The effects of nanoparticle drug loading on the pharmacokinetics of anticancer agents

Abstract

Major advances in carrier-mediated agents, which include nanoparticles, nanosomes and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages, such as greater solubility, duration of exposure and delivery to the site of action over their small-molecule counterparts, there is substantial variability in systemic clearance and distribution, tumor delivery and pharmacologic effects (efficacy and toxicity) of these agents. This review provides an overview of factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents in preclinical models and patients.

Keywords: Doxil; S-CKD602; carrier-mediated agents; clearance; nanoparticles; pharmacokinetics.

Figure 1. Metabolism and elimination pathway for small molecule and carrier mediated agents

Small-molecule anticancer agents undergo a standard route of metabolism and elimination, including enterohepatic recycling and removal through the kidney. Carrier-mediated agents, however, which are engulfed by phagocytes, are contained primarily in compartments such as the spleen, liver and peripheral blood mononuclear cells. IV: Intravenous administration; PBMC: Peripheral blood mononuclear cell; PO: Oral administration. Reproduced with permission from [2]. For color figures, see online at www.futuremedicine.com/doi/full/10.2217/NNM.14.179

Figure 2. Clearance of nanoparticles and carrier-mediated agents via the mononuclear phagocyte system

When nonstabilized liposomal agents were first tested, they were found to only minimally increase the circulation time of the small-molecule agent encapsulated within the carrier (rapid clearance). However, stabilization with PEG has helped to reduce uptake and CL of CMA by MPS (slower clearance). While the clearance of PEGylated liposomes are slower than non-PEGylated liposomes, both are phagocytized by peripheral blood mononuclear cells, phagocytes of the liver and spleen. Greater tumor exposure is seen after administration of PEGylated liposomes, which in part due to the EPR effect and possibly, the MPS in tumors. CL: Clearance; CMA: Carrier-mediated agent; EPR: Enhanced permeability and retention; MPS: Mononuclear phagocyte system. Adapted with permission from [2].

Figure 3. Intratumoral apoptosis in mice injected with siL12-2-SNA

(A) The amount of aCasp-3 and terminal deoxynucleotidyl TUNEL. Data points are the number of stained cells per field. p-values were calculated with two-tailed Student’s t-test. (B) Kaplan–Meier survival curves of mice with TNS-derived xenografts treated with siL12-2-SNA (n = 6) or siCo-SNA (n = 7). p-value was calculated with the Mantel–Cox test. aCasp-3: Activated caspase-3; HPF: High-power field; siCo: Scrambled control sequence; siL12-2-SNA: siRNA-loaded SNA; SNA: Spherical nucleic acid; TNS: Tumor neurosphere; TUNEL: Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling. Adapted with permission from [32].

Figure 4. Plasma and tumor doectaxel vs time curves in mice bearing SKOV3 ovarian flank xenografts after administration of three different docetaxel formulations

(A) Tumor (0–168 h), (B) tumor (0–24 h), (C) plasma, (D) lung, (E) spleen and (F) liver. Doc concentration values for each mouse are represented in the key. The lines are connected by the mean value for each time point. Reproduced with permission from [37].

Figure 5. Plasma and tumor doectaxel vs time curves in mice after administration of two different shaped nanoparticle docetaxel formulations

Pharmacokinetic profiles of (A) plasma, (B) tumor, (C) liver, (D) spleen and (E) lung. (F) In vitro release kinetics of 9%-NP (●) and 20%-NP (■). Each replicate is shown and the lines are connected by the mean of three replicates. Reproduced with permission from [41].

Figure 6. Relationship between phagocytosis in monocytes/dendritic cells from blood and clearance of PEGylated liposomal agents in mice, rats, dogs and patients

The mean values for three species are represented by individual symbols, with diamonds as PLD, squares as S-CKD602 and triangles as SPI-077. The species data are in vertical columns from left to right: rats, mice, dogs and patients. The best fit line for each group is represented by the solid lines. Across species, a positive association was observed between cell function and CL of PEGylated liposomes. CL: Clearance; MFI: Mean fluorescent intensity; MPS: Mononuclear phagocyte system; PK: Pharmacokinetics; PLD: PEGylated liposomal doxorubicin; R²: Coefficient of determination. Adapted with permission from [44].

Figure 7. Relationship between monocytes/dendritic cells function and encapsulated doxorubicin clearance in patients presented in a linear regression model

Measuring phagocytosis and production of ROS of MO/dendritic cell from patient blood samples at baseline (prior to the start of chemotherapy) was used as a phenotypic probe of MPS function and encapsulated doxorubicin CL. Each diamond represents an individual patient, and the solid line is the regression line. (A) Phagocytic activity (MFI) is significantly correlated with CL of encapsulated doxorubicin in ten patients receiving PLD alone or PLD + carboplatin (R² = 0.43, p = 0.04). (B) Production of ROS: MFI is significantly correlated with CL of encapsulated doxorubicin in ten patients receiving PLD alone or PLD + carboplatin (R² = 0.61, p = 0.008). (C) Phagocytic activity: MFI is significantly correlated with CL of encapsulated doxorubicin in six patients receiving PLD alone (R² = 0.57, p = 0.03). (D) Production of ROS: MFI is significantly correlated with CL of encapsulated doxorubicin in six patients receiving PLD alone (R² = 0.61, p = 0.001). CL: Clearance; MFI: Mean fluorescent intensity; MO: Monocyte; MPS: Mononuclear phagocyte system; PLD: PEGylated liposomal doxorubicin; R²: Coefficient of determination; ROS: Reactive oxygen species. Reproduced with permission from [44].

Figure 8. The relationship between hand foot syndrome and PLD pharmacokinetics or age in patients receiving PLD treatment

HFS (also called palmar-plantar erythrodysesthesia) association with PLD T_1/2 (A) and age (B). Longer PLD T_1/2 and advanced age resulted in an overall greater severity PPE grade. ANOVA: Analysis of variance; HFS: Hand foot syndrome; PLD: PEGylated liposomal doxorubicin; PPE: Palmar-plantar erythrodysesthesia. Reproduced with permission from [46].

Figure 9. Clearance of PEGylated liposomal doxorubicin after chemotherapy cycle in human subjects

Bars represent mean values and SEM of clearance of PLD by dose and cycle. p values shown were calculated by repeated measures analysis of variance. CL: Clearance; n.s: Not significant; PLD: PEGylated liposomal doxorubicin; SEM: Standard error of the mean. Adapted with permission from [57].

Figure 10. Summary of the process to use a phenotypic probe of mononuclear phagocyte system function in blood to measure mononuclear phagocyte system function in patients, which would predict nanoparticle pharmacokinetics, efficacy and toxicity

his type of probe could be used as a test that could retrospectively be used to explain patients with highly variable PK and PD. This type of probe could also be used as a method to individualize the dose of nanoparticles as needed. MPS: Mononuclear phagocyte system; PD: Pharmacodynamics; PK: Pharmacokinetics; PPE: Palmar-plantar erythrodysesthesia.