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

Abstract

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.

Nanoparticles Engineered with Rituximab and Loaded with Nutlin-3 Show Promising Therapeutic Activity in B-Leukemic Xenografts

“…Third, NP loaded with Nutlin-3 exhibited good drug content (at about 5 mg/100 mg of formulation) and encapsulation efficiency (close to 50%). This percentage is lower with respect to that reported by previous authors (8,9) and is likely a consequence of the repeated centrifugation required to purify the samples especially both from PVA and from the reagents used during the coupling with antibody. Finally, NP-Nut and NP-Rt-Nut were able to functionally activate the p53 pathway in vitro, as also shown by the induction of cell-cycle arrest and of apoptosis in JVM-2 cells.…”

“…The studies conducted so far by our and other groups of investigators have strongly suggested that the preclinical evaluation of Nutlin-3 appears highly warranted (2, 3). Interestingly, to overcome the potential problems related to the poor solubility of Nutlin-3, it has been proposed to use PLGA NPs, which showed improved delivery and efficacy of Nutlin-3 in vitro in solid tumor cell models (8,9). However, to the best of our knowledge, NPs loaded with Nutlin-3 have never been examined in animal models before the present study.…”

Lead Exposure in Different Organs of Mammals and Prevention by Curcumin–Nanocurcumin: a Review

“…The same higher competency of nanocurcumin was seen in reversal of lead-induced altered biochemical parameters (ROS, GSH, and TBARS) indicative of oxidative stress in the kidney, brain, and liver [96]. Nanocurcumin has shown signs of overcoming the multidrug resistance that commonly arises on administration of various ranges of typical and novel chemotherapeutic agents that proves to be a major bottleneck in the treatment of many diseases, particularly cancer [97][98][99]. Coating of nanocurcumin by polymer will shield if opposed to degradation by light and warmth.…”

Molecular mechanisms of drug resistance and its reversal in cancer

“…It was reported that the application of nutlin-3 and curcumin in nanoparticles results in the modulation of efflux proteins by curcumin, and thus results in an increase in nutlin-3 function. The outcome of these events reverses multidrug resistance in Y79 human retinoblastoma cell lines (Das & Sahoo, 2012). Benzodiazepinedione (BDA) is also a powerful molecule in recognizing the p53-binding domain of Mdm2 (Grasberger et al, 2005).…”