Folate Decorated Dual Drug Loaded Nanoparticle: Role of Curcumin in Enhancing Therapeutic Potential of Nutlin-3a by Reversing Multidrug Resistance

Aristotle University of Thessaloniki, Greece
PLoS ONE (Impact Factor: 3.23). 03/2012; 7(3):e32920. DOI: 10.1371/journal.pone.0032920
Source: PubMed


Retinoblastoma is the most common intraocular tumor in children. Malfunctioning of many signaling pathways regulating cell survival or apoptosis, make the disease more vulnerable. Notably, resistance to chemotherapy mediated by MRP-1, lung-resistance protein (LRP) is the most challenging aspect to treat this disease. Presently, much attention has been given to the recently developed anticancer drug nutlin-3a because of its non-genotoxic nature and potency to activate tumor suppressor protein p53. However, being a substrate of multidrug resistance protein MRP1 and Pgp its application has become limited. Currently, research has step towards reversing Multi drug resistance (MDR) by using curcumin, however its clinical relevance is restricted by plasma instability and poor bioavailability. In the present investigation we tried to encapsulate nutlin-3a and curcumin in PLGA nanoparticle (NPs) surface functionalized with folate to enhance therapeutic potential of nutlin-3a by modulating MDR. We document that curcumin can inhibit the expression of MRP-1 and LRP gene/protein in a concentration dependent manner in Y79 cells. In vitro cellular cytotoxicity, cell cycle analysis and apoptosis studies were done to compare the effectiveness of native drugs (single or combined) and single or dual drug loaded nanoparticles (unconjugated/folate conjugated). The result demonstrated an augmented therapeutic efficacy of targeted dual drug loaded NPs (Fol-Nut-Cur-NPs) over other formulation. Enhanced expression or down regulation of proapoptotic/antiapoptotic proteins respectively and down-regulation of bcl2 and NFκB gene/protein by Fol-Nut-Cur-NPs substantiate the above findings. This is the first investigation exploring the role of curcumin as MDR modulator to enhance the therapeutic potentiality of nutlin-3a, which may opens new direction for targeting cancer with multidrug resistance phenotype.

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    • "The qualitative analysis of CmPN uptake by HEC was performed using confocal microscopy (Das and Sahoo 2012). Human endothelial cells were seeded in a Labtech Tissue Culture Dishes in 300 ll of complete growth medium at a density of 80,000 cells/ml. "
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    ABSTRACT: Curcumin (Cm)-loaded poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) nanoparticles (CmPN) were obtained and characterized and their effect on human endothelial cells (HEC) was assessed. Different CmPN formulations have been prepared using the emulsion solvent evaporation technique, and characterized for size, structure, Zeta potential, Cm entrapment efficiency, and in vitro Cm release. CmPN cytotoxicity and cellular uptake have been followed using HEC. Also, the effect of CmPN treatment on the p38MAPK signaling pathway in endothelial cells was investigated. The results obtained by electron and atomic force microscopy revealed the spherical shape of the CmPN formulation. Based on size and encapsulation efficiency, the CmPN formulation with the average diameter of 186 nm and with the highest encapsulation efficiency (83 %) has been used in the further studies. The release of Cm from CmPN was ~18 % after 8 h of incubation at 37 °C, followed by a slow release until 144 h, when it reached 44 %, indicating a controlled release. CmPN are taken up by HEC and exhibited low cytotoxicity at concentrations up to 10 μM. The pre-treatment of HEC with CmPN before exposure to tumor necrosis factor-alpha (TNF-α) determined a decrease of p38MAPK phosphorylation. In conclusion, Cm encapsulated into PHBV nanoparticles, at concentration up to 10 μM, has low cytotoxicity and display anti-inflammatory activity on TNF-α-activated HEC by suppressing the phosphorylation of p38MAPK.
    Full-text · Article · Nov 2013 · Journal of Nanoparticle Research
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    • "For example, cancer cells show decreasing responses over the course of chemotherapy as a result of the development of defence mechanisms against the treatment, increasing drug metabolism, enhancing selfrepairing ability or expressing altered drug targets [1] [2] [3], thus leading to therapy failure and tumour relapse. In clinical practice, combination therapy has long been adopted as the primary treatment regimen to reduce drug resistance and to improve therapeutic effectiveness [1] [2] [7]. One of the most popular approaches to achieve combined therapy is to load multiple types of therapeutic agents into a single drug delivery vehicle and, concurrently, delivering them to the sites of action [2–6,8]. "
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    ABSTRACT: Nanoparticulate drug delivery systems offer remarkable opportunities for clinical treatment. However, there are several challenges when they are employed to deliver multiple cargos/payloads, particularly concerning the synchronous delivery of small molecular weight drugs and relatively larger peptides. Since porous silicon (PSi) nanoparticles (NPs) can easily contain high payloads of drugs with various properties, we evaluated their carrier potential in multi-drug delivery for co-loading of the hydrophobic drug indomethacin and the hydrophilic human peptide YY3-36 (PYY3-36). Sequential loading of these two drugs into the PSi NPs enhanced the drug release rate of each drug and also their amount permeated across Caco-2 and Caco-2/HT29 cell monolayers. Regardless of the loading approach used, dual or single, the drug permeation profiles were in good correlation with their drug release behavior. Furthermore, the permeation studies indicated the critical role of the mucus intestinal layer and the paracellular resistance in the permeation of the therapeutic compounds across the intestinal wall. Loading with PYY3-36 also greatly improved the cytocompatibility of the PSi NPs. Conformation analysis indicated that the PYY3-36 could still display biological activity after release from the PSi NPs and permeation across the intestinal cell monolayers. These results are the first demonstration of the promising potential of PSi NPs for simultaneous multi-drug delivery of both hydrophobic and hydrophilic compounds.
    Full-text · Article · Jun 2013 · Journal of Controlled Release
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    • "The results of this particular investigation highlighted an enhanced level of therapeutic efficacy on utilizing the nanoparticle-curcumin-nutlin-3a conjugates on the target retinoblastoma Y79 cell lines [106]. In addition, a downregulation of bcl2 and NFκB was also observed following cell line exposure to the nanoparticle conjugates [106]. "
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    ABSTRACT: The implementation of cytotoxic chemotherapeutic drugs in the fight against cancer has played an invariably essential role for minimizing the extent of tumour progression and/or metastases in the patient and thus allowing for longer event free survival periods following chemotherapy. However, such therapeutics are nonspecific and bring with them dose-dependent cumulative adverse effects which can severely exacerbate patient suffering. In addition, the emergence of innate and/or acquired chemoresistance to the exposed cytotoxic agents undoubtedly serves to thwart effective clinical efficacy of chemotherapy in the cancer patient. The advent of nanotechnology has led to the development of a myriad of nanoparticle-based strategies with the specific goal to overcome such therapeutic hurdles in multiple cancer conditions. This paper aims to provide a brief overview and recollection of all the latest advances in the last few years concerning the application of nanoparticle technology to enhance the safe and effective delivery of chemotherapeutic agents to the tumour site, together with providing possible solutions to circumvent cancer chemoresistance in the clinical setting.
    Full-text · Article · Nov 2012
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