Multimodal Applications of Zinc Gallate-Based Persistent Luminescent Nanoparticles in Cancer Treatment: Tumor Margining, Diagnosis, and Boron Neutron Capture Therapy

Abstract

On the basis of the boron neutron capture therapy (BNCT) modality, we have designed and synthesized a zinc gallate (ZnGa2O4)-based nanoformulation for developing an innovative theranostic approach for cancer treatment. Initially, the (ZnGa1.995Cr0.005O4 or ZnGa2O4:(0.5%)­Cr persistent luminescence nanoparticles (PLNPs) embedded on silica matrix were synthesized. Their surface functionalization was performed using organic synthesis strategies to attach the amine functional moieties which were further coupled with poly­(vicinal diol). These diols were helpful for conjugation with 10B­(OH)3, which subsequently served to couple with an in-house-synthesized variant of pH-(low)-insertion peptide (pHLIP) finally giving a tumor-targeting nanoformulation. Most importantly, the polymeric diols helped in conjugation of a substantial number of 10B to provide the therapeutic dose required for effective BNCT. This nanoformulation internalized substantially (∼80%) to WEHI-164 cancer cells within 6 h. Tumor homing studies indicated that the accumulation of this formulation at the acidic tumor site was within 2 h. The in vitro evaluation of the formulation against WEHI-164 cancer cells followed by neutron irradiation revealed its potent cytotoxicity with IC50 ∼ 25 μM. In the case of studies on animal models, the melanoma-induced C57BL/6 and fibrosarcoma-induced BALB/c mice were treated with formulations through intratumoral and intravenous injections, respectively, followed by neutron irradiation, leading to a significant killing of the cancer cells, which was evidenced by a reduction in tumor volume (75–80%) as compared with a control tumor. Furthermore, the histopathological studies confirmed a damaging effect only on tumor cells, while there was no sign of damage to the vital organs in treated mice as well as in controls.

Peptide Conjugated Boron Neutron Capture Therapy for Enhanced Tumor Targeting

“…The tumor volume in mice was significantly reduced by SZGO: Cr- 10 B-NF therapy and neutron irradiation, according to histopathological examinations. In comparison to untreated controls, treated mice showed decreased vascularity, fewer mitoses, and greater tumor necrosis ( Figure 4 D ) 99 .…”

“… (A) Treatment of mice with SZGO: Cr-10B-NF; (B) photographic images of the tumor, after irradiation with neutron; (C) plot of size of tumor versus number of days; (D) histopathological studies of treated and control tumor. Reprinted (adapted) with permission from 99 . Copyright {2024} American Chemical Society.…”

Aiming the magic bullet: targeted delivery of imaging and therapeutic agents to solid tumors by pHLIP peptides

“…A problem has been to concentrate enough boron in a tumor. The surface of ZGO-NPs was functionalized with poly (vicinal diol), conjugated with pHLIP and loaded with large amounts of boron 10 B for boron neutron capture therapy (BNCT) ( Sharma et al, 2022 ). The in vitro evaluation of the formulation against cancer cells followed by neutron irradiation revealed its potent cytotoxicity with IC 50 ∼ 25 μM.…”

Boron Vehiculating Nanosystems for Neutron Capture Therapy in Cancer Treatment

“…Confocal microscopy evidenced the superimposition of the green and red fluorescence deriving from cancer cells and from the Rhodamine B-labeled BPMO NPs, respectively, and after thermal neutron irradiation, significant tumor growth inhibition was observed (Figure 1). In a recent work, Sharma and his group [93] developed multimodal boron vehiculating silica-coated Cr-doped zinc gallate-based persistent luminescence NPs (PLNPs), by exploiting the reaction of boric acid with the vicinal diol functions present on the NPs surface, introduced by sequential surface functionalization with APTMS and dicarboxyterminated polybutadiene followed by reduction with KMnO4. To achieve tumor targeting, these NPs were functionalized with a pH-(low)-insertion peptide, exploiting the extracellular acidity typical of several diseases, including tumors [155].…”