## 7 Nanoplatforms, Natural Products, and Resistance
The use of nanocarriers improves the solubility, bioavailability, and specificity of natural products through the EPR effect, a reduction in hydrophobicity, or drug delivery strategies. sion of MRP-1 and LRP by curcumin in human retinoblastoma cells [99]. Some studies focused on the study of the synergistic antitumor effect of curcumin with other chemotherapeutics in resistant tumor models without testing its MDR modulatory effect. Studies on a paclitaxel-resistant SK-OV-3 TR ovarian tumor cell line showed that polymeric micelles loaded with curcumin and paclitaxel exhibited enhanced cytotoxicity in both monolayer cell cultures and tumor spheroids (a 3D multicellular tumor model) and 3-fold greater inhibition of tumor growth in vivo [100,101]. Similar in vitro and in vivo results were obtained in a DOX-resistant A2780 ovarian tumor model with the co-delivery of curcumin and DOX by alginate nanodroplets [92]. There were also studies on nanoformulations of paclitaxel in combination with other natural compounds such as baicalein and resveratrol with promising results for overcoming MDR in breast cancer [102,103]. Furthermore, demethylox Curcumin, another compound containing bioactive curcuminoids, showed better blood solubility than curcumin and could also be used as a mediator of chemoresistance by sensitizing tumor cells to conventional chemotherapeutic agents [104]. In fact, an enhanced synergistic effect between cisplatin and demethylox Curcumin loaded in CD133-targeted chitosan nanoparticles was shown against MDR lung cancer stem-like cells [105]. Also, the use of nimbolide, a triterpene compound that can be isolated from neon, loaded in Poly (D, l-lactide-co-glycolide) nanoparticles should be highlighted, achieving the downregulation of AKT, mTOR, mesenchymal marker N-cadherin, and MDR marker ABCG2 and the upregulation of the epithelial marker E-cadherin [65]. Moreover, [PERSON] et al. [106] employed polylactic-co-glycolic acid nanoparticles charged with bufalin, a compound secreted by the glands of toads, and 5 FU and GEM. With this strategy, the resistance of PC cells to GEM was reversed by inhibiting the expression of ABCB1 and ABCG2 and decreasing the expression of NF-\(\kappa\)B and NOD2, also synergistically increasing the anticarcinoma activity of 5 FU. Tumor weight was reduced by 60% with the combined therapy compared with the individual treatments. L-Arg, a nitrogen oxide donor, was charged in gold nanostructures with a biomimetic cell membrane coating with PEG2000 and GEM. A 63% cell viability reduction was achieved with the combination strategy with respect to the control (empty nanostructure with only GEM) in GEM-resistant Panc-1, with an 82% improvement in the apoptosis rate, reversing GEM resistance. A 95% tumor volume reduction was achieved with respect to the control at the end of experiment, with a 100% survival rate improvement 60 days after administration [107]. Piperine, a piperidine alkaloid extracted from black pepper, was used in albumin-bound nanoparticles. Through this strategy, PIP significantly reduced the IC50 value of paclitaxel, and the accumulation of paclitaxel increased after co-incubation with PIP compared with incubation with paclitaxel alone. PIP competed for the drug-binding site of paclitaxel on P-gp at specific concentrations. PIP decreased the P-gp protein level and the expression of the MDR1 gene, blocked tumor cell growth, and increased apoptosis [108].