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A glucose carbonate apatite complex exhibits in vitro and in vivo anti-tumour effects.

ABSTRACT: Tumour targeting nanotechnology has recently made therapeutic progress and several therapeutic nanoparticles have been approved for clinical application. However, an ideal nanotechnology based therapeutic for solid tumours, particularly for systemic administration, still remains a challenge in clinical cancer therapy. We previously reported a pH sensitive in vivo delivery system of doxorubicin, or microRNA, using carbonate apatite (CA) nanoparticles. To further explore utility of CA in cancer therapy, we attempted to transport excess glucose into tumour cells by conjugating glucose (Glc) to the nanoparticle. Despite the non-toxicity of CA and Glc, the complex (CA-[Glc]) exhibited an unexpected anti-cancer effect in vitro and in vivo. CA-[Glc] significantly reduced the growth of colon cancer cell lines. Intravenous injections successfully suppressed solid tumour growth. In mice and monkeys, intravenously injected CA-[Glc] complex resulted in no serious abnormalities in body weight or blood chemistry. Because cancer cells intensively metabolise glucose than normal cells, treatment of cancer using glucose seems paradoxical. However, with the aid of CA, this safe and 'sweet' complex may be a novel anti-cancer reagent.

SUBMITTER: Yamamoto H

PROVIDER: S-EPMC4648380 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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A glucose carbonate apatite complex exhibits in vitro and in vivo anti-tumour effects.

Yamamoto Hirofumi H Wu Xin X Nakanishi Hiroyuki H Yamamoto Yuki Y Uemura Mamoru M Hata Taishi T Nishimura Junichi J Takemasa Ichiro I Mizushima Tsunekazu T Sasaki Jun-Ichi J Imazato Satoshi S Matsuura Nariaki N Doki Yuichiro Y Mori Masaki M

Scientific reports 20150113

Tumour targeting nanotechnology has recently made therapeutic progress and several therapeutic nanoparticles have been approved for clinical application. However, an ideal nanotechnology based therapeutic for solid tumours, particularly for systemic administration, still remains a challenge in clinical cancer therapy. We previously reported a pH sensitive in vivo delivery system of doxorubicin, or microRNA, using carbonate apatite (CA) nanoparticles. To further explore utility of CA in cancer th ...[more]

PMID: 25582455

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Project description:Cancer is one of the top-ranked noncommunicable diseases causing deaths to nine million people and affecting almost double worldwide in 2018. Tremendous advancement in surgery, chemotherapy, radiation and targeted immunotherapy have improved the rate of cure and disease-free survival. As genetic mutations vary in different cancers, potential of customized treatment to silence the problem gene/s at the translational level is being explored too. Yet delivering therapeutics at the required dosage only to the affected cells without affecting the healthy ones, is a big hurdle to be overcome. Scientists worldwide have been working to invent a smart drug delivery system for targeted delivery of therapeutics to tumor tissues only. As part of such an effort, few organic nanocarriers went to clinical trials, while inorganic nanoparticles (NPs) are still in development stage despite their many customizable properties. Carbonate apatite (CA), a pH sensitive nanocarrier has emerged as an efficient delivery system for drugs, plasmids and siRNAs in preclinical models of breast and colon cancers. Like hydroxyapatite (HA) which serves as a classical tool for delivery of genetic materials such as siRNA and plasmid, CA is an apatite-based synthetic carrier. We developed simplified methods of formulating CA-in-DMEM and a DMEM-mimicking buffer and HA in a HEPES-buffered solution and characterized them in terms of size, stability, protein corona (PC) composition, cytotoxicity, siRNA delivery efficiency in breast cancer cells and siRNA biodistribution profile in a mouse model of breast cancer. Particle growth was analyzed via spectrophotometry and light microscopy, size was measured via dynamic light scattering and scanning electron microscopy and confirmation of functional groups in apatite structures was made by FT-IR. siRNA-binding was analyzed via spectrophotometry. Stability of the formulation solutions/buffers was tested over various time points and at different temperatures to determine their compatibility in the context of practical usage. Cellular uptake was studied via fluorescence microscopy. MTT assay was performed to measure the cytotoxicity of the NPs. Liquid chromatography-mass spectrometry was carried out to analyze the PC formed around all three different NPs in serum-containing media. To explore biodistribution of all the formulations, fluorescence-labeled siRNA-loaded NPs were administered intravenously prior to analysis of fluorescence intensity in the collected organs and tumors of the treated mice. The size of NPs in 10% serum-containing media was dramatically different where CA-in-DMB and HA were much larger than CA-in-DMEM. Effect of media was notable on the PC composition of all three NPs. All three NPs bound albumin and some common protease inhibitors involved in bone metabolism due to their compositional similarity to our bone materials. Moreover, CA also bound heme-binding proteins and opsonins. Unlike CA, HA bound different kinds of keratins. Difference in PC constitution was likely to influence accumulation of NPs in various organs including those of reticuloendothelial system, such as liver and spleen and the tumor. We found 10 times more tumor accumulation of CA-in-DMB than CA-in-DMEM, which could be due to more stable siRNA-binding and distinct PC composition of the former. As a nanocarrier CA is more efficient than HA for siRNA delivery to the tumor. CA prepared in a buffer containing only the mere constituents was potentially more efficient than classical CA prepared in DMEM, owing to the exclusion of interference attributed by the inorganic ions and organic molecules present in DMEM.

Project description:AIM Vitamin D deficiency is associated with risk of several common cancers, including colorectal cancer (CRC). We investigated the effects of vitamin D on in vitro and ex vivo epithelial cell gene expression and assessed dysregulation of pathways involved in anti-tumour effects. METHODS We performed in vitro and ex vivo intervention studies using established CRC cell lines and patient-derived epithelial organoids developed from normal human colonic (resectional colorectal surgery) and rectal mucosa (rectal biopsy). RNA and protein were harvested after 16-24 hours’ calcitriol treatment. Gene expression was assessed by qRT-PCR, microarray and RNA-sequencing, and protein expression by immunoblotting and mass-spectrometry. Gene Ontology enrichment analysis was performed using GOrilla and Gene Set Enrichment Analysis. RESULTS Calcitriol increased the expression of the tumour suppressor gene CDH1 in CRC cell lines (SW480; FC=3.60, 95%CI 2.17-5.03) and patient-derived epithelial cell organoids (n=6, FC=1.64, 95%CI 1.49-1.80), with associated in vitro E-cadherin protein induction. Significant differential expression of a further 6 common genes was observed on microarray analysis of in vitro and ex vivo experiments, including genes with established links to carcinogenesis GADD45, EFTUD1 and KIAA1199. Numerous ontologies relevant to carcinogenesis were enriched (e.g. ‘regulation of Wnt signaling pathway’, ‘regulation of cell death’), with common enriched processes across in vitro and ex vivo cultures including ‘negative regulation of cell proliferation’, ‘regulation of cell migration’ and ‘regulation of cell differentiation’. CONCLUSIONS We report for the first time, common genes and pathways modulated by calcitriol treatment in both in vitro and ex vivo models, with several differentially expressed genes strongly linked to CRC tumourigenesis. Enrichment of biological pathways after calcitriol treatment provides further evidence of anti-tumour effects. These findings support epidemiological data and provide strong rationale for well-designed trials of vitamin D supplementation as a novel CRC chemopreventive and chemotherapeutic agent. see above

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A glucose carbonate apatite complex exhibits in vitro and in vivo anti-tumour effects.

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A glucose carbonate apatite complex exhibits in vitro and in vivo anti-tumour effects.

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