Therapeutic nucleus-access BNCT drug combined CD47-targeting gene editing in glioblastoma

Abstract

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 Vehiculating Nanosystems for Neutron Capture Therapy in Cancer Treatment

“…An innovative approach to target glioblastoma was described by Chen and his group [ 52 ], developing a liposomal formulation with a double anti-cancer effect and functionalized with the internalizing-RGD (iRGD) peptide. The authors developed liposomes encapsulating both a complex of doxorubicin with 1-bromomethyl- o -carborane (DOX-CB), which should translocate into the nucleus thanks to the DOX nuclear tropism, and the CD47 gene-targeted CRISPR-Cas9 gene knock-out plasmid (pDNA) that, by directly knocking out the CD47 gene, promotes the macrophage-mediated phagocytosis of cancer cells.…”

“…In vitro: DHD/K12/TRb rat colon carcinoma and B16-F10 murine melanoma cells [52] Internalizing-RGD Doxorubicin conj. with 1-bromomethyl-o-carborane 150-225 nm/-/-In vitro: GL261 glioma cancer cells; in vivo: GL261-bearing C57BL/6 mice In vivo and ex vivo on mice: survival curve and average weight change curve, histopathological analysis [53] BPA -/-/- [54] BPA-fructose; BPA-fructose+BPA…”

Targeting tumor-associated macrophages for the immunotherapy of glioblastoma: Navigating the clinical and translational landscape

“…CD47, a receptor overexpressed on tumor cells, recognized the signal-regulatory protein a (SIRPa) on macrophages and protected the tumor cells from phagocytosis (160, 161). The immunosuppressive TME was shaped by antigen presentation due to DOX-induced ICD, and the reduction in CD47 and the boron neutron capture therapy (BNCT) enhanced immune surveillance (126). Additionally, Zhu et al constructed a ginsenoside Rg3 (Rg3)-based liposomal system containing paclitaxel (PTX) to remodel the immunosuppressive TME of GBM.…”

“…As a result, IL-6 secretion was reduced while the number of M1 macrophages doubled ( 125 ). Moreover, a multifunctional liposome delivery system, encapsulating DOX and carborane, was reported to enhance the immunotherapy of GBM ( 126 ). CD47, a receptor overexpressed on tumor cells, recognized the signal-regulatory protein α (SIRPα) on macrophages and protected the tumor cells from phagocytosis ( 160 , 161 ).…”

Study of the efficiency of cellular accumulation of doxorubicin supplied with a targeted delivery system based on phospholipid nanoparticles with integrin-directed peptide

“…Он обладает высокой активностью, но в клетках глиомы есть эпигенетические механизмы, способствующие их выживанию. Одним из подходов для преодоления резистентности опухоли к Dox и уменьшения его побочных проявлений служит адресная доставка лекарств к опухоли [18][19][20][21]. Нами разработана фосфолипидная композиция Dox (NPh-Dox) и исследована её эффективность in vivo [22,23].…”