Table 2.

Comparative analysis of bioavailability of pure natural products and their advanced formulations.

Natural Products/Extract	Strategy for Bioavailability Augmentations	Conc./ Dose	Bioavailability Enhancement (Effect of ADMET)		Effect on Oral Cancer	Mechanisms	Reference
			Bioavailability of Normal Drug	Bioavailability of Novel Formulation
Capsaicin	SNEDDS	305.41 g/mol	16.61 ± 3.64%	3.6-fold increase in bioavailability	Antiproliferative effects	MMP disruption, caspase-3, caspase-7 and caspase-9 activation through an intrinsic apoptotic pathway and subsequently, apoptotic DNA fragmentation	[186]
EGCG	NE	200–800 mg	NR	The bioavailability was more than 2.78-fold	Inhibition of both cell proliferation and migration	Targets multiple signaling pathways, including the downregulation of EGFR and associated downstream signaling molecules	[187,188,189,190]
Piperlongumine	NPs	7.4–11.3 μM	NR	NR	Antiproliferative effects, cell cycle arrest and senescence	↓PI3K/Akt/mTOR pathway, ↓ROS, ↑apoptosis, ↑G1 phase cell cycle arrest, ↑p21, ↑cleaved caspases-3, ↑PARP	[191,192]
Bromelain	Lipid-polymer hybrid nanoparticles	12.5–100 µg mL	NR	Maximum release of Bromelain from nanocarriers was obtained 30–35% after 5 days	Inhibited cell growth and proliferation	G1 cell cycle arrest, induced apoptosis	[26,193,194,195]
Curcumin	Curcumin nanocrystals/NPs	10 or 12 g/mL	1%	Over 5 times from simple curcumin powder	Inhibit growth, invasion and metastasis	Inhibits the invasive ability and EMT by reducing the MMP-2 and MMP-9 expression, downregulation of EGFR expression	[196]
Berberine	Vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate-mixed polymeric phospholipid micelles of berberine	100 or 300 mg/kg	<5% in plasma	15%	Antimitotic and proapoptotic actions, along with distinct antiangiogenic and antimetastatic activities	Suppresses the mRNA expression of NFKB1 and PTGS2 and AURKA, BIRC5, and EGFR	[26,197]
Honokiol	NPs	0–150 mg/kg	NR	53% of honokiol was released from the nanoparticles within 24 h	Antiproliferative effect	Blocks EMT through the modulation of Snail/Slug protein translation	[198]
Evodiamine	Nanocomposite system comprising folic acid- modified graphene quantum dots	1 mg	NR	Over 90% of drug was released in 72 h	Inhibited cell proliferation	Downregulates Mcl-1 expression, induces apoptosis mediated by a caspase-dependent pathway	[199]
Gedunin	Chitosan- encapsulated gedunin	1.5–50 µg/mL	NR	NR	3 to 8-fold decrease	Modulates AR, PI3K/Akt, and NF-κB pathways to block angiogenesis	[200]
Sinularin	Not found	NR	NR	NR	Selectively kill the oral cancer cells	Antiproliferative and apoptotic effects on oral cancer cells coupled with ROS generation and G2/M arrest	[201]

Abbreviations: AR, aldose reductase; AURKA, aurora kinase A; EGCG, epigallocatechin gallate; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition;; MMP, mitochondrial membrane potential; NF-κB, nuclear factor-κB; PARP, poly adenosine diphosphate-ribose polymerase; PI3K, phosphatidyl inositol-3-kinase; PTGS2, prostaglandin coding gene; ROS, reactive oxygen species; SNEDDS, self-nano emulsifying drug delivery system.