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Folate receptor-targeted aminoglycoside-derived polymers for transgene expression in cancer cells.

ABSTRACT: Targeted delivery of anticancer therapeutics can potentially overcome the limitations associated with current chemotherapeutic regimens. Folate receptors are overexpressed in several cancers, including ovarian, triple-negative breast and bladder cancers, making them attractive for targeted delivery of nucleic acid therapeutics to these tumors. This work describes the synthesis, characterization and evaluation of folic acid-conjugated, aminoglycoside-derived polymers for targeted delivery of transgenes to breast and bladder cancer cell lines. Transgene expression was significantly higher with FA-conjugated aminoglycoside-derived polymers than with Lipofectamine, and these polymers demonstrated minimal cytotoxicty. Competitive inhibition using free folic acid significantly reduced transgene expression efficacy of folate-targeted polymers, suggesting a role for folate receptor-mediated uptake. High efficacy FA-targeted polymers were employed to deliver a plasmid expressing the TRAIL protein, which induced death in cancer cells. These results indicate that FA-conjugated aminoglycoside-derived polymers are promising for targeted delivery of nucleic acids to cancer cells that overexpress folate receptors.

SUBMITTER: Godeshala S

PROVIDER: S-EPMC5675079 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Folate receptor-targeted aminoglycoside-derived polymers for transgene expression in cancer cells.

Godeshala Sudhakar S Nitiyanandan Rajeshwar R Thompson Brian B Goklany Sheba S Nielsen David R DR Rege Kaushal K

Bioengineering & translational medicine 20160601 2

Targeted delivery of anticancer therapeutics can potentially overcome the limitations associated with current chemotherapeutic regimens. Folate receptors are overexpressed in several cancers, including ovarian, triple-negative breast and bladder cancers, making them attractive for targeted delivery of nucleic acid therapeutics to these tumors. This work describes the synthesis, characterization and evaluation of folic acid-conjugated, aminoglycoside-derived polymers for targeted delivery of tran ...[more]

PMID: 29313013

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Project description:Folate uptake is largely mediated by folate receptor (FR)β, encoded by FOLR2 gene, in myeloid immune cells such as granulocytes, monocytes, and especially in macrophages that constitute the reticuloendothelial system (RES) and infiltrate the tumor microenvironment. Since the myeloid immune compartment dynamically changes during tumorigenesis, it is critical to assess the infiltration status of the tumors by FRβ-expressing myeloid cells to better define the targeting efficacy of folate-functionalized drug delivery systems. On the other hand, clearance by RES is a major limitation for the targeting efficacy of nanoparticles decorated with folate. Therefore, the aims of this study are (i) to determine the amount and subtypes of FRβ+ myeloid cells infiltrating the tumors at different stages, (ii) to compare the amount and subtype of FRβ+ myeloid cells in distinct organs of tumor-bearing and healthy animals, (iii) to test if the cancer-targeting efficacy and biodistribution of a prototypic folate-functionalized nanoparticle associates with the density of FRβ+ myeloid cells. Here, we report that myeloid cell infiltration was enhanced and FRβ was upregulated at distinct stages of tumorigenesis in a mouse breast cancer model. The CD206+ subset of macrophages highly expressed FRβ, prominently both in tumor-bearing and healthy mice. In tumor-bearing mice, the amount of all myeloid cells, but particularly granulocytes, was remarkably increased in the tumor, liver, lungs, spleen, kidneys, lymph nodes, peritoneal cavity, bone marrow, heart, and brain. Compared with macrophages, the level of FRβ was moderate in granulocytes and monocytes. The density of FRβ+ immune cells in the tumor microenvironment was not directly associated with the tumor-targeting efficacy of the folate-functionalized cyclodextrin nanoparticles. The lung was determined as a preferential site of accumulation for folate-functionalized nanoparticles, wherein FRβ+CD206+ macrophages significantly engulfed cyclodextrin nanoparticles. In conclusion, our results demonstrate that the tumor formation augments the FR levels and alters the infiltration and distribution of myeloid immune cells in all organs which should be considered as a major factor influencing the targeting efficacy of nanoparticles for drug delivery.

Dataset Information

Folate receptor-targeted aminoglycoside-derived polymers for transgene expression in cancer cells.

Publications

Folate receptor-targeted aminoglycoside-derived polymers for transgene expression in cancer cells.

Similar Datasets

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