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. |
22 |
| 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) | 23 | |
| 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) | 3 |
| 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. |
11 | |
| 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). | 7 | |
| 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: 3.52×103 vs 1.49 x 103 hr.ng/mL; t1⁄2: 5.33 vs 3.32 h; Vd: 2.17×103 vs 4.59×103 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) | 10 |
| 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 |
12 | |
| 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. |
2 | |
| 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. |
6 | |
| 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. |
13 | |
| 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. |
9 |
| 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. |
5 | |
| 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. |
20 |
| 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. |
21 | |
| 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 | 16 | |
| 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 |
14 | |
| 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. |
15 |
| 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 | 17 | |
| 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. |
19 | |
| 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). |
18 | |
| 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. |
30 |
| 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. |
24 |
| 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. |
28 |
| 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. |
26 |
| 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. |
27 |
| 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 |
31 |
| 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 | 25 |
| 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. | 4 |
| 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. |
1 | |
| 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. |
8 | |
| 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. |
32 |
| 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. |
33 |
| 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. |
29 |
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; Cmax, maximum plasma concentration; CL, total clearance; F, bioavailability; tmax, time to maximum plasma concentration; t1/2, elimination half-life; Vd, apparent volume of distribution; Vss, volume of distribution at steady-state.