Pharmacokinetic behaviors of soft nanoparticulate formulations of chemotherapeutics

Abstract

Chemotherapeutic treatment with conventional drug formulations pose numerous challenges, such as poor solubility, high cytotoxicity and serious off-target side effects, low bioavailability, and ultimately subtherapeutic tumoral concentration leading to poor therapeutic outcomes. In the field of Nanomedicine, advances in nanotechnology have been applied with great success to design and develop novel nanoparticle-based formulations for the treatment of various types of cancer. The approval of the first nanomedicine, Doxil® (liposomal doxorubicin) in 1995, paved the path for further development for various types of novel delivery platforms. Several different types of nanoparticles, especially organic (soft) nanoparticles (liposomes, polymeric micelles, and albumin-bound nanoparticles), have been developed and approved for several anticancer drugs. Nanoparticulate drug delivery platform have facilitated to overcome of these challenges and offered key advantages of improved bioavailability, higher intra-tumoral concentration of the drug, reduced toxicity, and improved efficacy. This review introduces various commonly used nanoparticulate systems in biomedical research and their pharmacokinetic (PK) attributes, then focuses on the various physicochemical and physiological factors affecting the in vivo disposition of chemotherapeutic agents encapsulated in nanoparticles in recent years. Further, it provides a review of the current landscape of soft nanoparticulate formulations for the two most widely investigated anticancer drugs, paclitaxel, and doxorubicin, that are either approved or under investigation. Formulation details, PK profiles, and therapeutic outcomes of these novel strategies have been discussed individually and in comparison, to traditional formulations. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Keywords: chemotherapeutics; doxorubicin; paclitaxel; pharmacokinetics; soft nanoparticles.

FIGURE 1

Effect of nanoparticle (a) size, (b) shape, and (c) surface charge on biodistribution among the different organs including the lungs, liver, spleen, and kidneys (adapted from Blanco et al., 2015)

FIGURE 2

Proposed model of paclitaxel pharmacokinetics, assuming pharmacokinetically distinguishable forms of paclitaxel in the blood compartment; Pharmacokinetically distinguishable forms: Unbound (C_Unbound), bound to plasma protein (C_Bound), in micellar form together with CrEL (C_Micellar), and bound to or distributed into red blood cells (Crbc). Further, C was assumed to be in equilibrium with tissues (Double-headed arrows denote processes with assumed instantaneous equilibrium. The star indicates a nonlinear process; van Zuylen et al., 2001)

FIGURE 3

The ratio of area under the curve (AUC_0–t) between select tissues (blood, fat pad, heart, lung, pancreas, and stomach) and plasma. Ratio (y-axis) of accumulated AUC in tissues scaled to its corresponding accumulated AUC of plasma for solvent-based PTX (pac-T), nab-PTX (nab-P), mouse albumin nab-PTX (m-nab-P), micellar PTX (pac-P), and polymeric nanoparticle PTX (pac-G; Li, Zhang, Zhu, et al., 2018)

FIGURE 4

(a) Schematic that shows how DOX-MFPL target S180 tumor in mice B. Pharmacokinetic behavior of different DOX preparations in S180 tumor-bearing mice. The data are expressed as mean ± SD (n = 3). (c) Quantification of the DOX distribution in tumor after i.v. administration of different DOX formulations. (d) AUC of DOX in tumors after intravenous administration of different DOX formulations into the S180-bearing mice at a DOX dosage of 5 mg/kg. **p < 0.01. (e) The S180 tumor stroma volume versus time curve of tumor-bearing mice i.v. injected with various DOX preparation (Li et al., 2019)

FIGURE 5

(a) Box-and-Whisker plot of doxorubicin (DOX) concentration in the tumors of KPC mice treated with 15 mg DOX/kg low-temperature-sensitive liposomal doxorubicin (LTSL-DOX) and nonliposomal doxorubicin (DOX), with and without the application of MR-HIFU. *Denotes significance at the p < 0.05 level. (b) Median doxorubicin concentration ([interquartile range] measured in pancreatic tumors following different treatment regimens (n = 4 in each group; Farr et al., 2018)

FIGURE 6

(a) Plasma concentration–time plot over a 24 h period of DOX after a 5 mg/kg intravenous injection in DOX and RBC-DOX groups. (b) Tumor growth over a 24-day period for control (gray), DOX (blue), and RBC-DOX (red) in treated mice. (c) Biodistribution of DOX in liver, spleen, lungs, and kidney. (d) Biodistribution of DOX in heart, skin, and tumor-treated mice after the 24-day treatment period (Lucas et al., 2019)