Nanoparticles for combination drug therapy

Abstract

Nanoparticles have recently emerged as a promising class of carriers for the co-delivery of multiple drugs. Combination therapies of small-molecule drugs are common in clinical practice, and it is anticipated that packaging into single macromolecular carriers will enable drug release in precisely balanced ratios and rates and in selectively targeted tissues and cells. This vast level of pharmacological control is intriguing, especially from the perspective of tailoring personalized treatments with maximized therapeutic synergy for individual patients. Here, we discuss promising formulations and opportunities to employ advanced screening tools and new animal models of disease that can improve chances for successful clinical translation.

Figure 1

Nanoparticle designs for co-delivery of multiple drugs.

Figure 2

Combination drug therapy with cytarabine/daunorubicin (CPX-351). (a) Plasma drug concentration of cytarabine and daunorubicin after IV co-injection as CPX-351 nanoparticles or as free drugs to mice. Inset: circulating plasma cytarabine:daunorubicin molar ratios for CPX-351 calculated from absolute plasma concentrations. (b) Survival of BDF-1 mice bearing P388 leukemia tumors at day 55 following IV treatment on days 1, 4, and 7 with saline or liposome co-encapsulated cytarabine and daunorubicin at different drug molar ratios. Formulations were dosed at their maximum tolerated dose (MTD) with the exception of CPX-351 (5:1 molar drug ratio), which was dosed at 0.8 of its MTD. Adapted with permission from ref . Copyright 2009 Elsevier.

Figure 3

Interactions between drugs A and B in the inhibition of a cellular effect, demonstrating synergy, additivity, or antagonism. Concentrations are defined relative to the minimum inhibitory concentration (MIC) at which the cellular effect is 100% inhibited. If A and B are similar drugs, their combined effect at equal concentrations is the same effect of one of the drugs in double the dose. For example, 0.5 MIC of drug A combined with 0.5 MIC of drug B (+ in the figure) is equivalent to 1 MIC of drug A or 1 MIC of drug B in an additive drug pair. Examples of different patterns of antagonism are depicted. Adapted with permission from ref . Copyright 2009 Nature Publishing Group.

Figure 4

In vitro screening to measure interactions between drugs A and B and to predict therapeutic windows. (a) Cell function is measured across a two-dimensional range of drug dosages in a multiwall plate. This can be performed for target cells (b, Test assay) and cells that are off target (c, Control assay). By determining the differences between the Test and Control (Ctrl), the therapeutic window can be evaluated (d) over which only target cells will be strongly impacted by the treatment. Adapted with permission from ref . Copyright 2009 Nature Publishing Group.