Table 2.

Formulation technologies designed to improve the bioavailability and efficacy of berberine as anticancer agent.

Preparation	Characteristics	Assay Model & Main Outcome	Reference
Nanosized carbon nanoparticle-C60 fullerene (C60)	Water dispersions of noncovalent C60-Ber nanocomplexes in the 1:2, 1:1, and 2:1 molar ratios.	Promote Ber intracellular uptake; higher antiproliferative potential towards CCRF-CEM cells free - Berberine < 1:2 < 1:1 < 2:1 molar ratio preparations; activate caspase 3/7; cell cycle arrest at sub-G1 phase; induce apoptosis.	Grebinyk et al. [106]
Anionic and cationic vitamin E-TPGS mixed polymeric phospholipid micellar vehicles	Lipid-based nanocarriers, amphiphilic mixed micelles composed of polymeric phospholipid conjugates and PEG-succinate ester of tocopherol.	Human prostate cancer cell lines (PC3 and LNPaC)—enhance apoptosis induction with 30-fold potential improvement of pharmacokinetics.	Yao and Elbayoumi [107]
Novel mitochondria targeting surface charge-reversal polymeric nanoparticles	Vitamin B6-oligomeric hyaluronic acid (OHA)-dithiodipropionic acid-berberine preparation; berberine conjugated with OHA and OHA further conjugated to B6. Micelles of 172.9 nm formed by formulating conjugates with Cur-loaded nanoparticles.	Induce cytotoxicity in vitro against PANC-1 cells and tumour growth in nude mice bearing PANC-1 cells xenograft; subcellular drug distribution shows mitochondria as target.	Fang et al. [108]
Planar side arm-tethered β-cyclodextrin encapsulation	Fluorenyl derivative of β-cyclodextrin used to encapsulate berberine.	Strongly binds with duplex and G-quadruplex DNAs although its association with the cavity of β-cyclodextrin diminishes the binding strength.	Suganthi et al. [109]
Cationic γ-cyclodextrin derivative	A cationic derivative of γ-cyclodextrin synthesised through modification with propylenediamine; mucoadhesive with resistance to digestion by ∝-amylase.	Localised in lysosomes with cytotoxicity twice higher than berberine in murine melanoma (B16-F10) and 4T1 cells.	Popiołek et al. [110]
PLGA nanoparticles	PLGA-doxorubicin conjugate used for encapsulation of berberine.	Anti-proliferative against MDA-MB-231 and T47D breast cancer cell lines were observed with IC50 of 1.94  ±  0.22 and 1.02  ±  0.36 μM; alter mitochondrial permeability and arrest cell cycle at sub G1 phase; 14-fold increase in half-life of berberine in rats.	Khan et al. [111]
Self-carried berberine microrods	Carrier prepared by mixing trimethylamine with berberine hydrochloride in DMSO to form about 20–100 μm length and 5–20 μm width irregular size product.	Hepatocellular carcinoma (HepG2, SMMC-7721, Hep3B, H22 cells) and normal cell lines (HL-7702 cells, HUVEC cells, C2C12 cells, and H9C2 cells) used for cytotoxicity assay; With about 40 µg/mL IC50 value, about twice more selective than berberine in cancer cells.	Zheng et al. [112]
Polyethyleneimine (PEI)-cholesterol (PC) berberine nanocarrier complexed with miR-122	Berberine incorporated to PC with further electrostatic complex with miR-122; good drug loading (8.4%) and release (63.0) capacity of nanoparticles of about 146 nm.	Decrease OSCC cells invasion and migration in transwell assay when compared with single drug treatments.	Lei et al. [113]
Berberine with PEGylated Liposomal Doxorubicin (PEG-lip-DOX)	Berberine combined with polyethylene glycolated liposomal doxorubicin.	Inhibit the vascular endothelial growth factor (VEGF) expression in human umbilical vein endothelial cells (HUVECs); inhibit (via i.v.) tumour growth in Meth A sarcoma-transplanted mice; effect stronger than berberine or PEG-lip-DOX alone.	Yahuafai et al. [114]
Zinc oxide-based nanoparticles	Berberine and zinc oxide (ZnO) combined through facile blending at the ratio of 39:61 to form 200–300 nm size nanoparticles.	Enhance antiproliferative activity in A549 (human lung adenocarcinoma) cells; no obvious severe hepatotoxicity, renal toxicity, and haemotoxicity in rats by i.v.	Kim et al. [115]
Folic acid- and berberine-loaded silver nanomaterial (FA-PEG@BBR-AgNPs)	Encapsulating berberine on citrate-capped silver nanoparticles (AgNPs) through electrostatic interactions (berberine-AgNPs) followed by conjugation with polyethylene glycol-functionalized folic acid through hydrogen bonding interactions.	Enhance apoptosis in MDA-MB-231 breast cancer cells; induce ROS; modulate PI3K, AKT, Ras, Raf, ERK, VEGF, HIF1α, Bcl-2, Bax, cytochrome-c, caspase-9, and caspase-3; inhibit tumour growth in vivo when administered intravenously into MDA-MB-231 tumour-bearing athymic nude mice.	Bhanumathi et al. [116]
Hypoxia-specific chemo-targeting iron-oxide nanoparticle–Berberine complexes	Hypoxic cell-sensitizer sanazole (SAN) -directed targeting of cytotoxic drug berberine and iron-oxide nanoparticle complexes.	Reduce tumour volume in mice bearing solid tumour in hind limb; increase DNA damage; suppress the levels of transcription of HIF-1α, VEGF, Akt and Bcl2; increase Bax and caspases expressions.	Sreeja and Krishnan [117]
Berberine-loaded Janus nanocarriers for magnetic field-enhanced therapy	Janus magnetic mesoporous silica nanoparticles (Fe3O4-mSiO2 nanoparticles): Fe3O4 head for magnetic targeting and a mesoporous SiO2 body for pH-dependent berberine delivery.	Magnetic field-induced endocytosis and pH-responsive drug release leading to improved cytotoxicity against hepatocellular HepG2 carcinoma cells.	Wang et al. [118]
Dendrimer encapsulated and conjugated delivery of berberine	Dendrimer (G4 PAMAM) encapsulated and conjugated berberine formulations of 100–200 nm size; entrapment efficiency of 29.9% or percentage conjugation of 37.49%.	Higher drug payload in conjugation method; sustained and efficient release pattern in vitro; higher anticancer effect in vitro against MCF-7 and MDA-MB-468 breast cancer cells; no haemolytic effect ex vivo; improved pharmacokinetic in rats with about 2-fold improvement in half-life (t1/2).	Gupta et al. [119]
Silver nanoparticles	Nanosize silver particles with berberine chloride.	Human tongue squamous carcinoma SCC-25–IC50 of 5.19 μg/mL; cell cycle arrest at G0/G1 phase; increase of Bax/Bcl-2 ratio gene expression.	Dziedzic et al. [120]
Graphene oxide-based berberine nanocarrier	Electric-sensitive drug release and redox sensitive graphene oxide nanocomposite loading berberine.	-	Yu et al. [121]
Solid lipid nanoparticle encapsulation.	Solid lipid nanoparticle (SLN) with particle size of 81 nm and zeta potential of 28.67  ±  0.71 mV.	More cell proliferation inhibitory effect on MCF-7, HepG 2, and A549 cancer cells than berberine; induce cell cycle arrest, and apoptosis.	Wang et al. [122]
Liposomal berberine	Polyethenyl glycol (PEG) with maximum encapsulation efficiency berberine as 14%.	2.5-times more active in inhibiting the growth of HepG2 cells than berberine (IC50 of 1.67 μg/mL vs. 4.23 μg/mL); induce apoptosis through the caspase/mitochondria-dependent pathway; lower rate of elimination in both plasma and tissues; improved antitumour effect in vivo when tested in tumour xenograft mice bearing HepG2-induced tumour.	Lin et al. [123]