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Investigation of PLGA nanoparticles in conjunction with nuclear localization sequence for enhanced delivery of antimiR phosphorothioates in cancer cells in vitro.

ABSTRACT: Numerous first generation phosphorothioates (PS) and their derivatives have shown promise targeting mRNA for therapeutic applications and also gained market approval for their use as a drug. However, PS have not been explored for targeting microRNAs (miRNAs or miRs). In particular, efficient delivery remains a critical cog in PS-based antimiR applications. In this study, we tested and characterized a series of poly-lactic-co-glycolic-acid (PLGA) polymers of different molecular weights that can encapsulate the optimum amount of antimiR-155 PS with uniform morphology and surface charge density. We found that nuclear localization sequence substantially increases loading of antimiR-155 PS in PLGA nanoparticles. Further, in a battery of cell culture studies, we confirmed that PLGA nanoparticles encapsulated nuclear localization sequence/antimiR-155 PS combination undergoes significant intracellular delivery and results in reduced expression of miR-155. In conclusion, we successfully demonstrate the feasibility and promise of optimized PLGA nanoparticles based PS delivery in combination with nuclear localization sequence for antimiRs based therapeutics.

SUBMITTER: Malik S

PROVIDER: S-EPMC6475967 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWe report the development of an efficient antibody delivery system for the incorporation of trastuzumab (TZ) into poly(lactic-co-glycolic) acid nanoparticles (PLGA NPs). The aim of the work was to overcome the current limitations in the clinical use of therapeutic antibodies, including immunogenicity, poor pharmacokinetics, low tumor penetration and safety issues.Materials and methodsTrastuzumab-loaded PLGA NPs (PLGA-TZ) were synthesized according to a double emulsion method. The same protocol was used to produce control batches of nonspecific IgG-loaded NPs and empty PLGA NPs. After release of TZ from PLGA NPs, the effects on the main biological activities of the antibody were evaluated on SKBR3 (human epidermal growth factor receptor 2 [HER2]-positive breast cancer cell line), including specific binding to HER2, phosphorylation of HER2 (Y1248), degradation of HER2 protein and antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. In addition, an MTT assay was performed for treating SKBR3 cells with PLGA NPs loaded with TZ and doxorubicin to evaluate the cytotoxic activity of the combined treatment.Results and discussionTZ was gradually released in a prolonged way over 30 days. The physical characterization performed with circular dichroism, Fourier transform infrared and fluorescence spectroscopy of TZ after release demonstrated that no structural alterations occurred compared to the native antibody. In vitro experiments using SKBR3 cells showed that TZ released from PLGA NPs maintained the same biological activity of native TZ. PLGA NPs allowed a good co-encapsulation efficiency of TZ and doxorubicin resulting in improved therapy.ConclusionWith the TZ case study, we demonstrate that the distinctive features of therapeutic monoclonal antibodies, including molecular targeting efficiency, capability to inhibit or properly affect the regulatory signaling pathways of cancer cells and stimulation of the ADCC, are fully preserved after loading into and release from PLGA NPs. In addition, PLGA NPs are shown to allow for the simultaneous incorporation of TZ and conventional chemotherapeutics, resulting in a potent antitumor nanodrug well suited for in situ combination and neoadjuvant therapy.

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Investigation of PLGA nanoparticles in conjunction with nuclear localization sequence for enhanced delivery of antimiR phosphorothioates in cancer cells in vitro.

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