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Abstract Pancreatic ductal adenocarcinoma (PDAC) poses challenges due to late-stage diagnosis and limited treatment response, often attributed to the hypoxic tumor microenvironment (TME). Sonoporation, combining ultrasound and microbubbles, holds promise for enhancing therapy. However, additional preclinical research utilizing commercially available ultrasound equipment for PDAC treatment while delving into the TME's intricacies is necessary. This study investigated the potential of using a clinically available ultrasound system and phase 2-proven microbubbles to relieve tumor hypoxia and enhance the efficacy of chemotherapy and immunotherapy in a murine PDAC model. This approach enables early PDAC detection and blood-flow-sensitive Power-Doppler sonoporation in combination with chemotherapy. It significantly extended treated mice's median survival compared to chemotherapy alone. Mechanistically, this combination therapy enhanced tumor perfusion and substantially reduced tumor hypoxia (77% and 67%, 1- and 3-days post-treatment). Additionally, cluster of differentiation 8 (CD8) T-cell infiltration increased four-fold afterward. The combined treatment demonstrated a strengthening of the anti-programmed death-ligand 1(αPDL1) therapy against PDAC. Our study illustrates the feasibility of using a clinically available ultrasound system with NH-002 microbubbles for early tumor detection, alleviating hypoxic TME, and improving chemotherapy and immunotherapy. It suggests the development of an adjuvant theragnostic protocol incorporating Power-Doppler sonoporation for pancreatic tumor treatment.

Glioblastoma multiforme (GBM) is one of the most aggressive, incurable, and difficult‐to‐treat malignant brain tumor with very poor survival rates. The gold standard in treating GBMs includes neurosurgical resection of the tumor, followed by the chemotherapy and radiotherapy. However, these strategies remain ineffective in treating patients with GBMs, as tumor recurrence always occur in most cases. Therefore, it remains a grand challenge to develop an effective strategy to combat orthotopic glioblastoma with simultaneous imaging capabilities to monitor the therapeutic outcomes. To tackle this challenge, this study demonstrates, for the first time, that a tumor‐specific europium hexaboride (EuB6)‐based nanomedicine surface‐modified with RGD‐K peptide to target αvβ3 integrin receptors overexpressed on the glioblastoma cells. Further, EuB6@RGD‐K NPs are able to exert theranostic capabilities to effectively diagnose and combat difficult‐to‐treat orthotopic glioblastoma tumors using NIR‐II 1064 nm and NIR‐III 1550 nm photodynamic therapy (NIR PDT) effects. In the in vivo experiments, the average half‐life of 55 d for mice treated with EuB6@RGD‐K NPs and exposed to NIR‐III 1550 nm light irradiation is far higher than that of EuB6@RGD‐K NPs exposed to NIR‐II 1064 nm light irradiation (25 d), PBS‐treated mice (20 d) and EuB6@RGD‐K NPs‐treated mice (no light irradiation, 18 d). To the best of our knowledge, this work represents the first example for destructing murine brain tumors via multi‐functional tumor‐specific europium hexaboride‐based nanotheranostic agent to mediate MR imaging‐guided NIR‐II/‐III photodynamic therapy.

Abstract Background It is well known that tumor-associated macrophages (TAMs) play essential roles in brain tumor resistance to chemotherapy. However, the detailed mechanisms of how TAMs are involved in brain tumor resistance are still unclear and lack a suitable analysis model. Methods A BV2 microglial cells with ALTS1C1 astrocytoma cells in vitro co-culture system was used to mimic the microglia dominating tumor stroma in the tumor invasion microenvironment and explore the interaction between microglia and brain tumor cells. Results Our result suggested that microglia could form colonies with glioma cells under high-density culturing conditions and protect glioma cells from apoptosis induced by chemotherapeutic drugs. Moreover, this study demonstrates that microglia could hijack drug substances from the glioma cells and reduce the drug intensity of ALTS1C1 via direct contact. Inhibition of gap junction protein prevented microglial-glioma colony formation and microglia-mediated chemoresistance. Conclusions This study provides novel insights into how glioma cells acquire chemoresistance via microglia-mediated drug substance transferring, providing a new option for treating chemo-resistant brain tumors.

Tissue-clearing and labeling techniques have revolutionized brain-wide imaging and analysis, yet their application to clinical formalin-fixed paraffin-embedded (FFPE) blocks remains challenging. We introduce HIF-Clear, a novel method for efficiently clearing and labeling centimeter-thick FFPE specimens using elevated temperature and concentrated detergents. HIF-Clear with multi-round immunolabeling reveals neuron circuitry regulating multiple neurotransmitter systems in a whole FFPE mouse brain and is able to be used as the evaluation of disease treatment efficiency. HIF-Clear also supports expansion microscopy and can be performed on a non-sectioned 15-year-old FFPE specimen, as well as a 3-month formalin-fixed mouse brain. Thus, HIF-Clear represents a feasible approach for researching archived FFPE specimens for future neuroscientific and 3D neuropathological analyses.