Elimination of Hypoxic Tumors

“…Ultrasound (US) irradiation activates the sonosensitizer accumulated at the tumor site and excites large amounts of reactive oxygen species (ROS) to kill tumor cells . SDT mainly produces high-energy singlet oxygen ( 1 O 2 ) and hydroxyl radicals ( • OH), which cause apoptosis of tumor cells. , Additionally, US radiation rapidly raises the mechanical pressure of the tissue fluid, and the development of numerous cavitated microbubble triggers mechanical dynamic processes that lead to ROS generation, cell membrane rupture, and increased permeability. , SDT has been successively incorporated into clinical treatment protocols for a variety of tumors, including pancreatic, hepatocellular, and urologic cancers. − And nanoparticles containing IR780 and perfluoro-hexane have been used in SDT for CCa based on the idea of pretreatment penetration . SDT generates ROS that break the intracellular redox balance and is a reliable option for effective noninvasive treatment of hypoxic cervical tumors …”

“…12 SDT mainly produces high-energy singlet oxygen ( 1 O 2 ) and hydroxyl radicals ( • OH), which cause apoptosis of tumor cells. 13,14 Additionally, US radiation rapidly raises the mechanical pressure of the tissue fluid, and the development of numerous cavitated microbubble triggers mechanical dynamic processes that lead to ROS generation, cell membrane rupture, and increased permeability. 15,16 SDT has been successively incorporated into clinical treatment protocols for a variety of tumors, including pancreatic, hepatocellular, and urologic cancers.…”

Modulation of Intratumoral Fusobacterium nucleatum to Enhance Sonodynamic Therapy for Colorectal Cancer with Reduced Phototoxic Skin Injury

“…Due to its ability to deeply penetrate tissues and ensure safety, sonodynamic therapy (SDT) shows great potential as a supplementary technique to traditional cancer treatments, making it an emerging and promising method in the field of cancer treatment. − Ultrasonic (US) is utilized by SDT to stimulate sonosensitizers, resulting in the generation of reactive oxygen species (ROS) that trigger cancer cell apoptosis. − Currently, organic sonosensitizers for SDT are frequently developed from organic porphyrins and their derivatives, such as hematoporphyrin, protoporphyrin IX, and hematoporphyrin monomethyl ether, ,− because of their exceptional attributes including extensive π-electron-conjugated systems as well as versatile optoelectronic and catalytic features. , Several porphyrin-based sonosensitizers have been reported to show effective ROS production upon US radiation for tumor treatment. , However, the TLR4/NF-κB pathway in CRC cells is triggered by F. nucleatum infection, leading to the activation of various antiapoptosis target genes, including TNFR-associated factor (TRAF-1, TRAF-2), BIRC3, inhibitor of apoptosis proteins (IAPs), and Bcl-2, − which resists ROS and promotes cell survival . Therefore, integrating the elimination of intratumoral F. nucleatum and SDT is likely to provide the best choice for improving the efficacy of SDT and obtaining high clinical therapeutic value.…”