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Modulation of anti-angiogenic activity using ultrasound-activated nutlin-loaded piezoelectric nanovectors.

ABSTRACT: Angiogenesis plays a fundamental role in tumor development, as it is crucial for tumor progression, metastasis development, and invasion. In this view, anti-angiogenic therapy has received considerable attention in several cancer types in order to inhibit tumor vascularization, and the progress of nanotechnology offers opportunities to target and release anti-angiogenic agents in specific diseased areas. In this work, we showed that the angiogenic behavior of human cerebral microvascular endothelial cells can be inhibited by using nutlin-3a-loaded ApoE-functionalized polymeric piezoelectric nanoparticles, which can remotely respond to ultrasound stimulation. The anti-angiogenic effect, derived from the use of chemotherapy and chronic piezoelectric stimulation, leads to disruption of tubular vessel formation, decreased cell migration and invasion, and inhibition of angiogenic growth factors in the presence of migratory cues released by the tumor cells. Overall, the proposed use of remotely activated piezoelectric nanoparticles could provide a promising approach to hinder tumor-induced angiogenesis.

SUBMITTER: Sen O

PROVIDER: S-EPMC8717239 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Therapies targeted to the immune system, such as immunotherapy, are currently shaping a new, rapidly developing branch of promising cancer treatments, offering the potential to change the prognosis of previously non-responding patients. Macrophages comprise the most abundant population of immune cells in the tumor microenvironment (TME) and can undergo differentiation into functional phenotypes depending on the local tissue environment. Based on these functional phenotypes, tumor-associated macrophages (TAMs) can either aid tumor progression (M2 phenotype) or inhibit it (M1 phenotype). Presence of M2 macrophages and a high ratio of M2/M1 macrophages in the TME are clinically associated with poor prognosis in many types of cancers. Herein, we evaluate the effect of macrophage phenotype on the transport and anti-cancer efficacy of albumin-bound paclitaxel (nAb-PTX) loaded into porous silicon multistage nanovectors (MSV). Studies in a coculture of breast cancer cells (3D-spheroid) with macrophages and in vivo models were conducted to evaluate the therapeutic efficacy of MSV-nAb-PTX as a function of macrophage phenotype. Association with MSV increased drug accumulation within the macrophages and the tumor spheroids, shifting the inflammation state of the TME toward the pro-inflammatory, anti-tumorigenic milieu. Additionally, the treatment increased macrophage motility toward cancer cells, promoting the active transport of therapeutic nanovectors into the tumor lesion. Consequently, apoptosis of cancer cells was increased and proliferation decreased in the MSV-nAb-PTX-treated group as compared to controls. The results also confirmed that the tested system shifts the macrophage differentiation toward an M1 phenotype, possessing an anti-proliferative effect toward the breast cancer cells. These factors were further incorporated into a mathematical model to help analyze the synergistic effect of the macrophage polarization state on the efficacy of MSV-nAb-PTX in alleviating hypovascularized tumor lesions. In conclusion, the ability of MSV-nAb-PTX to polarize TAM to the M1 phenotype, causing (1) enhanced penetration of the drug-carrying macrophages to the center of the tumor lesion and (2) increased toxicity to tumor cells may explain the increased anti-cancer efficacy of the system in comparison to nAb-PTX and other controls.

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Modulation of anti-angiogenic activity using ultrasound-activated nutlin-loaded piezoelectric nanovectors.

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