Technology

Overview

The Protected Graft Copolymer (PGC™) is an injectable delivery system which provides the benefits of PEGylation for peptides, proteins, and potent small molecules but without chemical modification of the drug payload. Based on technology originally licensed from Harvard/Massachusetts General Hospital for imaging applications, PharmaIN has developed PGC for the formulation of human therapeutics. PGC offers extended drug release and passive targeting to inflamed and infected tissue without chemical modification of the drug molecule.

PGC Microstructure

The PGC Design

PGC is comprised of three components. The first is a polyamino acid backbone polymer, typically poly-L-lysine. Bound to a portion of those amino groups are relatively short (5-10 kDa) MPEG chains. On the balance of the amino groups is a reversible binding moiety which binds the drug payload with high affinity. In total, the mass of the carrier molecule is approximately 350 kDa, but can be tuned to suit the needs of a particular formulation.

Poly-L-lysine backbone: The backbone molecule is α-poly-L-lysine, which exposes the epsilon amino groups for derivatization.
Protective Chains: These linear PEG chains are typically 5-10 kDa in mass, significantly shorter than those commonly used for PEGylation. There are several advantages of using shorter PEG, including lower immunogenicity and reduced viscosity.
Reversible binding moiety: PharmaIN has developed two primary reversible binding platforms; the PGC-Hydrophobic Core (PGC-HC™) and the PGC-Metal Bridge (PGC-MB™). These platforms allow for non-covalent, affinity based attachment of the drug to the carrier. The ability to modify the reversible binding moiety contributes to the broad applicability of the PGC technology.
- PGC-HC: This platform consists of a hydrophobic reversible binding moiety. The specific molecule used varies, but often consists of a fatty acid chain (C18-C22). The length of this molecule may be adjusted to allow for an ideal binding affinity of the drug to the carrier. In essence, this creates a carrier with properties much like a reverse-phase HPLC column. Many proteins and peptides have hydrophobic domains which bind with high affinity to the PGC-HC carrier.
- PGC-MB: This platform takes advantage of the metal binding properties of some proteins and peptides to create a high affinity interaction between the drug and carrier. In this platform, the reversible binding moiety is a metal chelator, typically binding Zn or Cu. With the addition of metal ion, the resulting carrier coordinates metal binding molecules with high affinity. Insulin, for example, has a high affinity for Zn, and binds the PGC-MB carrier with nanomolar affinity.

Half-life Extension

A primary benefit of the PGC nanocarrier platform is half-life extension. This half-life extension is a result of the protective effect of the PGC polymer from chemical or enzymatic degradation in the blood as well as reducing renal elimination. The diameter of the PGC carrier (~20 nm) is well above the glomerular filtration limit (~5 nm), and association of smaller molecules with the carrier protects them from renal elimination.

Drug Release from Carrier

By virtue of its affinity binding mechanism, PGC creates an equilibrium system between bound and free drug in the bloodstream and interstitial space.

Dosage Forms and Routes of Administration

PGC's ~20 nm size and single-molecule construction form a true solution in water, allowing for parenteral administration, including intravenous (IV) and subcutaneous (SC). Also, unlike a depot system, the entire carrier traffics to the bloodstream with the drug payload after SC administration.

Improved Solubility of Drugs

Because the PGC carrier's PEG chains protect the loaded drug from the external environment, the solubility of hydrophobic drugs is improved by association with PGC. PGC is capable of forming a true solution in aqueous environments without affecting viscosity to concentrations as high as 100 mg/mL, and would solubilize loaded drugs to that level.

Passive and Active Targeting

For some indications, where the site of drug action is infection, inflammation, or solid tumors, PGC has the added advantage of passive accumulation. The PGC copolymer has a diameter of approximately 20nm, the ideal size to take advantage of the Enhanced Permeability and Retention (EPR) effect. At this size, permeable vasculature, such as in infection, allows particles of this size to extravasate out of the bloodstream and into the tissue, but does not allow them to easily move back into the bloodstream. The net effect is accumulation of the copolymer at the target site while still carrying the drug. While in the target tissue, the drug then releases into the interstitial space.

Active Targeting is also a benefit of the PGC nanocarrier. It is possible to covalently attach targeting molecules, such as antibody fragments, to the exposed PEG groups. Coupled with passive targeting, there is a potential for improved targeted delivery, improving efficacy and reducing toxicity.

Demonstrated Results In Vivo

	API Size	Administration	In Vivo Results
*PGC-Hydrophobic Core*
Native GLP-1	3.5 kDa	IV and SC	Extended t1/2 of native peptide 100-fold with 100% retained activity
Vasoactive Intestinal Peptide (VIP)	3.0 kDa	SC	>100-fold increase in VIP half-life in rat models
*PGC-Metal Bridge*
Native Human Insulin	5.8 kDa	SC	Glucose control for a full 24h post injection
Anti-MRSA protein	~30 kDa	IV	Increased AUC three-fold, 100-fold bioburden reduction 24h post injection relative to unformulated protein
6His-Vasopressin	1.1 kDa	IV and SC	80-fold subcutaneous t1/2 extension (19-fold IV), 9-fold increase in apparent bioavailability

PGC Advantages

No chemical modification of the drug payload
Longer acting formulations
Passive Targeting to infection, inflammation, and solid tumors
IV, SC, or IM administration
Improved solubility; forms a true solution. No effect on viscosity at concentrations as high as 100 mg/mL
Highly stable; >10 months lyophilized and >1 month at 37°C in solution.
Non-toxic, non-immunogenic nanocarrier
Strong IP position; over 15 families of patents
Simple formulation and manufacturing