Design of a novel theranostic nanomedicine: synthesis and physicochemical properties of a biocompatible polyphosphazene–platinum(II) conjugate

Abstract

To develop a theranostic nanomedicine involving the antitumor-active moiety (dach)Pt(II) (dach: trans -(±)-1,2-diaminocyclohexane) of oxaliplatin (OX), a new biocompatible polyphosphazene carrier polymer was designed by grafting with a methoxy poly(ethylene glycol) (MPEG) to increase duration of circulation in the blood and with aminoethanol (AE) as a spacer group. The antitumor (dach)Pt moiety was conjugated to the carrier polymer using cis -aconitic acid (AA) as a linker, resulting in a polymer conjugate formulated as [NP(MPEG550)(AE-AA)Pt(dach)] n , named “Polyplatin” (PP). PP was found to self-assemble into very stable polymeric nanoparticles with a mean diameter of 55.1 nm and a critical aggregation concentration of 18.5 mg/L in saline. PP could easily be labeled with a fluorescence dye such as Cy5.5 for imaging studies. The time-dependent ex vivo image studies on organ distributions and clearance of Cy-labeled PP have shown that PP accumulated in the tumor with high selectivity by the enhanced permeability and retention effect but was cleared out from all the major organs including the liver in about 4 weeks postinjection. Another time-dependent bioimaging study on distribution and clearance of PP in mouse kidney using laser ablation inductively coupled plasma mass spectroscopy has shown that PP accumulates much less in kidney and is more rapidly excreted than monomeric OX, which is in accord with the very low acute toxicity of PP as shown by its high LD 50 value of more than 2000 mg/kg. The pharmacokinetic study of PP has shown that it has a much longer half-life ( t 1/2 β) of 13.3 hours compared with the 5.21 hours of OX and about a 20 times higher area under the curve value of 42,850.8 ng h/mL compared with the 2,320.4 ng h/mL of OX. The nude mouse xenograft trials of PP against the gastric MKN-28 tumor cell line exhibited remarkably better tumor efficacy compared with OX at the higher tolerated dose, with lower systemic toxicity.

Gadolinium and Platinum in Tandem: Real-time Multi-Modal Monitoring of Drug Delivery by MRI and Fluorescence Imaging

“…Despite the clinical success of several prodrugs, unprecedented challenges remain in achieving their desired pharmacokinetics with minimal adverse side effects since they are non-specifically distributed throughout the body 9 . The major drawback of prodrugs, according to the literature, lies in the difficulties of tracing their activities in vitro/in vivo 10 - 11 . Intriguingly, the recent advent of theranostic nanomedicine - an emerging paradigm combining diagnostic and therapeutic entities into one - creates a new research landscape and provides a promising solution to the prodrug conundrum 12 - 14 .…”