The effect of co-delivery of paclitaxel and curcumin by transferrin-targeted PEG-PE-based mixed micelles on resistant ovarian cancer in 3-D spheroids and in vivo tumors

Abstract

Multicellular 3D cancer cell culture (spheroids) resemble to in vivo tumors in terms of shape, cell morphology, growth kinetics, gene expression and drug response. However, these characteristics cause very limited drug penetration into deeper parts of the spheroids. In this study, we used multi drug resistant (MDR) ovarian cancer cell spheroid and in vivo tumor models to evaluate the co-delivery of paclitaxel (PCL) and a potent NF-κB inhibitor curcumin (CUR). PCL and CUR were co-loaded into the polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) based polymeric micelles modified with Transferrin (TF) as the targeting ligand. Cytotoxicity, cellular association and accumulation into the deeper layers were investigated in the spheroids and compared with the monolayer cell culture. Comparing to non-targeted micelles, flow cytometry and confocal imaging proved significantly deeper and higher micelle penetration into the spheroids with TF-targeting. Both in monolayers and spheroids, PCL cytotoxicity was significantly increased when co-delivered with CUR in non-targeted micelles or as single agent in TF-targeted micelles, whereas TF-modification of co-loaded micelles did not further enhance the cytotoxicity. In vivo tumor inhibition studies showed good correlation with the 3D cell culture experiments, which suggests the current spheroid model can be used as an intermediate model for evaluation of co-delivery of anticancer compounds in targeted micelles.

Polyphenols delivery by polymeric materials: challenges in cancer treatment

“…linoleic acid -LNA, palmitic acid -PAC, and oleic acid -OA) allows the obtainment of CUR delivery nanocarriers suitable for the treatment of cervical (Sahu et al, 2008a;Song et al, 2014), brain (Erfani-Moghadam et al, 2014, and lung tumors (Erfani-Moghadam et al, 2014), with superior efficiency and pharmacokinetics (Song et al, 2014). A different approach involves the employment of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] in a thin-layer evaporation methods for the preparation of CUR micelles able to treat ovarian Sarisozen et al, 2014) and colon (Abouzeid et al, 2013) cancer cells in vitro and in vivo (Abouzeid et al, 2013;Sarisozen et al, 2014), conferring synergistic effect to PTX- and DOX- (Abouzeid et al, 2013) based therapies.…”

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

“…94 In this regard, MCTS from MDR cell lines such as breast cancer MCF7/ Adr or ovarian cancer NCI-ADR-RES are useful tools to evaluate innovative solutions to restore DOX cytotoxicity as was shown with intrinsic drug-resistant glioblastoma U87MG cells. 70,71,[95][96][97][98] DOX-loaded nanoplatforms (targeted or nontargeted) that allow the simultaneous administration of several anticancer agents were evaluated in MCTS based on three criteria: accumulation, penetration and cytotoxic effects (Table 2). 70,71,[95][96][97][98] An excellent example of what can be done was the coloading of DOX with the MDR modulator curcumin (CUR) that inhibits different resistance-related pathways.…”

“…70,71,[95][96][97][98] DOX-loaded nanoplatforms (targeted or nontargeted) that allow the simultaneous administration of several anticancer agents were evaluated in MCTS based on three criteria: accumulation, penetration and cytotoxic effects (Table 2). 70,71,[95][96][97][98] An excellent example of what can be done was the coloading of DOX with the MDR modulator curcumin (CUR) that inhibits different resistance-related pathways. 94,98 Polymeric micelles loaded with DOX and/or CUR (zeta potential of -4.4 mV, 15 nm in size) were decorated with a single-chain fragment variable (scFv), smaller, more stable and less immunogenic than IgG antibody, and were addressed against the GLUT1 protein in overexpressed glioblastoma cells.…”

Possible role of nanocarriers in drug delivery against cervical cancer

“…Bioadhesive pellets of hexylaminolevulinate (HAL) containing Carbopol 934 were developed by Hiorth et al [62] using a spheronization technique for photodynamic therapy of cervical cancer, and the prepared pellets were found to be mechanically stable with good bioadhesivity and proficient HAL release, thus proving to be an efficient therapy for cervical cancer. Moreover, Sarisozen et al [63] fabricated transferrin-modified polyethylene glycol phosphatidyl ethanolamine (PEG-PE)-based polymeric micelles for co-delivery of PTX and curcumin, which were assessed for cytotoxicity, cellular accumulation, and association against spheroids of multidrug-resistant ovarian cancer cells and in vivo tumor models using confocal imaging and flow cytometry. The results indicated that micelles penetrate significantly deeper in spheroids, delivering cytotoxic agents efficiently and thereby enhancing the cytotoxicity.…”