Protected Graft Copolymer (PGC) in Imaging and Therapy: A Platform for the Delivery of Covalently and Non-Covalently Bound Drugs

Abstract

Initially developed in 1992 as an MR imaging agent, the family of protected graft copolymers (PGC) is based on a conjugate of polylysine backbone to which methoxypoly(ethylene glycol) (MPEG) chains are covalently linked in a random fasion via N-ε-amino groups. While PGC is relatively simple in terms of its chemcial composition and structure, it has proved to be a versatile platform for in vivo drug delivery. The advantages of poly amino acid backbone grafting include multiple available linking sites for drug and adaptor molecules. The grafting of PEG chains to PGC does not compromise biodegradability and does not result in measurable toxicity or immunogenicity. In fact, the biocompatablility of PGC has resulted in its being one of the few 100% synthetic non-proteinaceous macromolecules that has suceeded in passing the initial safety phase of clinical trials. PGC is capable of long circulation times after injection into the blood stream and as such found use early on as a carrier system for delivery of paramagnetic imaging compounds for angiography. Other PGC types were later developed for use in nuclear medicine and optical imaging applications in vivo. Recent developments in PGC-based drug carrier formulations include the use of zinc as a bridge between the PGC carrier and zinc-binding proteins and re-engineering of the PGC carrier as a covalent amphiphile that is capabe of binding to hydrophobic residues of small proteins and peptides. At present, PGC-based formulations have been developed and tested in various disease models for: 1) MR imaging local blood circulation in stroke, cancer and diabetes; 2) MR and nuclear imaging of blood volume and vascular permeability in inflammation; 3) optical imaging of proteolytic activity in cancer and inflammation; 4) delivery of platinum(II) compounds for treating cancer; 5) delivery of small proteins and peptides for treating diabetes, obesity and myocardial infarction. This review summarizes the experience accumulated by various research groups that chose to use PGC as a drug delivery platform.

Hydrophobic-core PEGylated graft copolymer-stabilized nanoparticles composed of insoluble non-nucleoside reverse transcriptase inhibitors exhibit strong anti-HIV activity

“…HC-PGC has been initially developed for transient binding of bio-active peptides for improving their PK, e.g. for designing a long-acting native GLP-1 formulation for type 2 diabetes therapy 24, 25 . We decided to expand the potential applications of this technology to provide a component that affords stabilization of poorly water-soluble low molecular weight drugs instead of peptides.…”

Immune Rejection after Pancreatic Islet Cell Transplantation: In Vivo Dual Contrast-enhanced MR Imaging in a Mouse Model

“…The diameter of PGCGd-DTPA is 16 nm 6 4 in phosphatebuffered saline solution with a pH of 7 at 25°C as determined by means of submicron particle analysis. The agent has an r1 value in the range of 2000-2500 L · mmol 21 · sec 21 in water (13,15). It has been previously used in imaging studies in animal models of cancer (16), microvascular network and an increase in microvascular permeability, capillary widening, intravascular accumulation of white blood cells, and finally, breakdown of the integrity of the microcirculary system after xenogenic islet transplantation.…”

“…Imaging Agent PGC is based on a conjugate of a polylysine backbone to which methoxypoly (ethylene glycol) chains are covalently and randomly linked via N-´-amino groups (15). PGC-bearing covalently linked gadolinium-diethylenetriaminepentaacetic acid residues conjugated to the fluorescent dye fluorescein isothiocyanate (Gd-DTPA-F) was obtained from PharmaIN (Seattle, Wash).…”

Substrate-Based Near-Infrared Imaging Sensors Enable Fluorescence Lifetime Contrast via Built-in Dynamic Fluorescence Quenching Elements

“…enzyme activity) by following changes in overall fluorescence intensity of enzyme-reporting “substrate-based” as well as “activity-based” probes (or sensors, reviewed in 3, 4 ). The design of enzyme activity-reporting substrate-based sensors has traditionally relied on the effect of spatial separation of initially quenched fluorophores, such as cyanine dyes, which can be covalently linked directly to the enzyme-cleavable polymer 5–7 . Alternatively, such macromolecular sensors can harbor enzyme-cleavable pendant peptides, which are terminated with NIR fluorophores or quenchers 8–10, 11 .…”

“…Alternatively, such macromolecular sensors can harbor enzyme-cleavable pendant peptides, which are terminated with NIR fluorophores or quenchers 8–10, 11 . These sensors are known to be strongly affected by static quenching including radiative and non-radiative resonance energy transfer, and non-radiative energy transfer either to structurally different acceptors or to molecules of the same kind, which enables exceptional flexibility in designing FLT-based sensors for imaging 7, 12 . The simplest case of static quenching is a consequence of interaction of the individual cyanine molecules with the formation of intermolecular H -aggregates in polar solvents 12–15 .…”