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Dual tumor-targeted poly(lactic-co-glycolic acid)-polyethylene glycol-folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery.

ABSTRACT: Further specific target-ability development of biodegradable nanocarriers is extremely important to promote their security and efficiency in antitumor drug-delivery applications. In this study, a facilely prepared poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-folic acid (FA) copolymer was able to self-assemble into nanoparticles with favorable hydrodynamic diameters of around 100 nm and negative surface charge in aqueous solution, which was expected to enhance intracellular antitumor drug delivery by advanced dual tumor-target effects, ie, enhanced permeability and retention induced the passive target, and FA mediated the positive target. Fluorescence-activated cell-sorting and confocal laser-scanning microscopy results confirmed that doxorubicin (model drug) loaded into PLGA-PEG-FA nanoparticles was able to be delivered efficiently into tumor cells and accumulated at nuclei. In addition, all hemolysis, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, and zebrafish-development experiments demonstrated that PLGA-PEG-FA nanoparticles were biocompatible and secure for biomedical applications, even at high polymer concentration (0.1 mg/mL), both in vitro and in vivo. Therefore, PLGA-PEG-FA nanoparticles provide a feasible controlled-release platform for secure and efficient antitumor drug delivery.

SUBMITTER: Chen J

PROVIDER: S-EPMC5557624 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Dual tumor-targeted poly(lactic-<i>co</i>-glycolic acid)-polyethylene glycol-folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery.

Chen Jia J Wu Qi Q Luo Li L Wang Yi Y Zhong Yuan Y Dai Han-Bin HB Sun Da D Luo Mao-Ling ML Wu Wei W Wang Gui-Xue GX

International journal of nanomedicine 20170810

Further specific target-ability development of biodegradable nanocarriers is extremely important to promote their security and efficiency in antitumor drug-delivery applications. In this study, a facilely prepared poly(lactic-<i>co</i>-glycolic acid) (PLGA)-polyethylene glycol (PEG)-folic acid (FA) copolymer was able to self-assemble into nanoparticles with favorable hydrodynamic diameters of around 100 nm and negative surface charge in aqueous solution, which was expected to enhance intracellul ...[more]

PMID: 28848351

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Project description:The addition of polyethylene glycol (PEG) chains to poly(lactic-co-glycolic acid) (PLGA) matrices is extensively used to modulate the biodegradation, drug loading and release, mechanical properties, and chemical stability of the original system. Multiple parameters, including the molecular weight, relative concentration, polarity, and solubility, affect the physicochemical properties of the polymer blend. Here, molecular dynamics simulations with the united-atom 2016H66 force field are used to model the behavior of PLGA and PEG chains and thus predict the overall physicochemical features of the resulting blend. First, the model accuracy is validated against fundamental properties of pure PLGA and PEG samples. In agreement with previous experimental and theoretical observations, the PLGA solubility results to be higher in acetonitrile than in water, with Flory parameters νACN = 0.63 ± 0.01 and νW = 0.21 ± 0.02, and the Young's modulus of PLGA and PEG equal to Y = 2.0 ± 0.43 and 0.32 ± 0.34 GPa, respectively. Next, four PEG/PLGA blending regimes are identified by varying the relative concentrations and molecular weights of the individual polymers. The computational results demonstrate that at low PEG concentrations (<8% w/w), homogeneous blends are generated for both low and high PEG molecular weights. In contrast, at comparable PEG and PLGA concentrations (∼50% w/w), short PEG chains are only partially miscible whereas long PEG chains segregate within the PLGA matrix. This behavior has been confirmed experimentally via differential scanning calorimetry and is in agreement with previous observations. Finally, the computed Young's modulus of PLGA/PEG blends is observed to decrease with the PEG content returning the lowest values for the partial and fully segregated regimens (Y ≈ 1.3 GPa). This work proposes a computational scheme for predicting the physicochemical properties of PLGA/PEG blends paving the way toward the rational design of polymer mixtures for biomedical applications.

Project description:Mucous-penetrating nanoparticles consisting of poly lactic acid-co-glycolic acid (PLGA)-polyethylene glycol (PEG) could improve targeting of microbicidal drugs for sexually transmitted diseases by intravaginal inoculation. Nanoparticles can induce inflammatory responses, which may exacerbate the inflammation that occurs in the vaginal tracts of women with yeast infections. This study evaluated the effects of these drug-delivery nanoparticles on VK2(E6/E7) vaginal epithelial cell proinflammatory responses to Candida albicans yeast infections. Vaginal epithelial cell monolayers were infected with C. albicans and exposed to 100 μg/ml 49.5 nm PLGA-PEG nanospheres or 20 μg/ml 1.1 x 500 nm PEG-functionalized graphene oxide (GO-PEG) sheets. The cells were assessed for changes in mRNA and protein expression of inflammation-related genes by RT-qPCR and physiological markers of cell stress using high content analysis and flow cytometry. C. albicans exposure suppressed apoptotic gene expression, but induced oxidative stress in the cells. The nanomaterials induced cytotoxicity and programmed cell death responses alone and with C. albicans. PLGA-PEG nanoparticles induced mRNA expression of apoptosis-related genes and induced poly (ADP-ribose) polymerase (PARP) cleavage, increased BAX/BCL2 ratios, and chromatin condensation indicative of apoptosis. They also induced autophagy, endoplasmic reticulum stress, and DNA damage. They caused the cells to excrete inflammatory recruitment molecules chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-1α (IL1A), interleukin-1β (IL1B), calprotectin (S100A8), and tumor necrosis factor α (TNF). GO-PEG nanoparticles induced expression of necrosis-related genes and cytotoxicity. They reduced autophagy and endoplasmic reticulum stress, and apoptotic gene expression responses. The results show that stealth nanoparticle drug-delivery vehicles may cause intracellular damage to vaginal epithelial cells by several mechanisms and that their use for intravaginal drug delivery may exacerbate inflammation in active yeast infections by increased inflammatory recruitment.

Project description:In a recent study, using an in vitro model to study intravaginal nanoparticle exposure during yeast infections, we demonstrated that C. albicans exposure suppressed apoptotic gene expression and induced oxidative stress and pyroptosis in vaginal epithelial cells. The mucous-penetrating drug delivery nanoparticles made from poly-(D, L-lactic-co-glycolic acid)-(polyethylene glycol) induced cytotoxicity by activating apoptosis, endoplasmic reticulum (ER) stress, oxidative stress, and DNA damage repair responses alone and, in some cases with C. albicans. In the current study we evaluated the effects of fluorescently-labelled nanoparticles in CBA/J mice challenged intravaginally for two hours followed by intravaginal challenge with C. albicans for 18 hours. Nanoparticle treatment increased systemic translocation of C. albicans threefold in the heart. C. albicans also increased systemic distribution of the nanoparticles fivefold in the heart. Flow cytometric assays showed co-localization of the nanoparticles with epithelial cells, macrophages and dendritic cells. Nanoparticle-treated, C. albicans-infected mice exhibited induction of autophagy, ER stress, apoptosis, and inflammatory serum cytokines. C. albicans infection was associated with pyroptosis and suppressed expression of ER stress and apoptosis-related genes. Induction of apoptosis during nanoparticle treatment and in nanoparticle-treated-C. albicans infected mice was observed as DNA damage responses, mitochondrial depolarization and (Poly [ADP-Ribose] Polymerase) cleavage. C. albicans infection was associated with increased mRNA expression of anti-apoptotic genes. Both C. albicans infection and nanoparticle treatment showed enhanced chemoattraction of dendritic cells and polymorphonuclear cells to factors in vaginal washings in a chemotaxis assay. This study shows that both intravaginal treatment of mice with the nanoparticles and infection with C. albicans induce cytotoxic and inflammatory responses. C. albicans also suppressed cell apoptosis. These results clarify our understanding of how nanoparticles modulate host cellular responses during C. albicans infection and will be applicable for future research and development of intravaginal nanomedicines.

Dataset Information

Dual tumor-targeted poly(lactic-co-glycolic acid)-polyethylene glycol-folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery.

Publications

Dual tumor-targeted poly(lactic-<i>co</i>-glycolic acid)-polyethylene glycol-folic acid nanoparticles: a novel biodegradable nanocarrier for secure and efficient antitumor drug delivery.

Similar Datasets

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