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Repurposing suramin for the treatment of breast cancer lung metastasis with glycol chitosan-based nanoparticles.

ABSTRACT: Suramin (SM), a drug for African sleeping sickness and river blindness therapy, has been investigated in various clinical trials for cancer therapy. However, SM was eventually withdrawn from the market because of its narrow therapeutic window and the side effects associated with multiple targets. In this work, we developed a simple but effective system based on a nontoxic dose of SM combined with a chemotherapeutic agent for the treatment of metastatic triple-negative breast cancer (TNBC). SM and glycol chitosan (GCS) formed nanogels because of the electrostatic effect, whereas doxorubicin (DOX) was incorporated into the system through the hydrophilic and hydrophobic interactions between DOX and GCS as well as the ionic interactions between DOX and SM to yield GCS-SM/DOX nanoparticles (NPs). GCS-SM/DOX NPs have a size of approximately 186?nm and a spherical morphology. In vitro experiments showed that GCS-SM NPs could effectively inhibit cancer cell migration and invasion, as well as angiogenesis. Furthermore, in a TNBC lung metastasis animal model, GCS-SM/DOX NPs significantly reduced tumor burden and extended the lifespan of animals, while not inducing cardio and renal toxicities associated with the DOX and SM, respectively. As all the components used in this system are biocompatible and easy for large-scale fabrication, the GCS-SM/DOX system is highly translatable for the metastatic breast cancer treatment. STATEMENT OF SIGNIFICANCE: The doxorubicin-loaded glycol chitosan-suramin nanoparticle (GCS-SM/DOX) is novel in the following aspects: SM acts as not only a gelator for the first time in the preparation of the nanoparticle but also an active pharmaceutical agent in the dosage form. GCS-SM/DOX NP significantly reduced tumor burden and extended the lifespan of animals with triple-negative breast cancer lung metastasis. GCS-SM/DOX NPs attenuate cardio and renal toxicities associated with the DOX and SM. The GCS-SM/DOX system is highly translatable because of its simple, one-pot, and easy-to-scale-up preparation protocol.

SUBMITTER: Cheng B

PROVIDER: S-EPMC6362832 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Repurposing suramin for the treatment of breast cancer lung metastasis with glycol chitosan-based nanoparticles.

Cheng Bei B Gao Feng F Maissy Erica E Xu Peisheng P

Acta biomaterialia 20181205

Suramin (SM), a drug for African sleeping sickness and river blindness therapy, has been investigated in various clinical trials for cancer therapy. However, SM was eventually withdrawn from the market because of its narrow therapeutic window and the side effects associated with multiple targets. In this work, we developed a simple but effective system based on a nontoxic dose of SM combined with a chemotherapeutic agent for the treatment of metastatic triple-negative breast cancer (TNBC). SM an ...[more]

PMID: 30528604

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Project description:Recent progress in nanomedicine has shown a strong possibility of targeted therapy for obstinate chronic lung diseases including idiopathic pulmonary fibrosis (IPF). IPF is a fatal lung disease characterized by persistent fibrotic fibroblasts in response to type I collagen-rich extracellular matrix. As a pathological microenvironment is important in understanding the biological behavior of nanoparticles, in vitro cellular uptake of glycol chitosan nanoparticles (CNPs) in human lung fibroblasts was comparatively studied in the presence or absence of type I collagen matrix. Primary human lung fibroblasts from non-IPF and IPF patients (n=6/group) showed significantly increased cellular uptake of CNPs (>33.6-78.1 times) when they were cultured on collagen matrix. To elucidate the underlying mechanism of enhanced cellular delivery of CNPs in lung fibroblasts on collagen, cells were pretreated with chlorpromazine, genistein, and amiloride to inhibit clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis, respectively. Amiloride pretreatment remarkably reduced the cellular uptake of CNPs, suggesting that lung fibroblasts mainly utilize the macropinocytosis-dependent mechanism when interacted with collagen. In addition, the internalization of CNPs was predominantly suppressed by a phosphoinositide 3-kinase (PI3K) inhibitor in IPF fibroblasts, indicating that enhanced PI3K activity associated with late-stage macropinocytosis can be particularly important for the enhanced cellular delivery of CNPs in IPF fibroblasts. Our study strongly supports the concept that a pathological microenvironment which surrounds lung fibroblasts has a significant impact on the intracellular delivery of nanoparticles. Based on the property of enhanced intracellular delivery of CNPs when fibroblasts are made to interact with a collagen-rich matrix, we suggest that CNPs may have great potential as a drug-carrier system for targeting fibrotic lung fibroblasts.

Project description:BackgroundBreast cancer lung metastasis occurs in more than 60% of all patients with breast cancer, and most of those afflicted by it eventually die of recurrence. The tumor microenvironment plays vital roles in metastasis. Modulating the tumor microenvironment via multiple pathways could efficiently prevent or inhibit lung metastasis. Silibinin and cryptotanshinone are natural plant products that demonstrate anti-metastasis effects and modulate the tumor microenvironment via different pathways. However, they have poor aqueous solubility, membrane permeability, and oral bioavailability. Oral drug administration may help improve the quality of life and compliance of patients with breast cancer, primarily under long-term and/or follow-up therapy. Herein, we developed poly-N-(2-hydroxypropyl) methacrylamide (pHPMA)-coated wheat germ agglutinin-modified lipid-polymer hybrid nanoparticles, co-loaded with silibinin and cryptotanshinone (S/C-pW-LPNs). We assessed their oral bioavailability, and evaluated their anti-metastasis efficacy in a 4T1 breast cancer tumor-bearing nude mouse model.ResultsAn in vitro mucus diffusion study revealed that pHPMA enhanced W-LPN mucus penetration. After oral administration, pHPMA enhanced nanoparticle distribution in rat jejunum and substantially augmented oral bioavailability. S/C-W-LPNs markedly increased 4T1 cell toxicity and inhibited cell invasion and migration. Compared to LPNs loaded with either silibinin or cryptotanshinone alone, S/C-pW-LPNs dramatically slowed tumor progression in 4T1 tumor-bearing nude mice. S/C-pW-LPNs presented with the most robust anti-metastasis activity on smooth lung surfaces and mitigated lung metastasis foci. They also downregulated tumor microenvironment biomarkers such as CD31, TGF-?1, and MMP-9 that promote metastasis.ConclusionsSilibinin- and cryptotanshinone-co-loaded pW-LPNs efficiently penetrate intestinal barriers, thereby enhancing the oral bioavailability of the drug loads. These nanoparticles exhibit favorable anti-metastasis effects in breast cancer-bearing nude mice. Hence, S/C-pW-LPNs are promising oral drug nanocarriers that inhibit breast cancer lung metastasis.

Dataset Information

Repurposing suramin for the treatment of breast cancer lung metastasis with glycol chitosan-based nanoparticles.

Publications

Repurposing suramin for the treatment of breast cancer lung metastasis with glycol chitosan-based nanoparticles.

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