Pharmacokinetic studies of nanoparticles as a delivery system for conventional drugs and herb-derived compounds for cancer therapy: a systematic review

Figures & data

Figure 1 Schematic diagram showing the four pharmacokinetic processes: absorption, distribution, metabolism and excretion (ADME) including their pharmacokinetic parameters.

Table 1 Summary of the in vivo/clinical pharmacokinetic studies of conventional chemotherapeutic drugs for cancer included in the analysis. Data are presented as mean values for nanoformulation vs free drug

Drug-loaded	Nanoparticle	Animals used (n)/cell line	Route, dose	Analytical technique	Pharmacokinetic parameters (mean)	Outcomes	Reference
Daunorubicin	CS–PLGA and PLGA	Wister rats (n=6) MCF-7 cell line	Oral, 10 mg/kg bw	UHPLC-MS/MS	AUC0–48: 15,729, 8674.65 vs 1393 ng.hr/mL; Cmax: 591, 318.55 vs 44.65 ng/mL: Tmax: 4.00, 4.00 vs 2.00 hrs; t1⁄2: 152.7, 119.39 vs 54.55 hrs.	Improved pharmacokinetics with CS-PLGA loaded drug than PLGA loaded drug with increased AUC (11.29-fold), Cmax (1.86-fold), Tmax (2-fold), and prolonged t1/2 (2.8-fold). Potential to avoid first pass metabolism with CYP450 and P-gp mediated efflux.	^Citation22
Lecithmer	Wistar rats (n=6) K562and Hop62celllines	IV, 4 mg/kg bw	HPLC	AUC: 31.2 vs 39.7 ng hr/mL; t1⁄2: 1.96 vs 1.63 hrs; Vd: 81.68 vs 57.46 L; CL: 28.87 vs 23.24 L/hrs	The only significantly improved pharmacokinetic was Vd (1.42-fold) with the rapid uptake of the reticuloendothelial system. Slightly Prolonged t1/2 (1.2-fold) decreased AUC (1.3-fold); Increased CL (1.24-fold)	^Citation23
Docetaxel	PHBV	Charles Foster Rats (n=6). MCF-7 cell line	IV, 25 mg/kg bw	HPLC	AUC0-t: 914.9 vs 565 μg/mL*hr; Cmax: 15.53 vs 41.06 μg/mL; Tmax: 72 vs 6 hrs; t1⁄2: 41.8 vs 5.09 hrs; CL: 0.019 vs 0.044 L/hr; Vss: 2.49 vs 0.171 L/hrs	Improved pharmacokinetics: Increased AUC (1.6-fold); prolonged t1/2(8.2-fold); increased Vd (2.3-fold); decreased CL (2.3-fold)	^Citation3
	LCG-SNELS vs MCG-SNELS	Rats (n=3) Caco-2 cell line	Oral, 20 mg/kg bw	UPLC	AUC: 9197.7, 7425.8 vs 847.2 ng·hr/mL; Cmax: 1597.2, 612.5 vs 346.9 ng/mL; Tmax: 1.42, 2.74 vs 3.27 hrs	Improved pharmacokinetics: Increased AUC and Cmax of LCG-SNELS loaded drug compared with MCH-SNELS loaded drug and free drug; LCG-SNELS: a preferred drug carrier than MCG-SNELS for better drug delivery to tumor cells.	^Citation11
	PS-PDLLA	Male Sprague–Dawley (SD) rats (n=3). PC-3 cell line	IV, 1 mg/kg bw	(LC-MS/MS)	AUC: 23.56 vs 10.18 μg·min/mL; t1⁄2: 134.7 vs 57.8 mins; CL: 42.60 vs 99.03 mL/min/kg; Vss: 3260.9 vs 864.3 mL/kg	Improved pharmacokinetics: Increased AUC (2.31-fold); prolonged t1/2 (2.33-fold); decreased CL (due to sustained release and stability of the drug in the serum).	^Citation7
Docetaxel	Poly (TMCC-co-LA)-g-PEG	Tumor (MDA-MB-231-H2N) bearing female mice (n=15).	IV, 1.5 mg/kg bw	UPLC-MS	AUC0-8hr: 3.52×10^3 vs 1.49 x 10^3 hr.ng/mL; t1⁄2: 5.33 vs 3.32 h; Vd: 2.17×10^3 vs 4.59×10^3 mL/kg; CL: 282 vs 958 mL/hr/kg	Improved pharmacokinetics: Decreased Vd (2-fold); prolonged t1/2 (1.6-fold); increased AUC0-8h (2-fold); decreased CL (3-fold)	^Citation10
	PLA-TPGS Vs PLGA	Male Sprague–Dawley (SD) rats (n=4)	IV, 10 mg/kg bw	HPLC	AUC0-72hr: 49.9, 28.0 vs 23.4 mg/L*hr; Cmax: 11.0, 10.2 vs 15.9 mg/L; Tmax: 0.5, 0.5 vs 0.5 hr; t1⁄2: 27.9, 4.4 vs 2.1 hrs; Vd: 7.8, 1.6 vs 1.4 L/kg; CL:0.2, 0.3 vs 0.4 L/hr/kg	Improved pharmacokinetics of PLA-TPGS: Increased AUC0-72h (2.13-fold); prolonged t1/2 (13.2-fold); decreased CL; increased Vd	^Citation12
	PLGA–PEG Vs PLGA	female BALB/c mice (n=4)	IV, 5 mg/kg bw	Mass spectrometer	AUC: 9221, 6601 vs 1688±373 ng.h/mL; t1⁄2: 15.87, 6.05 vs 4.30 hrs; Vd: 290.41, 150.81 vs 383.57 mL; CL: 12.54, 17.23 vs 61.79 mL/hrs	Improved pharmacokinetics of PLGA-PEG-loaded drug compared with free drug solution and PLGA-loaded drug: Prolonged t1/2 (3.7-fold); increased AUC (5.4-fold); decreased CL (5-fold); decreased Vd (1.3-fold) PEG contributed extended circulation and sustained drug delivery.	^Citation2
	Thiolated chitosan	Wistar rats (n=5) Caco-2 cells	Oral, 10 mg/kg bw	HPLC analysis	AUC: 44,998 vs 4243 ng.hr/mL; Cmax: 341 vs 456 ng/mL; Tmax: 5 vs 2 hrs; t1⁄2:102.5 vs 11.7 hrs	Improved pharmacokinetics: Increased oral F, sustained release; Prolonged t1/2 . The improvement of pharmacokinetics could be related to muco-adhesion properties, P-gp efflux inhibition, and permeability-enhancing effects of thiolated chitosan.	^Citation6
	PLGA–mPEG	Tumor (C26 colon carcinoma) bearing mice (n=6). MCF-7 breast and C26 colon cancer cells	IV, 15 mg/kg bw	HPLC	AUC: (101.0 vs 36.8) μg.hr/mL; Cmax: 16.3 vs 17.5 μg/mL); t1⁄2:7.26 vs 1.93 hrs; CL: 148.4 vs 407.1 mL/hr/kg	Improved pharmacokinetics: increased AUC (2.7-fold), prolonged t1/2 (3.76-fold), and lowered CL (2.7-fold). Sustained release with increased accumulation in tumor cells and enhanced cytotoxicity against colon cancer.	^Citation13
Docetaxel	CMS-PEG	Tumor bearing BALB/c mice (n=3) LL/2 lung and EMT-6 mammary carcinoma cell lines.	IV, 40 mg/kg bw	LC/MS	AUC: 881 vs 22.8 µg.hr/mL; Cmax: 27.4 vs 1.6 µg/mL; t1⁄2: 53.8 vs 10.3 hrs; CL: 43.9 vs 1752 mL/hr/kg; Vd: 3418 vs 25,957 mL/kg	Improved pharmacokinetics: Increased AUC (38.6-fold); prolonged t1/2 (5.2-fold); decreased CL (2.5%); decreased Vd (13.2%). Improved cytotoxic efficacy and cellular uptake of the loaded drug in tumor cells.	^Citation9
PALA micelles	Male Sprague–Dawley (SD) rats (n=6) human MCF-7 breast cell line.	IV, 2.5 mg/kg bw	HPLC	AUC0–12: 2.67 vs 1.763 μg.hr/mL; t1⁄2: 1.16 vs 0.76 hrs; CL: 0.849 vs 1.151 L/hr/kg	Improved pharmacokinetics: Prolonged t1/2 (1.53-fold); increased AUC (1.51-fold). Increased cytotoxicity against human MCF-7 breast cancer.	^Citation5
Doxorubicin	CHGC	Male Sprague–Dawley rats (n=6)	IV, 2 mg/kg bw	HPLC	AUC: 4.403 vs 0.666 mg.hr/L; CL: 0.454 vs 3.005 L/hr/kg	Improved pharmacokinetics: Increased AUC (6.61-fold); decreased CL. Improved pharmacokinetics is due to slow release of the drug from nanoparticle.	^Citation20
	PAD–PPI	Tumor-inducing albino rats (n=4) Lung cancer cell (A549)	IV, 5 mg/kg bw	HPLC	AUC: 35.53 vs 11.23 mg. hr/mL; Tmax: 7.27 vs 1.49 hrs; CL: 140.726 vs 444.278 mg hr/mL	Improved pharmacokinetics: Increased AUC (3.2-fold); decreased CL (3.12-fold). Improved cytotoxic effect of drug against cancer cell.	^Citation21
	PLGA	Sprague–Dawley rats (n=3)	Oral, 10 mg/kg bw	HPLC	AUC: 5282 vs 1452 ng.hr/mL; Cmax: 154.08 vs 64.68 ng/mL; Tmax: 36 vs 6 hrs	Improved pharmacokinetics: Increased F and Cmax; prolonged t1/2	^Citation16
	mPEG-b-PCL	Male Sprague–Dawley rats (n=4) MCF-7 and MCF-7/ADR cells	IV, 5 mg/kg bw	Mass spectrometry	AUC0–24: 2268.426 vs 379.92 μg.hr/L; Cmax: 3617.1 vs 1704.6 mg/L; t1⁄2:1.95 vs 0.4 hrs; Vd: 0.006 vs 0.009±0.006 L/kg; CL: 0.002 vs 0.013 L/hr/kg	Improved pharmacokinetics: Increased AUC (5.97-fold); prolonged t1/2 (4.54-fold). Significantly increased cytotoxicity and reduced resistance in MCF-7/ADR cells	^Citation14
Doxorubicin	CS-g-TPGS	Female Sprague−Dawley rats (n=4) HepG2, BEL-7402, MCF-7, BEL-7402/5-Fu, and MCF-7/DOX cells	Oral, 10 mg/kg bw	HPLC	AUC: 3.439 vs 1.459 mg.hr/L; Cmax: 0.451 vs 0.390 μg.hr/mL; Tmax: 2 vs 2 hrs; t1⁄2: 10.93 vs 4.33 hrs; CL: 2.899 vs 6.856 L/hr/kg	Improved pharmacokinetics: Increased AUC (2.36-fold); prolonged t1/2 (2.53-fold); decreased CL. Chitosan (CT) nanoparticles shown as suitable carrier in drug-resistant cancer cells and increased cytotoxicity.	^Citation15
	Mannosylated- SLNs	Tumor bearing Male Balb/c mice (n=3) A549 and MCF-7 cell lines	IV, 5 mgkg bw	HPLC	AUC: 55.99 vs 11.31 µg.hr/mL; Cmax: 4.0 vs 5.01 µg/mL; t1⁄2:14.53 vs 1.56 hrs; CL: 8.01 vs 43.03 mL/hr	Improved pharmacokinetics: Increased AUC (5-fold); prolonged t1/2 (9.3-fold); decreased CL	^Citation17
	CSD-PEG	Male Sprague–Dawley (SD) rats (n=3). SKOV-3 cells	IV, 4 mg/kg bw	HPLC	AUC: 234.42 vs 96.05 μg·min/mL; t1⁄2: 327.86 vs 60.09 mins; CL: 17.35 vs 41.95±4.22 mL/min/kg; Vss: 3153.22 vs 1105.95 mL/kg.	Improved pharmacokinetics: Prolonged t1/2; increased AUC; decreased CL. Promising anticancer activity.	^Citation19
	Nanodisk	Wistar rats (n=6) MCF-7 and P-gp overexpressing MCF-7/Adr cells	IV, 5 mg/kg bw	UPLC−MS−MS	AUC: 17,452.5 vs 550.8 μg·hr/L; t1⁄2: 41.9 vs 3.5 hrs	Improved pharmacokinetics: Prolonged t1/2 (11.7-fold); increased AUC (31.7-fold). Increased cytotoxicity activity against tumor resistant cells (MCF-7/Adr cells).	^Citation18
Estrone (ESC8)	SLN NLC Liposome	Sprague–Dawley rats (n=3) MDA-MB-231 (HTB-26), MDA-MB-468 (HTB-132), BT-474 (HTB-20), and SK-BR-3 (HTB-30)	Oral, 20 mg/kg bw	HPLC	AUC: 17,728.97, 16,047.25, 8991.76 vs 12,357.10 μg.hr/mL; Cmax: 890.62, 792.53, 486.53 vs 534.70 μg/mL; Tmax: 7.32, 7.45, 6.80 vs 8.50 hrs; t1⁄2: 5.08, 5.16, 4.71 vs 5.89 hrs; Vd: 2.07, 2.32, 3.78 vs 8.60 mL; CL: 0.28, 0.31, 0.56 vs 1.01 L/hr	Improved pharmacokinetics: SLN and NLC increased AUC, decreased both CL and Vd. Improved cytotoxicity activity of solid lipid-loaded estrone against triple negative and nontriple negative breast cancer cell lines compared to NLC, liposome nanoparticles and free drug.	^Citation30
5-Fluorouracil (5-FU)	PEG-PBLG	Rabbit. Human colon (LoVo) and oral squamous (Tca8113) carcinoma cells	IV, 30 mg/kg bw	HPLC	AUC: 5794.7 vs 6263.8 μg.hr/L; Cmax: 4563.5 vs 17,047.3 μg/L; Tmax: 1.25 vs 0 hr; t1⁄2: 33.3 vs 0.088 hr; Vd: 0.114 vs 0.069 L	Prolonged t1/2; increased distribution time; decreased (slightly) AUC. Significantly improved antitumor activity against colon and oral cancer cells.	^Citation24
Gemcitabine	mPEG-PLGA co-polymer	Balb-c mice (n=4) MiaPaCa-2 and MCF-7 carcinoma cell lines	IV, 2 mg/kg bw	LC-MS	AUC: 312.5, 209.5 vs 96.6 ng·hr/mL; t1⁄2: 3.8, 0.4 vs 0.2 hr; CL: 6400.3, 9545.8 vs 20,709.3 mL/hr/kg	Improved pharmacokinetics of PEGylated PLGA loaded drug compared to non-PEGylated PLGA NPs loaded drug and free drug: Increased AUC; prolonged t1/2 (slightly); decreased CL. Increased cytotoxicity against MiaPaCa-2 and MCF-7 cancer cell lines.	^Citation28
Methotrexate (MTX)	Glycine-PLGA	Wistar rats (n=3) MDA-MB-231 cells	IV, 5 mg/kg bw	RP-HPLC	AUC: 130.1 (30.9) μg.hr/mL; Vd: 0.52 (0.65) L; t1⁄2: 4.30 (2.47) hrs	Improved pharmacokinetics: Increased AUC (4-fold); Prolonged t1/2 (2-fold); decreased Vd (1-fold) Substantial increase of cytotoxicity against cancer cells.	^Citation26
Mifepristone (MIF)	CS	Male rats (n=4) A549, Hela, RL95-2 and HepG2 cancer cells	Oral, 30 mg/kg bw	LC-MS/MS	AUC0-24: 6.3 vs 2.0 mg.hr/L; Cmax: 0.79 vs 0.36 mg/L; Tmax: 5.0 vs 3.4 hrs; t1⁄2: 4.0 vs 3.0 hrs	Improved pharmacokinetics: Improved AUC and Cmax, prolonged t1/2. Chitosan improved cytotoxicity of MIF against cancer cells.	^Citation27
Noscapine (NOS)	PCL-PEG	Wistar rats (n=3). MCF-7 cell line	IV, 50 mg/kg bw	HPLC	AUC: 9351.74 vs 7308.96 ng.hr/mL; Cmax: 2055.97 vs 3642.28 ng/mL; t1⁄2: 22.92 vs 5.12 hrs	Improved pharmacokinetics: Increased AUC; prolonged t1/2 (4.47-fold); increased F. Improve cytotoxicity against breast cancer cells	^Citation31
Oxaliplatin	FESNS	Male Sprague-Dawley (SD) rats (n=6)	Oral, 10 mg/kg bw	HPLC	AUC: 22,280.4, 17, 585.2 vs 3733.9 ng.hr/mL; Cmax: 8621.8, 4653.0 vs 304.6 ng/mL; Tmax: 1.3, 1.7 vs 1.9 hrs	Improved pharmacokinetics: Increased AUC (4–6 fold); increased F	^Citation25
Paclitaxel	PEG2000, PEG6000, PEG10000	Male Wistar rats (n=6)	Oral, 10 mg/kg bw	HPLC	AUC: 56, 32, 13 vs 81 µg.hr/mL; Cmax: 2.1, 1.9, 1.4 vs 204 µg/mL; Tmax: 5.8, 3.0, 3.3 vs 0.01 hr; t1⁄2: 9.3, 6.2, 29 vs 2.6 hrs	PEGylation of nanoparticles with either PEG6000 or PEG2000 as carriers were more adhesive in the GI mucosal than nanoparticles PEGylated with 1000 as they were located at the surface of the absorptive membrane for a long period, and slowly release the loaded drug.	^Citation4
	TPGS-PLGA	Sprague–Dawley rats (n=3) C6 glioma cells	IV, 10 mg/kg bw	LC/MS/MS	AUC: 27,200 vs 35,470 ng.hr/mL; t1⁄2: 16.8 vs 0.830 hrs	Decreased AUC (slightly); prolonged t1/2 (20-fold) Greater cytotoxicity activity against C6 glioma cells.	^Citation1
	PCL–TPGS	Wistar rats (n=5) MCF-7 and MDA-MB 231 human breast cancer cell lines	IV, 6 mg/kg bw	HPLC	AUC: 7.07 vs 2.62 μg.hr/mL; t1⁄2: 10.13 vs 0.87 hrs; CL: 15.86 vs 49.15 mL/min; Vss: 8.89 vs 2.13 L	Improved pharmacokinetics: Increased AUC (2.7-fold); prolonged t1/2 (11.6-fold); Decreased CL (3-fold) Improved anticancer activity against breast cancer cells.	^Citation8
Sirolimus	mPEG–PLA	Male Sprague-Dawley (SD) rats (n=3) A549, MCF7, NCI-H460 and MDA-MB-231 cells	IV, 10 mg/kg bw	LC-MS/MS	AUC: 16,901.7 vs 5366.7 µg.hr/mL; Cmax: 11,303.3 vs 2890 µg/mL; Tmax: 0.25 vs 0.25 hrs	Improved pharmacokinetics: Increased AUC (3.15-fold) and Cmax (3.91- fold). High cytotoxic activity against human cancer cells.	^Citation32
Temozolomide (TMZ)	PAMAM-CT	Wistar rats (n=6) U-251 and T-98G cells	IP, 3 mg/kg bw	UV-Visible Spectrophotometer	AUC: 4643.94 vs 3820.77 μg.hr/mL; Vd: 0.041 vs 0.0373 L/kg; t1⁄2:22.74 vs 15.348 hrs; CL: 0.00125 vs 0.00168 L/hr/kg	Improved pharmacokinetics: Increased AUC (1.2-fold); prolonged t1/2 (1.5-fold). Improved cytotoxic potential against cancer cells.	^Citation33
Anastrozole	PLGA, PLA and PCL	Wistar rats (n=6) breast cancer cell lines (BT-549 and MCF-7)	IV, 1 mg/kg bw	HPLC	AUC: 100.2, 405.7, 416.2 vs 21.0 μg.hr/mL; Cmax: 1.2, 2.0, 4.6 vs 8.3 μg/mL; t1⁄2: 196.12, 322.32, 293.19 vs 9.08 hrs; Vd: 2.8, 1.146, 1.01 vs 0.623 L/kg; CL: 0.009, 0.0024, 0.0023 vs 0.0475 L/hr/kg	Improved pharmacokinetics: Increased AUC (4.77, 19.31, and 19.81-fold, respectively); prolonged t1/2. Dose dependent cytotoxicity activity against breast cancer cells.	^Citation29

Abbreviations: Nano carriers: CHGC, cholesterol-modified glycol chitosan; CMS-PEG, PEGylated carboxymethyl cellulose; CS, chitosan; CSD-PEG, chondroitin sulfate A-deoxycholic acid-polyethylene glycol; CS-g-TPGS, chitosan-D-α-tocopheryl polyethylene glycol succinate; CS-PLGA, chitosan-poly(lactic-co-glycolic acid); FESNS, fat employing supercritical nano system; LCG-SNELS, long-chain glyceride-self-nanoemulsifying lipidic nanomicelles systems; MCG-SNELS, medium-chain glyceride-self-nanoemulsifying lipidic nanomicelles systems; mPEG-b-PCL, methoxy poly(ethylene glycol)-b-poly(ε-caprolactone); mPEG-PLA, methoxy poly(ethylene glycol)-b- poly(lactic acid); mPEG-PLGA, methoxy poly(ethylene glycol)-b- poly (lactic-co-glycolic acid); NLC, nanostructured lipid carriers; PAD-PPI, polyaldehydodextran-polypropylene imine; PALA, poly(d,L-lactic acid); PAMAM-CT, polyamidoamine-chitosan; PCL, poly(ε-caprolactone); PCL-PEG, polyethylene glycol-co-poly(ε-caprolactone); PCL-TPGS, Polyethylene glycol-co-D-α-tocopheryl polyethylene glycol succinate; PEG, polyethylene glycol; PEG10000, polyethylene glycol molecular weight 10,000; PEG2000, polyethylene glycol molecular weight 2000; PEG6000, polyethylene glycol molecular weight 6000; PEG-PBLG, poly(ethylene glycol) and poly(γ-benzyl-L-glutamate); PHBV, polyhydroxybutyrate-co-hydroxyvalerate; PLA,poly(lactic acid); PLA-TPGS, poly(lactic acid)-D-alpha-tocopheryl polyethylene glycol 1000 succinate; PLGA, poly (lactic-co-glycolic acid); PLGA-mPEG, poly(lactic-co-glycolic acid)-b-methoxy poly(ethylene glycol); PLGA-PEG, poly(lactic-co-glycolic acid)-poly(ethylene glycol); Poly(TMCC-co-LA)-g-PEG, poly(2-methyl-2-carboxytrimethylene carbonate-co-D,L-lactide)-graft-poly(ethylene glycol); PS-PDLLA, poly (styrene)-b-poly(DL-lactide); SLN, solid lipid nanoparticles; TPGS-PLGA, D-α-tocopheryl polyethylene glycol succinate-poly(lactic-co-glycolic acid). Pharmacokinetic parameters: AUC, area under plasma concentration–time profile; C_max, maximum plasma concentration; CL, total clearance; F, bioavailability; t_max, time to maximum plasma concentration; t_1/2, elimination half-life; V_d, apparent volume of distribution; V_ss, volume of distribution at steady-state.

Table 2 Summary of the in vivo/clinical pharmacokinetic studies of the nanoparticles of herb-derived compounds for cancer included in the analysis. Data are presented as mean values for nanoformulation vs free compound

Drug-loaded	Nanoparticle	Animal used (number)/cell line	Route, dose	Analytical technique	Pharmacokinetic parameters (mean)	Outcomes	Reference
α -Tocopherol succinate (α -TOS)	Nanoemulsion	Wistar male rats (n=6) MCF-7 cells	IP, 100 mg/kg bw	HPLC.	AUC: 1141.56 vs 637.98 mg.hr/mL; Cmax: 33.84 vs 19.40 mg/mL; Tmax: 5.00 vs 9.00 hrs; t1⁄2: 16.99 vs 7.82 hrs; CL: 0.10 vs 0.18 L/hr	Improved pharmacokinetics: Increased Cmax(1.74-fold); increased AUC (1.79-fold); prolonged t1/2 (2.17-fold); decreased CL (slightly). Improved the anti-cancer activity against cancer cells.	^Citation50
Topotecan (Topo)	PLGA	Swiss albino mice (n=6) SKOV3 cells	IV, 10 mg/kg bw	LC-MS	AUC: 35,667.5 vs 7479.75 ng hr/mL; Cmax: 1326 vs 2100 ng/mL; Tmax: 3 vs 0.5 hr	Improved pharmacokinetics: Increased F (13.05-fold). Enhanced cytotoxicity effect against cancer cells.	^Citation42
Protopana-xadiol (PPD) Contain ginsenosides, derived from Araliaceae	Cubosomes	Male rats (n=6)	Oral, 2 mg/kg bw	Mass spectrometry	AUC: 43.37 vs 25.76 mg.min/L; Cmax: 1004 vs 73.45 ng/mL; Tmax: 125 vs 85 mins; t1⁄2:372.59 vs 324.01 mins; CL: 0.068 vs 0.071 L/min/kg	Improved oral bioavailability and prolonged t1/2 (slightly).	^Citation45
Hydroxy-camptothecin (HCPT)	PEG-PBLG	New Zealand rabbits (n=3)	IV, 12 mg/kg bw	HPLC	AUC: 2175.9 vs 2459.0 µg.hr/L; Cmax: 1513.5 vs 2627.8 µg/L; Tmax: 1 vs 0 hr; t1⁄2:10.1 vs 4.5 hrs; Vd: 20 vs 7.3 L	Improved pharmacokinetics: Decreased Cmax and AUC; increased Vd; increased t1/2.	^Citation41
10-Hydroxy-camptothecin (10-HCPT)	Nanocrystals	Sprague–Dawley rats (n=10)	IV, 5 mg/kg bw	HPLC	AUC: 4867.7 vs 1735.9 ng.hr/mL; CL: 10.65 vs 484.99 mL/hr; t1⁄2: 1.85 vs 0.62 hrs	Improved pharmacokinetics: Increased AUC (2.98-fold); prolonged t1/2 (2.81-fold); decreased CL (45.5-fold). Effective drug delivery for HCPT.	^Citation40
Genistein (Gen)	mPEG-PCL/MCTs	Male Sprague–Dawley rats (n=5)	IV, 10 mg/kg bw	UPLC-QTOF/MS	AUC0-t: 8.48 vs 2.97 µM*hr; t1⁄2: 9.96 vs 2.15 hrs; CL: 0.73 vs 2.94 L/hrs	Improved pharmacokinetics of Gen containing micellar emulsions as nanocarriers: Increased AUC (4.6-fold); prolonged t1/2 (2.86-fold); decreased CL	^Citation49
Curcumin	PC-SNEDDS	Male Sprague–Dawley rats (n=3). MDA-MB-231 breast cancer cell line	Oral, 100 mg/kg bw	LC-MS/MS	AUC: 2196.9 vs 41.8 ng.hr/L; Cmax: 487.7 vs 21.6 ng/mL; Tmax: 1.0 vs 1.0 hr; t1⁄2: 21.0 vs 4.1 hrs; CL: 46.0 vs 2421.7 L/hr/kg; Vd: 144.5 vs 5607.3 L/kg	Improved pharmacokinetics: Increased AUC (52-fold); prolongedt1/2 (5-fold); decreased CL (50-fold); decreased Vd (38.8-fold).	^Citation34
	Lipid nanocapsules	Rats (n=3). Rat 9L glioma cells	IV, 10 mg/kg bw	LC-MS/MS	AUC: 72.98 vs 18.77 μg.hr/mL; Cmax: 70.05 vs 13.05 μg/mL; t1⁄2: 3.25 vs 1.15 hrs; CL: 0.04 vs 0.13 μg/mL/hr	Improved pharmacokinetics: Increased AUC (3.9-fold) and Cmax (5.3-fold); decreased CL.	^Citation36
	Cationic Copolymer (EE100)	Albino Wistar rats (n=6) Colorectal cancer cells (Colon-26)	Oral, 50 mg/kg bw	HPLC	AUC: 2199.116 vs 23.225 ng.hr/mL; Cmax: 870.3104 vs 9.582 ng/mL; Tmax: 0.5 vs 0.5 hr; t1⁄2: 4.811 vs 1.25 hrs	Improved pharmacokinetics: Increased oral bioavailability. Improved cytotoxicity against colorectal cancer cells.	^Citation35
	mPEG-PCL	Wistar rats (n=6). Hela and HT-29 cells	IV, 15 mg/kg bw	HPLC	AUC: 4464.601 vs 967.221 μg.hr/L; Vd: 6.271 vs 4.432 L/kg; CL: 3.36 vs 15.508 L/hr/kg; t1⁄2:1.294 vs 0.198 hrs	Improved pharmacokinetics: Increased AUC; prolonged t1/2; increased Vd; decreased CL.	^Citation38
	PDLLA-G	Male Sprague–Dawley (SD) rats (n=3). MDA-MB-231 cells	IV, 12 mg/kg bw	LC–MS/MS	AUC: 1810.09 vs 1.79 μg.min/mL; t1⁄2: 85.7 vs 6.62 h; CL: 6.87 vs 6817.94 mL/min/kg; Vss: 123.56 vs 62,061.86 mL/kg	Improved pharmacokinetics: Increased AUC; prolonged t1/2.	^Citation39
Curcumin and Rutin	Chitosan	Rabbits (n=3)	Oral, 35 mg each	RP-UFLC	AUC: 4322.37, 1219.80, 7621.79 vs 1146.73 ng.h/mL; Cmax: 971.72, 317.97, 1113.55 vs 262.85 ng/mL; Tmax: 1 hr for all; t1⁄2: 2.62, 1.78, 3.357 vs 1.74 hrs	Improved pharmacokinetics: Increased AUC of curcumin (3.5-fold) and rutin (6.65-fold); increased Cmax of curcumin (3.06-fold) and rutin(4.24-fold).	^Citation37
Brucea javanicaoil (BJO) is from Brucea javanica of the family Simaroubaceae	Cationic nanoemulsion	Male Sprague–Dawley (SD) rats (n=6). Human lung adenocarcinoma line A549 cells xenografts in nude mice.	Oral, 505 mg/kg bw	UPLC-MS/MS	AUC: 1203.4 vs 982.5 mg·hrs/L; Cmax: 210.2 vs 164.2 mg/L; Tmax: 3.5 vs 3.0 hrs; t1⁄2: 4.5 vs 3.3 hrs	Improved pharmacokinetics: Increased AUC and t1/2 (1.6- and 1.3-fold, respectively). Reduced growth of lung cancer and decreased the frequency of dosing.	^Citation48
Camptothecin (CPT)	SLN	BALB/c mice (n=4). Caco-2, HT-29, HepG2 and MCF-7 cell lines.	Oral, 30 mg/kg bw	HPLC	AUC: 17.19 vs 7.22 μg.hr/L; Cmax: 3.28 vs 0.69 μg/mL	Improved pharmacokinetics: Increased AUC and Cmax (2.38- and 4.75-fold, respectively). Higher cytotoxicity against all four cell lines.	^Citation43
Celastrol (CST) Isolated from Trypterygium wilfordii hook	Phytosomes	Rabbits (n=6)	Oral, 40 mg/kg bw	HPLC	AUC: 767.51 vs 186.84 ng.hr/mL; Cmax: 460 vs 92 ng/mL; Tmax: 0.5 vs 1 hr; t1⁄2: 10.1 vs 0.96 hrs	Improved pharmacokinetics: Increased Cmax and AUC; prolonged t1/2. The phospholipid component of phytosomes enhanced the fluidity of cell membrane, solubility, and intestinal absorption.	^Citation47
Amoitone B Cytosporone B (Csn-B) analog, derived from Dothiorella sp. HTF3.	Nanocrystals	New Zealand white rabbits (n=4)	IV, 8.0 mg/kg bw	HPLC	AUC: 4.902 vs 3.439 mg.hr/L; t1⁄2: 8.446 vs 2.999 hrs; CL: 1.632 vs 2.327 L/hr/kg; Vd: 0.626 vs 0.283 L/kg	Improved pharmacokinetics: Increased AUC (1.4-fold); prolonged t1/2 (2.8-fold); decreased CL; increased Vd (slightly).	^Citation44
Biochanin A (BCA) From red clover	PEG–NLC	Female Sprague–Dawley (SD) rats (n=6) Human breast cancer cell line (MCF-7)	Oral, 4 mg/kg bw	HPLC	AUC: 590.01 vs 203.71 ng.hr/mL; Cmax: 165.82 vs 10.53 ng/mL; Tmax: 0.50 vs 0.33 hr	Improved pharmacokinetics: Increased AUC (2.9-fold) and Cmax Increased cytotoxicity in MCF-7 cells.	^Citation46

Abbreviations: Nanocarriers: mPEG-PCL/MCTs, methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) and medium-chain triglycerides; mPEG-PCL, methoxy poly(ethylene glycol)-b-poly(ε -caprolactone); PCL, poly(ε-caprolactone); PC-SNEDDS, phospholipid complexes and self-nano-emulsifying drug delivery system; PDLLA-G, poly(D,L-lactic acid)-glycerol; PDLLA-G, poly(D,L-lactic acid)-glycerol; PEG-NLC, poly(ethylene glycol)-nanostructured lipid carriers; PEG-PBLG, poly(ethylene-glycol)-poly(gamma-benzyl-L-glutamate); PLA, poly(lactic acid); PLGA, poly(lactic-co-glycolic acid); SLN, solid lipid nanoparticles. Pharmacokinetic parameters: AUC, area under plasma concentration–time profile; C_max, maximum plasma concentration; CL, total clearance; F, bioavailability; t_max, time to maximum plasma concentration; t_1/2, elimination half-life; V_d, apparent volume of distribution; V_ss, volume of distribution at steady-state.

Figure 2 Flowchart summarizing inclusion and exclusion of the articles for the study.

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