Current development in novel drug delivery systems of bioactive molecule plumbagin

Figures & data

Figure 1. Schematic of the plumbagin structural activity relationship.

Figure 2. (A) Schematic presentation of mechanisms for anticancer activities of plumbagin in-vitro. (B) Summary of documented molecular-biological effects of plumbagin.

Figure 3. Redesign of plumbagin through various strategies to enhance bioavailability. PL: phospholipid; TPGS: D-a-tocopheryl polyethylene glycol 1000 succinate; FA: folciacid; PLGA: polylactic-co-glycolic acid; β-CyD: betacyclodextrin; PMCA: polymethylcyanoacrylate.

Table 1. Biological activities and mechanism of actions of plumbagin.

Biological activities	Mechanism of action	References
Anti-inflammatory	Suppress the NF-kB and inhibit neutrophil activation, angiogenesis and expression of collagenase	[6]
	Inhibits the NOX4/PKM2-dependent immunometabolic pathway	[7]
Antioxidant	Inhibits ascorbate and NADPH-dependent lipid peroxidation and decrease liver glutathione (GSH) as well as microsomal glucose-6-phosphatase levels	[8]
Antimalarial	Inhibit succinate dehydrogenanse (SDH) enzyme in P. falciparum	[9]
Anticancer	Breast cancer: Induce apoptosis in BRCA cells with concomitant down regulation of Bcl-2 expression and NF-kB activity	[10]
	Pancreatic cancer: Upregulation of Bax, a rapid decline in mitochondrial transmembrane potential, apoptosis-inducing factor over expression in cytosol and cleavage of pro-caspase-9 and PARP (poly ADP-ribose polymerase)	[11]
	Activation of caspase-3
	Myeloma: Inhibits both constitutive and interleukin(IL)-6-inducible STAT-3	[12]
	phosphorylation and over expression of constitutively active STAT-3
	Lung cancer: Inhibits the activation of NF-κB which down-regulated the	[13]
	expression of anti-apoptotic proteins and up-regulated pro-apoptotic proteins
	In non-small cell lung cancer (NSCLC), it increases the intracellular level of ROS, inhibits NF-kB/p65 nuclear translocation, suppress the degradation of IkBk, increases the activity of caspase-9 and caspase-3, downregulates the expression of Bcl-2 and upregulates the expression of Bax, Bak and CytC. It modulates expression of multiple factors that regulate cell cycle such as p21, cyclinB1,	[14]
	Cdc2, Cdc25C, etc. It inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced	[15]
	invasion and migration. It inhibits the expression of MMPs and urokinase-type plasminogen activator (uPA)
	Skin carcinoma: Induce apoptosis and S-G2/M cell cycle arrest, elevate level of	[16]
	p21 and reduce levels of cyclin B1, cyclin A, Cdc2 and Cdc25C. It also induce a
	change in Bax/Bcl-2 ratios and activate caspase-9 resulting in apoptotic cell death
	Liver cancer: Inhibit the migration and invasion of liver cancer cells through	[17]
	downregulation of MMP-2 and uPA
	Renal cancer: Inhibit Nox-4 activity, a renal NAD(P)H oxidase	[18]
	Cervical cancer: Activation of caspase-3, caspase-9, translocation of	[19]
	phosphatidyl serine, nuclear condenzation and DNA fragmentation
	The anticancer mechanisms related to apoptosis, cell cycle, invasion, metastasis, angiogenesis and
	autophagy which are summarized in Figure 2

Table 2. The pharmacokinetic parameters of plumbagin after oral administration of 100 mg/kg body weight of plumbagin to healthy male Wistar rats [3].

Parameters	Plumbagin
T1/2 (h)	9.63 (3.04)
Tmax (h)	5.0 (0.0)
Cmax (μg/mL)	0.46 (0.15)
AUC0–48h (μg h/mL)	6.51 (1.16)
AUC0–∞ (μg h/mL)	6.71 (1.41)
MRT (h)	12.88 (2.49)
Vd/F (L/mg dose/kg body weight)	0.0022 (0.00)
CL/F (L/h/mg dose/kg body weight)	0.15 (0.3)

Table 3. Various novel drug delivery systems of plumbagin along with their key findings.

Delivery system	Key finding	References
PLB-loaded thermosensitive liposomes	Enhanced volume double time and growth delay in tumour (melanoma B16F1) bearing C57BL/6J mice	[27]
PLB-loaded pegylated liposomes	Increased 36 and threefold in plasma t1/2 and bioavailability with significant reduction in the tumour volume in tumour (melanoma B16F1) bearing C57BL/6l mice	[28]
PLB-HPβCD-loaded niosomes	Enhanced antifertility activity of PLB	[31]
PLB-β-CD-loaded niosomes	Pronounced anti-tumour activity of PLB-β-CyD complex in C57BL/6J mice bearing melanoma B16F1	[32]
PLB-loaded niosome	Better anti-tumour activity in a solid tumour (sarcoma-180)	[33]
PLB-loaded albumin microsphares	Increased anti-tumour efficiency and reduced toxicity of PLB against B16F1 melanoma	[34]
PLB-loaded polymethylcyanoacrylate	Emulsion polymerization is better choice for preparation of nanoparticles	[37]
PLB-loaded PL and Tween micelles	2.1-fold enhancement in vitro anti-tumour activity towards human breast cancer MCF-7 cells	[38]
PLB-TPGS– folic acid nanomicelles	Enhanced in vitro anticancer activity in folate over expressed human breast cancer MCF-7 cells	[39]
PLB-loaded PLGA microspheres	Significantly increased volume doubling time in sarcoma-I80 tumour bearing BALB/c mice	[41]
PLB-loaded chitosan microspheres	22-, 25- and 9-fold improved half-life, mean residence time and bioavailability of PLB with enhanced anti-tumour efficacy and reduced systemic toxicity	[42]
Gold nanoparticles with PLB	Reduced cytotoxicity and apoptosis	[44]
PLB-Silver nanoparticles	PLB-AgNPs enhanced internalization of PLB, inhibited proliferation of human cervical cancer cells HeLa	[45]
PLB-loaded magnetic nanoparticle	Exhibited efficient (fourfold) internalization in human PanCa cells (HPAF-II, AsPc1 and Panc-1) with fourfold inhibition in colony formation	[46]
Surface modified PLB crystals	Twofold increase PLB solubility	[49]
PLB crystals by sonocrystallization	Improved biopharmaceutical properties of PLB	[50]

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