Table 4.

Details of in-vitro and animal studies of curcumin combinations with other therapeutic molecules and modified curcumin formulations administration in inflammatory bowel disease treatment.

S. No	Author/Year	Study Title	Modified Curcumin Formulations/Curcumin with Other Therapeutic Molecules	Cell Line/Animal Model	Main Findings
1	Li et al., 2007 [99]	Liposomal curcumin with and without oxaliplatin: effects on cell growth, apoptosis, and angiogenesis in colorectal cancer	Liposomal curcumin with oxaliplatin	LoVo and Colo205 cells and nu/nu mice	Liposomal curcumin exhibited a dose-based inhibition in the growth of colon cell lines LoVo and Colo205. The in vivo studies revealed the efficiency of liposomal curcumin by attenuating the CD3 expression, vascular endothelial growth factor, and IL-8 in a mice model.
2	Yadav et al., 2009a [100]	Effect of cyclodextrin complexation of curcumin on its solubility and antiangiogenic and anti-inflammatory activity in rat colitis model	Curcumin-cyclodextrin complex	Sprague–Dawley rats, DSS colitis	Curcumin-cyclodextrin complex inhibited the activation of NF-κB and blockade of infiltration of inflammatory cells (CD4 and CD8 T cells). It attenuated DSS-induced colitis in rats.
3	Yadav et al., 2009b [101]	Novel formulation of solid lipid microparticles of curcumin for anti-angiogenic and anti-inflammatory activity for optimization of therapy of inflammatory bowel disease	Solid lipid microparticles of curcumin (curcumin SLM)	Sprague–Dawley rats, DSS colitis	The increase in body weight and colon length in curcumin SLM-treated rats when compared with native curcumin-treated and DSS control rats. It reduced the number of cells in the mucosa of the colon and effectively reduced the degree of colitis.
4	Gugulothu et al., 2014 [102]	pH-Sensitive nanoparticles of curcumin-celecoxib combination: evaluating drug synergy in ulcerative colitis model	Curcumin-celecoxib-loaded polymeric nanoparticles (CUR-CelNPs)	Sprague-Dawley rats TNBS colitis	CUR—CelNPs considerably reduced the MPO and LPO activity as well as increased the superoxide dismutase (SOD) activity when compared with curcumin or nanoparticles alone. The synergic effect of curcumin and celecoxib exhibits the better therapeutic effect in treating UC.
5	Beloqui et al., 2014 [29]	pH-sensitive nanoparticles for colonic delivery of curcumin in inflammatory bowel disease	Curcumin polymeric nanoparticles combining both poly (lactic-co-glycolic) acid (PLGA) and polymethacrylate	Caco-2 cells, C57BL/6 mice, DSS-induced colitis	Curcumin polymeric nanoparticles considerably decreased the secretion of TNF-α in LPS-stimulated macrophages. They effectively reduced the neutrophil infiltration and secretion of TNF-α and helped maintain the colon structure like in the control group in a DSS-induced colitis model.
6	Li et al., 2015 [105]	Curcumin—piperine mixtures in self-microemulsifying drug delivery system for ulcerative colitis therapy	Curcumin and piperine co-encapsulated into a nanoformulation (CUR-PIP-SMEDDS)	BALB/c mice (pathogen-free), DSS-induced colitis	More stable in colons, increased encapsulation. Use of CUR-PIP-SMEDDS showed a better anti-colitis activity in the inflamed colon region.
7	Mutalik et al., 2016 [106]	Development and performance evaluation of novel nanoparticles of a grafted copolymer loaded with curcumin	Curcumin polymeric nanoparticles	HCT116 cells Wistar rats, acetic acid-induced colitis	Curcumin polymeric nanoparticles showed a controlled and targeted release of curcumin as well as better absorption than when delivered as free curcumin. They effectively decreased the myeloperoxidase and nitrite levels. Furthermore, they prevented the loss of body weight and attenuated colonicinflammation.
8	Beloqui et al., 2016 [30]	A comparative study of curcumin-loaded lipid-based nanocarriers in the treatment of IBD	Curcumin—lipid based nanocarriers	J774 murine macrophages and Caco-2 cells, C57BL/6 mice, DSS-induced colitis	Increased curcumin retention at the intestinal site and permeability. Curcumin—lipid-based nanocarriers reduced the infiltration of neutrophils and secretion of TNF-α as well as exhibited efficiency for IBD treatment.
9	Huang et al., 2017 [109]	Effects of curcumin plus soy oligosaccharides on intestinal flora of rats with ulcerative colitis	Curcumin + soy oligosaccharides	Sprague–Dawley rats, DNCB-induced colitis	Combination of curcumin and soy oligosaccharide attenuated the TNF-α and IL- 8 activity and reduced the colonic mucosa inflammation and tissue damage
10	Ohno et al., 2017 [111]	Nanoparticle curcumin ameliorates experimental colitis via modulation of gut microbiota and induction of regulatory T cells	Curcumin nanoparticles (theracurmin)	HT29 cells, BALB/c mice, DSS-induced colitis	Curcumin nanoparticles decreased the disease activity index, considerably improved mucosal permeability and the histological colitis score. Furthermore, curcumin nanoparticles suppressed the NF-κB activation.
11	Qiao et al., 2017 [112]	Orally delivered polycurcumin responsive to bacterial reduction for targeted therapy of inflammatory bowel disease	Curcumin polymeric nanoparticles (polyethylene glycol) (PEG) and curcumin (CUR) linked by a disulfide bond)	Caco-2 cells, C57BL/6 mice, DSS-induced colitis	Better solubility and targeted drug delivery in the inflamed regions of the gut. Enhanced transmembrane permeability and bioavailability. Notably, curcumin nanoparticles reduced the progression of the colon disease and effectively protected mice from IBD.
12	Kesharwani et al., 2018 [113]	Site-directed non-covalent polymer-drug complexes for IBD: formulation development, characterization, and pharmacological evaluation	Curcumin polymeric nanoparticles (Ora-Curcumin-S)	HCT116 and HT29 cells, BALB/cJ mice, DSS-induced colitis	Ora-Curcumin-S exhibited better solubility and stability. It reduced the colitis-associated symptoms. Controlled the loss of body weight, improved the colon length, colon edema, and spleen weight in DSS-induced colitis.
13	Chen et al., 2018 [114]	Facile fabrication of bowl-shaped microparticles for oral curcumin delivery to ulcerative colitis tissue	Bowl-shaped microparticles loaded with curcumin	Mice, DSS-induced colitis	Prolonged drug release, better encapsulation efficiency, targeted delivery, and excellent hydrophilicity. Supplementation with BMPs loaded with curcumin alleviates UC well based on the DSS-induced mouse model.
14	Chen et al., 2019 [116]	Oral administration of colitis tissue-accumulating porous nanoparticles for ulcerative colitis therapy	Porous poly (lactic-co-glycolic acid) nanoparticles and pluronic F127 (PF127) loaded with curcumin	Raw 264.7 macrophages, mice, DSS-induced colitis	Better biocompatibility and cellular uptake rate of curcumin than those of porous curcumin-loaded nanoparticles without PF127 modification (porous nanoparticles). They also effectively obstructed secretion of important proinflammatory cytokines (i.e., IL-6, IL-12, and TNF-α) and ameliorated the symptoms of UC.
15	Sharma et al., 2019 [32]	Improved uptake and therapeutic intervention of curcumin via designing binary lipid nanoparticulate formulation for oral delivery in inflammatory bowel disorder	Curcumin-loaded solid binary lipid nanoparticles (C-SBLNs)	Guinea pigs, DSS-induced colitis	Control and stable release of curcumin, improved cellular uptake, and targeted delivery. Supplementation with C-SBLNs decreased the infiltration of leucocytes, oxidative stress, and secretion of TNF-α and helped to keep the structure of the colon healthy as compared to free curcumin.
16	Desai and Monim, 2020 [118]	Colon targeted bioadhesive pellets of curcumin and cyclosporine for improved management of inflammatory bowel disease	Polymeric nanoparticles (bioadhesive pellet cores of curcumin)	Wistar rats, acetic acid-induced colitis	Combining curcumin and cyclosporine exhibited synergistic effects of managing IBD. Controlled the loss of weight and enhanced the clinical response, macroscopic and microscopic parameters of induced colitis when compared to cyclosporine and native curcumin.
17	Oshi et al., 2020 [119]	Curcumin nanocrystal/pH-responsive polyelectrolyte multilayer core−shell nanoparticles for inflammation-targeted alleviation of ulcerative colitis	Curcumin nanocrystal polyelectrolyte (chitosan/sodium alginate/cellulose acetate phthalate as shells)	Mice, DSS-induced colitis	Targeted delivery of curcumin into the inflamed colon tissue and enhanced biodistribution in the stomach and small intestine. Improved effectiveness in reducing inflammation-associated indicators in a DSS-induced colitis mice model.
18	Luo et al., 2020 [120]	Genipin-cross-linked human serum albumin coating using a tannic acid layer for enhanced oral administration of curcumin in the treatment of UC	Tannic acid (TA)-coated, genipin (Gnp)-crosslinked human serum albumin (HSA)-encapsulated curcumin nanoparticles (TA/CUR-NPs)	Caco-2 cells, mice, DSS-induced colitis	Controlled curcumin release and increased the curcumin uptake in cells. Oral administration of TA/CUR-NPs obstructed the TLR4-linked NF-κB signaling pathway and reduced the colitis symptoms compared to the controls.
19	Huang et al., 2021 [121]	Oral nanotherapeutics with enhanced mucus penetration and ROS-responsive drug release capacities for delivery of curcumin to colitis tissues	Hydrogel (chitosan/alginate)-embedding pluronic F127—catalase/curcumin nanoparticles (P-CUR/CAT-NPs)	Raw 264.7 macrophages, FVB male mice, DSS-induced colitis	Improved the cellular uptake efficiency of macrophage cells, effectively reduced the symptoms, and suppressed secretion of the major proinflammatory cytokines
20	Rotrekl et al., 2021 [122]	Composites of yeast glucan particles and curcumin lead to improvement of dextran sulfate sodium-induced acute bowel inflammation in rats	Curcumin loaded into yeast glucan particles	Wistar rats, DSS-induced colitis	Curcumin loaded into yeast glucan particles decreased the activity of proinflammatory cytokines (i.e., TNF-α, IL-1β, and IL-6) and MMP activity as compared to native curcumin in DSS-induced colitis rats.