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.
Highlights
Retinoblastoma is the third most common form of cancer in infants and is an ocular disease that requires attention, as in approximately 90% of cases metastatic retinoblastoma is lethal [1]
Conjugation of folate to PLGA NPs was confirmed by FTIR analysis and the amide bond peak at 1630.11 cm21 in folate functionalized NPs clearly indicates the formation of amide bond following conjugation (Results S1, Figure S1) The conjugation yield was found to be 8.5 mg and it was estimated that approximately 8 mg of folate was conjugated per mg of nanoparticles
The result indicates a significant inhibition in expression of lungresistance protein (LRP) and MRP-1 at gene and protein level with 2 mg/ml of native curcumin treatment, we further investigated the effect of nanoformulation in modulating the expression of these Multi drug resistance (MDR) proteins in comparison to native curcumin at this particular concentration (Results S1, Figure S2)
Summary
Retinoblastoma is the third most common form of cancer in infants and is an ocular disease that requires attention, as in approximately 90% of cases metastatic retinoblastoma is lethal [1]. Chemotherapy is the treatment of choice following enucleation in patients with nerve and choroid invasion and orbital extension [2]. Their clinical use is limited by systemic toxicity, rapid blood clearance and nonspecific side effects. An altered apoptosis regulatory pathway plays an imperative function in exhibiting chemo-resistance in retinoblastoma. The tumor suppressor protein p53 remains functional but its activity is highly regulated by its negative regulator murin double minute (MDM2) [4]. All these resistance mechanisms, classical multidrug resistance (MDR)
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