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. 2023 Jun 16;15(6):1751. doi: 10.3390/pharmaceutics15061751

Table 2.

Drug Nano-Delivery Systems Including Hyaluronic Acid and Phenolic Compounds (Non-Flavonoids: Phenolic acids, Stilbenes, Curcuminoids) for cancer targeting.

Preclinical Model Nanoformulation
(as Reported by the Authors)		 Antineoplastic Drug/Nutraceutic enclosed in One Nanoformulation or Administered Separately PheC (Non-Flavonoid) in the Nanoformulation Anticancer Effect(s) of the Nanoformulation (or Combination of Formulations) Respect to the Enclosed Free Compounds Ref.
In vitro: DOX-resistant HL-60 promyelocytic leukemia cells and DOX-resistant K562 chronic myeloid leukemia cells.
In vivo: DOX-resistant HL-60 cells subcutaneously injected in Balb/c nude mice. Drugs i.v. injected every 3 days for 7 times.		 Lipid-polymeric hybrid NPs consisting in: HA conjugated with PEG-DSPE co-loading DOX and GA.
Size: 165.7 ± 4.6 nm		 DOX GA
(Phenolic acid)		 In vitro: ↓Cell viability
↓ IC50
(maximally at 2:1 DOX/GA ratio)
In vivo: ↓ Tumor volume
↓ Decrease in body weight		 [55]
In vitro: Human MCF-7 and CAL-51 breast cancer cell lines. Liquid crystalline NPs (LCNPs) enclosing Tamoxifen plus RES and coated with multiple layers of chitosan and HA. Size: about 217 nm TAM RES
(Stilbene) 		In vitro:
↓ Cell viability *; ↑ Apoptosis *
In vivo:
No change in body weight during treatment		 [61]
In vitro:
4T1 murine breast cancer cells 		RES-loaded Zein-SHA NPs.
Average size: about 152.13 nm		 None RES
(Stilbene) 		In vitro: ↓ Cell viability
↓ IC50		 [62]
In vitro: MDA-MB-231 triple-negative breast cancer cells

In vivo: subcutaneous inoculation of MDA-MB-231 cells in the abdomen of nude mice. Drugs injected into the tumors as they reached a volume of about 80 mm3.		 Injectable Res-Cx-HA hydrogel
Size: Non reported		 None Resveratrol (RES)
(Stilbene) 		In vitro: ↓ Cell viability;

In vivo: Tumor tissue inject with the Hydrogel: ↑ necrosis rate of tumor tissue; ↓ Angiogenesis		 [63]
In vitro: CT26 colon cancer cell line;
In vivo: CT26 cells xenografted in the flank of Balb/c nude mice. Drugs i.v. injected every day for 2 weeks.		 HA-Zein-CUR NG
Size: from 200–250 nm.		 None CUR
(Curcuminoid) 		In vitro:
↓ Cell viability; ↑ Apoptosis
In vivo: ↓ Tumor volume and weight		 [64]
In vitro:
MDA-MB-231 and
MDA-MB-468 breast cancer cells		 CDF loaded in HA-SMA-TPGS nanomicelles.
Average size: 129.4 nm		 None CDF
(Curcuminoid) 		In vitro:
↓ Cell viability; ↑ Apoptosis
↑ PTEN (pro-apoptotic) and ↓ NF-kB (tumorigenic) expression		 [65]
In vitro: MDA-MB-231 breast cancer cell line.
In vivo: Swiss albino mice injected with Erlich Ascites Carcinoma. Drugs i.v. injected after 10 days every 2 days for 2 weeks.		 HA-tagged mesoporous silica NPs loaded with CUR.
Average size: 161.3 nm		 None CUR
(Curcuminoid) 		In vitro:
↓ Cell viability; ↓ in-vitro cellular migration;
↑ Apoptosis; Cell cycle arrest at G2/M phase
In vivo:
↓ Tumor volume and tumor mass		 [66]
In vitro: MCF-7 cells breast cancer cells and breast cancer stem cells.
In vivo: MCF-7 cells injected in nude mice. Drugs i.v. injected as tumors reached 400 mm3 		Icariin and CUR co-encapsulated in polymeric micelles based on pH-sensitive hydrazone bond, FA and biotin-conjugated HA.
Size: 162.7 ± 5 nm.		 Icariin CUR
(Curcuminoid) 		In vitro:
↓ Cell viability; ↓ Invasion ability (Transwell assay)
In vivo:
↓ Tumor volume		 [67]
In vitro: A549 lung carcinoma cells and RAW264.7 cells.
In vivo: A549 cells trasplanted in mice. Drugs i.v. injected as the tumor reached an appropriate size.		 QU-dithiodipropionic acid-oligomeric HA-mannose-ferulic acid self-assembled and encapsulating CUR and Baicalin.
Size: 121.0 ± 15 nm		 Baicalin CUR
(Curcuminoid) 		In vitro:
↓ Cell viability;
In vivo:
↓ Tumor volume; ↓ Decrease in body weight		 [68]
In vitro: MG-63 osteosarcoma cells
In vivo: MG-63 cells injected into the right tibia of nude mice; at 12 days, drugs injected every 2 days for 20 days.		 ALN-HA-C18 loading CUR.
Size: 118 ± 3.6 nm		 None CUR
(Curcuminoid) 		In vitro:
↓ Cell viability;
In vivo:
↓ Tumor volume;		 [69]
In vitro: Human SKOV3 and SKOV3-TR30 ovarian cancer cells (multi-drug resistant);
In vivo: SKOV3 cells subcutaneously xenografted. Drugs i.v. injected as tumor reached 200 mm3.		 HA-coated PEI-SA copolymer co-encapsulating PTX and CUR.
Average Size: 187.77 nm		 PTX CUR
(Curcuminoid) 		In vitro:
↓ IC50 (in both the cells)
↓ Cell invasiveness (of both cells)
In vivo:
↓ Tumor volume		 [70]
In vitro: LX-2 human hepatic stellate cells (HSCs) and SMMC-7721 human hepatocarcinoma cells (HCCs).
In vivo: H22 mouse HCCs, mouse HSCs and SP subcutaneously injected into the right flank of mice. Drugs i.v. injected 7 times as tumors reached 150 mm3.		 HA and glycyrrhetinic acid-modified liposomes co-delivering aprepitant and CUR.
Size: 117.40 ± 0.62		 APR CUR
(Curcuminoid) 		In vitro:
↓ Cell viability of LX-2 cells and of SP-treated LX-2 + HCCs co-culture;
↓ Cell migration in HCCs and in SP-treated LX-2 + HCCs co-culture
In vivo:
↓ Tumor volume		 [71]
In vitro: HCT116, HCT8, and HT29 colon cancer cells. Zein-HA NPs enclosing CUR.
Average size: about 300 nm		 None CUR
(Curcuminoid) 		In vitro: ↓ Cell viability of all cancer cell and IC50 with Zein-HA NPs (respect to CUR alone or to all other NPs) [72]
In vitro: Human HCCs (BEL-7402), human-derived HSCs (LX-2), mouse HCCs (H22), and mouse HSCs (mHSCs);
In vivo: H22+mHSCs injected in the flank of Balb/c mice. Drugs i.v. injected as tumors reached 200 mm3.		 Glycyrrhetinic acid- and HA-modified liposomes co-delivering Berberine and CUR.
Size: 159.39 ± 3.16 nm		 Berberine CUR
(Curcuminoid) 		In vitro:
↓ Cell viability of BEL-7402 cells and co-cultured BEL-7402+LX- cells;
In vivo:
↓Tumor volume in H22+m-HSC tumor-bearing mice model		 [73]
In vitro:
Human breast adenocarcinoma cell line (MDA).		 HA- and riboflavin-coated transition metals-based nanoplatforms enclosing CUR.
Average size: about 70 nm		 None CUR
(Curcuminoid) 		In vitro:
↓ Cancer cell viability (vs. NPs not containing CUR, not vs. CUR alone)		 [74]
In vitro:
human HT-29 and mouse CT-26 colon cancer cells		 Lactoferrin-EGCG-NP coated with HA and loading CUR.
Average size: 144.7 nm		 None CUR
(Curcuminoid) 		↓ Cancer cell viability
↑ Apoptosis		 [75]

ALN-HA-C18: Alendronate-HA-octadecanoic acid; APR: aprepitant; CD/QU: 2-hydroxypropyl-β-cyclodextrin/Quercetin; CDF: 3,4-difluorobenzylidene diferuloylmethane; CUR: curcumin; DMAEP: 2,2-dimethacroyloxy-1-ethoxypropane; EGCG: epigallocatechin-3-gallate; FA: folic acid; GA: gallic acid; HA: hyaluronic acid; HA-Zein-CUR NG: HA cross-linked zein nanogel including curcumin; HCD-A: 2-hydroxypropyl-β-cyclodextrin acrylate; MDR: multidrug resistant; ND: not detected; NPs: nanoparticles; PEG-DSPE: polyethylene glycol-distearoyl phosphoethanolamine; PEI-SA: polyethylenimine and stearic acid; PTX: paclitaxel; QU: Quercetin; RES: resveratrol; Res-Cx-HA: RES-loaded click-crosslinked HA; SHA: low-molecular-weight sodium hyaluronate); SMA: styrene maleic anhydrase polymer; SP: substance P; TAM: tamoxifen; TPGS: Tocopherol polyethylene glycol 1000 succinate. *: In this case, the comparison was made only between cells treated or not with the nanosystem.