RGD-functionalised melanin nanoparticles for intraoperative photoacoustic imaging-guided breast cancer surgery

Purpose Obtaining tumour-free margins is critical for avoiding re-excision and reducing local recurrence following breast-conserving surgery; however, it remains challenging. Imaging-guided surgery provides precise detection of residual lesions and assists surgical resection. Herein, we described water-soluble melanin nanoparticles (MNPs) conjugated with cyclic Arg-Gly-Asp (cRGD) peptides for breast cancer photoacoustic imaging (PAI) and surgical navigation. Methods The cRGD-MNPs were synthesised and characterized for morphology, photoacoustic characteristics and stability. Tumour targeting and toxicity of cRGD-MNPs were determined by using either breast cancer cells, MDA-MB-231 tumour-bearing mice or the FVB/N-Tg (MMTV-PyVT) 634Mul/J mice model. PAI was used to locate the tumour and guide surgical resection in MDA-MB-231 tumour-bearing mice. Results The cRGD-MNPs exhibited excellent in vitro and in vivo tumour targeting with low toxicity. Intravenous administration of cRGD-MNPs to MDA-MB-231 tumour-bearing mice showed an approximately 2.1-fold enhancement in photoacoustic (PA) intensity at 2 h, and the ratio of the PA intensity at the tumour site to that in the surrounding normal tissue was 3.2 ± 0.1, which was higher than that using MNPs (1.7 ± 0.3). Similarly, the PA signal in the spontaneous breast cancer increased ~ 2.5-fold at 2 h post-injection of cRGD-MNPs in MMTV-PyVT transgenic mice. Preoperative PAI assessed tumour volume and offered three-dimensional (3D) reconstruction images for accurate surgical planning. Surgical resection following real-time PAI showed high consistency with histopathological analysis. Conclusion These results highlight that cRGD-MNP-mediated PAI provide a powerful tool for breast cancer imaging and precise tumour resection. cRGD-MNPs with fine PA properties have great potential for clinical translation.

NOSE-TO-BRAIN DELIVERY, A ROUTE OF CHOICE FOR TARGETING BRAIN TUMORS

Brain tumours are the most lethal type of cancer, which is difficult to manage due to the inherent suboptimal bioavailability of the chemotherapy agent at tumour sites, consequent of high levels of protection of physiological blood-brain barrier (BBB), blood tumour barrier (BTB) and blood-cerebrospinal fluid barrier (CSF). Improving the permeability of these barriers would enhance the disease's clinical prognosis and promote patients' quality of life. To this end, scientists have conducted several studies to determine the most suitable route for CNS delivery. Most of which show that the nose-to-brain is proposed to be the most convenient, efficacious and clinically beneficial non-invasive means of delivering chemotherapeutic agents directly to the brain. Therefore, this study compares the therapeutic benefits of intranasal and other conventional brain delivery systems and further evaluates the clinical benefits of using different nanocarriers for brain tumour targeting. However, we surveyed the literature by conducting an in-depth search of the research keywords and their combinations in recognized scientific databases, primarily Science Direct, PubMed, Google Scholar, and Research Gate. Our findings have shown that the nose-to-brain delivery of chemotherapeutics is a breakthrough in bypassing the effects of BBB, BTB, and CSF barriers, improving the delivery of drugs to the brain for specific tumour targeting with desired clinical prognosis.

RGD-Functionalized Melanin Nanoparticles for Intraoperative Photoacoustic Imaging-Guided Breast Cancer Surgery

Purpose: Obtaining tumour-free margins is critical for avoiding re-excision and 35 reducing local recurrence following breast-conserving surgery (BCS); however, it 36 remains challenging. Imaging-guided surgery provides precise detection of residual 37 lesions and assists surgical resection. Herein, we describe water-soluble melanin 38 nanoparticles (MNPs) conjugated with cyclic Arg-Gly-Asp (cRGD) peptides for breast 39 cancer photoacoustic imaging (PAI) and surgery navigation. 40Methods: cRGD-MNPs was synthesized and characterized for morphology, 41 photoacoustic characteristics and stability. Tumour targeting and toxicity were 42 determined by cells and tumour-bearing mice. PAI was used to locate the tumour and 43 guide surgical resection in MDA-MB-231 tumour-bearing mice. 44Results: The cRGD-MNPs exhibited excellent tumour-targeting in vitro and in vivo, 45 with low toxicity. Intravenous administration of cRGD-MNPs to MDA-MB-231 46 tumour-bearing mice showed an approximately 2.1-fold enhancement in photoacoustic 47 (PA) intensity at 2 h, and the ratio of the PA intensity at the tumour site compared to 48 that in the surrounding normal tissue was 3.2 ± 0.1, which was much higher than that 49 using MNPs alone (1.7 ± 0.3). Similarly, the PA signal in the mammary glands 50 containing spontaneous breast cancer was enhanced (2.5 ± 0.3-fold) in MMTV-PyVT 51 transgenic murine model. Preoperative screening by PAI could assess tumour volume 52 and offer a three-dimensional (3D) reconstruction image for accurate surgical planning. 53 Surgical resection following real-time PAI on the tumour bed showed high consistency 54 with histopathological analysis. 55Conclusion: These results highlight that cRGD-MNPs combined with PAI provide 56 a powerful tool for breast cancer imaging and precise tumour resection. cRGD-MNPs 57 with good PA properties have great potential for clinical translation.

A DM1-doped porous gold nanoshell system for NIR accelerated redox-responsive release and triple modal imaging guided photothermal synergistic chemotherapy

Background Although many treatments for breast cancer are available, poor tumour targeting limits the effectiveness of most approaches. Consequently, it is difficult to achieve satisfactory results with monotherapies. The lack of accurate diagnostic and monitoring methods also limit the benefits of cancer treatment. The aim of this study was to design a nanocarrier comprising porous gold nanoshells (PGNSs) co-decorated with methoxy polyethylene glycol (mPEG) and trastuzumab (Herceptin®, HER), a therapeutic monoclonal antibody that binds specifically to human epidermal receptor-2 (HER2)-overexpressing breast cancer cells. Furthermore, a derivative of the microtubule-targeting drug maytansine (DM1) was incorporated in the PGNSs. Methods Prepared PGNSs were coated with mPEG, DM1 and HER via electrostatic interactions and Au–S bonds to yield DM1-mPEG/HER-PGNSs. SK-BR-3 (high HER2 expression) and MCF-7 (low HER2) breast cancer cells were treated with DM1-mPEG/HER-PGNSs, and cytotoxicity was evaluated in terms of cell viability and apoptosis. The selective uptake of the coated PGNSs by cancer cells and subsequent intracellular accumulation were studied in vitro and in vivo using inductively coupled plasma mass spectrometry and fluorescence imaging. The multimodal imaging feasibility and synergistic chemo-photothermal therapeutic efficacy of the DM1-mPEG/HER-PGNSs were investigated in breast cancer tumour-bearing mice. The molecular mechanisms associated with the anti-tumour therapeutic use of the nanoparticles were also elucidated. Result The prepared DM1-mPEG/HER-PGNSs had a size of 78.6 nm and displayed excellent colloidal stability, photothermal conversion ability and redox-sensitive drug release. These DM1-mPEG/HER-PGNSs were taken up selectively by cancer cells in vitro and accumulated at tumour sites in vivo. Moreover, the DM1-mPEG/HER-PGNSs enhanced the performance of multimodal computed tomography (CT), photoacoustic (PA) and photothermal (PT) imaging and enabled chemo-thermal combination therapy. The therapeutic mechanism involved the induction of tumour cell apoptosis via the activation of tubulin, caspase-3 and the heat shock protein 70 pathway. M2 macrophage suppression and anti-metastatic functions were also observed. Conclusion The prepared DM1-mPEG/HER-PGNSs enabled nanodart-like tumour targeting, visibility by CT, PA and PT imaging in vivo and powerful tumour inhibition mediated by chemo-thermal combination therapy in vivo. In summary, these unique gold nanocarriers appear to have good potential as theranostic nanoagents that can serve both as a probe for enhanced multimodal imaging and as a novel targeted anti-tumour drug delivery system to achieve precision nanomedicine for cancers.

One-pot peptide cyclisation and surface modification of photosensitiser-loaded red blood cells for targeted photodynamic therapy

We report herein a one-pot approach to cyclise a tumour-targeting peptide and conjugate it on the surface of red blood cells loaded with a boron dipyrromethene-based photosensitiser using a bifunctional...