Glioblastoma is the most common brain primary malignant tumor with the highest mortality. Boron neutron capture therapy (BNCT) can efficiently kill cancer cells on the cellular scale, with high accuracy, short course and low side-effects, which is regarded as the most promising therapy for malignant brain tumors like glioma. As the keypoint of BNCT, all boron delivery agents currently in clinical use are beset by insufficient tumor uptake, especially in the tumor nucleus, which limits the clinical application of BNCT. In this study, nuclear targeting of boron is achieved by DOX-CB, consisting of doxorubicin (DOX) and carborane (CB) utilizing the nuclear translocation property of DOX. The nucleus of GL261 cells takes up almost three times the concentration of boron required for BNCT. To further kill glioma and inhibit recurrence, a new multifunctional nanoliposome delivery system DOX-CB@lipo-pDNA-iRGD is constructed. It combines DOX-CB with immunotherapy strategy of blocking macrophage immune checkpoint pathway CD47-SIRPα by CRISPR-Cas9 system, coupling BNCT with immunotherapy simultaneously. Compared with clinical drug Borocaptate Sodium (BSH), DOX-CB@lipo-pDNA-iRGD significantly enhances the survival rate of tumor-bearing mice, reduces tumor stemness, and improves the prognosis. The excellent curative effect of this nanoliposome delivery system provides an insight into the combined treatment of BNCT.
Graphical Abstract
Boron
neutron capture therapy (BNCT) is a selective biological
targeted nuclide technique for cancer therapy. It has the following
attractive features: good targeting, high effectiveness, and causes
slight damage to surrounding healthy tissue compared with other traditional
methods. It has been considered as one of the promising methods for
the treatment of various cancers. Measuring 10B concentrations
is vital for BNCT. However, the existing technology and equipment
cannot satisfy the real-time and accurate measurement requirements,
and more efficient methods are in demand. The development of methods
and imaging applied in BNCT to help measure boron concentration is
described in this review.
There is evidence to suggest that the primary tumor induces the formation of a pre-metastatic niche in distal organs by stimulating the production of pro-metastatic factors. Given the fundamental role of the pre-metastatic niche in the development of metastases, interruption of its formation would be a promising strategy to take early action against tumor metastasis. Here we report an enzyme-activated assembled peptide FR17 that can serve as a “flame-retarding blanket” in the pre-metastatic niche specifically to extinguish the “fire” of tumor-supportive microenvironment adaption. We show that the in-situ assembled peptide nano-blanket inhibits fibroblasts activation, suppressing the remodeling of the metastasis-supportive host stromal tissue, and reversing vascular destabilization and angiogenesis. Furthermore, we demonstrate that the nano-blanket prevents the recruitment of myeloid cells to the pre-metastatic niche, regulating the immune-suppressive microenvironment. We show that FR17 administration effectively inhibits the formation of the pulmonary pre-metastatic niche and postoperative metastasis, offering a therapeutic strategy against pre-metastatic niche formation.
Inefficient tumor penetration caused by the characteristics
of
tumor microenvironments is a primary obstacle to improving drug delivery
efficiency, which restricts the chemotherapy drug efficacy. One such
promising idea is to construct micro/nanomotors (MNMs) as an effective
delivery vehicle by way of producing autonomous motion and converting
exogenous stimuli or external energies from the surrounding environment
into mechanical forces. In this research, the Pt/DOX nanomotor was
prepared, and the enhanced diffusion and positive chemotaxis driven
by substrates were verified in vitro, proof of the
enhanced cellular uptake and deep penetration of Pt/DOX. As a novel
nanovehicle, Pt/DOX potentially provides an intriguing approach to
foster the tumor-deep penetration and enhance the drug delivery efficiency.
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