The effect of ligand lipophilicity on the nanoparticle encapsulation of Pt(IV) prodrugs

Abstract

In an effort to expand the therapeutic range of platinum anticancer agents, several new approaches to platinum-based therapy, including nanodelivery, are under active investigation. To better understand the effect of ligand lipophilicity on the encapsulation of Pt(IV) prodrugs within polymer nanoparticles, the series of compounds cis,cis,trans-[Pt(NH3)2Cl2L2] was prepared, where L = acetate, propanoate, butanoate, pentanoate, hexanoate, heptanoate, octanoate, nonanoate, and decanoate. The lipophilicities of these compounds, assessed by reversed-phase HPLC, correlate with the octanol/water partition coefficients of their respective free carboxylic acid ligands, which in turn affect the degree of encapsulation of the Pt(IV) complex within the hydrophobic core of poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-PEG-COOH) nanoparticles. The most lipophilic compound investigated, cis,cis,trans-[Pt(NH3)2Cl2(O2C(CH2)8CH3)2], displayed the best encapsulation. This compound was therefore selected to evaluate the effect of increased platinum concentration on encapsulation. As the platinum concentration was increased, there was an initial increase in encapsulation followed by a decrease due to macroscopic precipitation. Maximal loading occurred when the platinum complex was present at a 40% w/w ratio with respect to polymer during the nanoprecipitation step. Particles formed under these optimal conditions had diameters of approximately 50 nm, as determined by transmission electron microscopy.

Figure 1

Molecular diagrams of 2 (left) and 3 (right). Thermal ellipsoids are drawn at the 50% probability level.

Figure 2

Correlation between the log of the capacity factors for 2 = 6 (abscissa) and the log of the octanol/water partition coefficients of the carboxylic acids from which the carboxylates of 2 – 6 are derived (ordinate).

Figure 3

Schematic depiction of the nanoprecipitation process, whereby the amphiphilic block copolymer chains self-assemble into polymeric micelles, trapping hydrophobic guest molecules within.

Figure 4

Correlation between log of encapsulation efficiency (%EE) for 2 – 10 (ordinate) and log P of the carboxylic acids from which the carboxylates of 2 – 10 are derived (abscissa).

Figure 5

Variation in the platinum loaded into PLGA-PEG-COOH nanoparticles as the feed of 10 was varied.

Figure 6

Transmission electron micrograph of PLGA-PEG-COOH nanoparticles loaded with 10. Scale bar of main image = 500 nm, scale bar of inset = 100 nm.

Scheme 1

The synthesis and general structure of the Pt(IV) carboxylate species studied here.