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Phospholipase A2-Responsive Phosphate Micelle-Loaded UCNPs for Bioimaging of Prostate Cancer Cells.

ABSTRACT: We report the effective synthesis of biocompatible upconversion nanoparticles (UCNP)-loaded phosphate micelles and successful delivery of UCNPs to prostate cancer cells via secreted phospholipase A2 (sPLA-2) enzyme cleavage of the loaded micelles for the first time. The activity of the (sPLA-2) enzyme toward the synthesized micelles was investigated and confirmed by LC-MS. TEM results showed that the micelles have a size distribution of 80 to 150?nm, whereas UCNP-loaded micelles range from 200 to 350?nm, indicating the successful loading of UCNPs. The selective release of UCNPs to prostate cancer cells rather than other cells, specifically cervical cancer cells, was observed and confirmed by a range of bioimaging studies. Moreover, cytotoxicity assays confirmed the biocompatibility of the UCNP-loaded micelles.

SUBMITTER: Sharipov M

PROVIDER: S-EPMC5700164 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Phospholipase A2-Responsive Phosphate Micelle-Loaded UCNPs for Bioimaging of Prostate Cancer Cells.

Sharipov Mirkomil M Tawfik Salah M SM Gerelkhuu Zayakhuu Z Huy Bui The BT Lee Yong-Ill YI

Scientific reports 20171122 1

We report the effective synthesis of biocompatible upconversion nanoparticles (UCNP)-loaded phosphate micelles and successful delivery of UCNPs to prostate cancer cells via secreted phospholipase A2 (sPLA-2) enzyme cleavage of the loaded micelles for the first time. The activity of the (sPLA-2) enzyme toward the synthesized micelles was investigated and confirmed by LC-MS. TEM results showed that the micelles have a size distribution of 80 to 150 nm, whereas UCNP-loaded micelles range from 200 t ...[more]

PMID: 29167526

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Project description:Secretory phospholipase A(2) (sPLA(2)) cleave phospholipids at sn-2 ester bonds, releasing lysophospholipids and fatty acids, and are over expressed in several pathologies, including inflammation, arthritis, sepsis and breast and prostate cancers. Herein we evaluated the therapeutic activity of liposomes engineered to be responsive to different sPLA(2) isoforms compared to clinically used long-circulating (pegylated) sterically stabilized liposomes (SSL) in vitro and in vivo, and assessed differences in roles of sPLA(2) in the mechanism of uptake and delivery of these nanoparticles. Exposing sPLA(2) responsive liposomes (SPRL) to sPLA(2) increased the release of intraluminal entrapped contents in a time-dependent manner that was inhibited by the sPLA(2) inhibitor LY3117273. Treatment of prostate cancer cells with doxorubicin encapsulated in SSL and SPRL resulted in cytotoxicity in LNCaP, DU-145 and PC-3 cells lines comparable to free drug. Interestingly, cytotoxicity was not altered by sPLA(2) inhibition. Tracking of drug and liposome delivery using fluorescence microscopy and flow cytometry, we demonstrated that drug uptake was liposome-dependent, as encapsulation of doxorubicin in SPRL resulted in 1.5 to 2-fold greater intracellular drug levels compared to SSL. Liposome uptake was cell-dependent and did not correlate to doxorubicin uptake; however, doxorubicin uptake was generally greatest in PC-3 cells, followed by DU-145 cells and then LNCaP cells. In almost all cases, uptake of one of our formulations, SPRL-E, was greater than SSL. The therapeutic activity of SPRL in vivo was demonstrated using a mouse xenograft model of human prostate cancer, which showed that doxorubicin entrapped within SPRL decreased tumor growth compared to SSL, suggesting that SPRL are more effective at slowing tumor growth than a SSL formulation similar to the FDA approved DOXIL™. Collectively, these data show the therapeutic activity of SPRL compared to SSL, yield insights into the mechanisms of action of these nanoparticles and suggest that SPRL could be useful for treatment of other pathologies that over express sPLA(2).

Project description:BackgroundIt has recently been proposed that the M-type phospholipase A2 receptor (PLA2R1) acts as a tumour suppressor in certain malignancies including mammary cancer. Considering that DNA methylation is an important regulator of gene transcription during carcinogenesis, in the current study we analyzed the PLA2R1 expression, PLA2R1 promoter methylation, and selected micro RNA (miRNA) levels in normal human mammary epithelial cells (HMEC) and cancer cell lines.MethodsLevels of PLA2R1 and DNA methyltransferases (DNMT) specific mRNA were determined using real-time RT-PCR. Methylation specific-high resolution melting (MS-HRM) analysis was utilized to quantify the methylation degree of selected CpG sites localized in the promoter region of the PLA2R1 gene. Expression of miRNA was tested using miScript Primer Assay system.ResultsNearly complete methylation of the analyzed PLA2R1 promoter region along with PLA2R1 gene silencing was identified in MDA-MB-453 mammary cancer cells. In MCF-7 and BT-474 mammary cancer cell lines, a higher DNA methylation degree and reduced PLA2R1 expression were found in comparison with those in normal HMEC. Synergistic effects of demethylating agent (5-aza-2'-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) on PLA2R1 transcription in MDA-MB-453 cells confirmed the importance of DNA methylation and histone modification in the regulation of the PLA2R1 gene expression in mammary cells. Furthermore, significant positive correlation between the expression of DNMT1 and PLA2R1 gene methylation and negative correlation between the cellular levels of hsa-mir-141, -181b, and -181d-1 and the expression of PLA2R1 were identified in the analyzed cells. Analysis of combined z-score of miR-23b, -154 and -302d demonstrated a strong and significant positive correlation with PLA2R1 expression.ConclusionsOur data indicate that (i) PLA2R1 expression in breast cancer cells is controlled by DNA methylation and histone modifications, (ii) hypermethylation of the PLA2R1 promoter region is associated with up-regulation of DNMT1, and (iii) hsa-miR-23b, -154, and -302d, as well as hsa-miR-141, -181b, and -181d-1 are potential candidates for post-transcriptional regulation of PLA2R1 expression in mammary cancer cells.

Dataset Information

Phospholipase A2-Responsive Phosphate Micelle-Loaded UCNPs for Bioimaging of Prostate Cancer Cells.

Publications

Phospholipase A2-Responsive Phosphate Micelle-Loaded UCNPs for Bioimaging of Prostate Cancer Cells.

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