## 7 Nanoplatforms, Natural Products, and Resistance  
In the case of gastrointestinal cancer, the use of nanocarriers for overcoming MDR phenotypes is a field attracting increasing interest due to nanocarriers' ability to overcome the limitations associated with efflux mechanisms, in addition to improving the solubility, bioavailability, and specificity of many of the conventional drugs used for the treatment of cancer [89]. The use of nanomedicines permits the exploitation of the enhanced permeation and retention effect (EPR) of solid tumors and the establishment of targeted delivery strategies by targeting surface receptors that are overexpressed on tumor cells. Natural products are being studied in detail due to their numerous benefits in the field of drug resistance; however, their hydrophobic character impedes aqueous solubility and decreases absorption. In this context, nanoplatforms can be used as transport/delivery systems for natural compounds by reducing solubility limitations and improving their bioavailability. Furthermore, the use of natural compounds for the synthesis of nanoformulations comprises a promising new strategy in overcoming drug resistance [90] (Figure 5). The effect of curcumin as a modulator of MDR has been extensively studied in different tumors, demonstrating its ability to regulate the expression of proteins such as Pgp, MRP, and LRP, and therefore its sensitizing activity in tumor cell lines that are resistant to chemotherapy. However, the clinical application of curcumin is limited by its low aqueous solubility [91]. Encapsulation in micelles, polymeric nanoparticles, and lipid nanoformulations, among other nanoplatforms, is an effective strategy for overcoming hydrophobicityproblems and increasing its MDR modulation and anticancer activity (Table 2). In this sense, there are numerous studies on the therapeutic benefits of combining curcumin with antitumor drugs such as DOX in a single nanoformulation to treat resistant tumors [92; 93]. In this context, [PERSON] et al. synthesized NVA622 polymeric nanoparticles loaded with DOX and curcumin that showed increased nuclear retention of DOX compared with the formulation without curcumin in in vitro and in vivo models of DOX-resistant ovarian, prostate, and multiple myeloma tumors, which all had a high expression of the MDR1 and MRP1 proteins [94]. Similarly, the combination of curcumin and DOX in Poly(lactic-co-glycolic acid) (PLGA) nanoparticles decreased the mRNA expression of MDR1 and BCL-2 by more than 12-fold compared with free DOX treatment and resulted in increased nuclear accumulation of DOX in chronic myeloid leukemia (CML) blasts like K562 cells [95]. Likewise, co-delivery of curcumin and DOX encapsulated in polymeric micelles showed increased cellular entry in a time-dependent manner, significantly enhancing intracellular accumulation and thus the cytotoxic effect of DOX, in addition to reducing the amount of DOX effluxed in a DOX-resistant MCF-7 human breast carcinoma cell line [96]. There are, in addition, studies on the delivery of curcumin and paclitaxel in solid lipid nanoparticles and through a nanoemulsion in resistant breast and ovarian tumor cell lines, respectively [97; 98]. According to [PERSON] and [PERSON]'s study, polymeric micelles loaded with paclitaxel and curcumin were shown to reduce Pgp protein expression by more than 80% compared with the untreated control [97]. Further, [PERSON] and [PERSON] showed that curcumin vehicleized in a nanoemulsion showed its regulatory activity against NFxB factor as well [98]. On the other hand, nutlin-3a, an antitumor agent with efficacy in various tumors such as glioblastoma, is limited by acting as a substrate for the resistance proteins MRP-1 and LRP. [PERSON] et al. encapsulated curcumin and nutlin-3a in folate-functionalized PLGA nanoparticles and demonstrated dose-dependent inhibition of the gene and protein expres  
Figure 5: EPR effect and mechanism of action in natural-product-loaded nanoformulations.