PharmaIN

Platform Technology

Protected Graft Copolymer (PGC)TM

Novel drug carrier that maximizes therapeutic potential

  • Alternative to PEGylation
  • No modification of API
  • Extend API half life and bioavailability
  • Increase stability and improve safety of API
  • Target API to diseased and inflamed tissue
  • Bind peptides, proteins, and RNA

to topHydrophobic CoreTM

This platform consists of a hydrophobic reversible binding moiety. The specific molecule used varies, but often consists of a fatty acid chain with 18-22 carbons. The length of this molecule may be adjusted to optimize the 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-HCTM carrier.

Applications: Glucagon like peptide-1 (GLP-1), a human hormone involved in glucose control, insulin secretion, and gastric emptying

to topMetal BridgeTM

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 a 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-MBTM carrier with nanomolar affinity.

Applications: Native Human Insulin (has a high affinity for Zn ions)

to topAnionic CoreTM

This platform consists of an anionic reversible binding moiety such as chondroitin sulfate. In essence, this creates a carrier with properties much like an ion-exchange column. Many proteins and peptides have charged domains which bind with high affinity to the PGC-ACTM carrier.

Applications: Basic peptides or protein that contain amino acid residues such as lysine or arginine which are positively charged at physiological pH such as heparin-binding Epidermal Growth Factor.

to topOligo CoreTM

This platform consists of oligonucleotide reversible binding moiety such as polyG, polyC, polyA or polyT. The specific molecule used varies, but will contain an oligonucleotide complementary to the binding moiety. In essence, this creates a carrier with properties which take advantage of polynucleotide complementation. The affinity can be changed by changing the number of complementing oligonucleotides.

Applications: drugs that contain RNA or DNA.

to topPGCTM Affinity Binding Mechanism

The loading and release of the API / drug from PGCTM is equilibrium based, with a Kd that favors binding.

Empty PGCTM
Load Molecule
(drug)
PGCTM loaded with drug

Kd = [Free Drug] [Empty PGCTM sites] = ~10 -9 M
[Total PGCTM sites]

to topPGCTM Application Guide

PGCTM Technology Load Molecule Attributes
Hydrophobic CoreTM Lipophilic
contains a-helix
Loading 2-10%
Anionic CoreTM Isoelectric point > 8.0
multiple formal charges
Loading 20-50%

Note: Loading is defined as weight of API per weight of carrier, so 10% loading is 10 mg of API per 100 mg carrier.

to topPro-drug Technology with PGCTM

PGCTM protects the peptide-ligand conjugate. When the peptide-ligand conjugate is released from the PGCTM, the linker is cleaved to release active peptide into the blood.

Advantages

to topAdvantages of PGCTM

  • Affinity based binding of drug to carrier

    • No irreversible chemical modification of drugs
    • Improves PK, solubility, and safety
    • Useful for peptides, proteins, and potent small molecules
    • Ease of formulation and manufacturing
  • Targeted delivery

    • Passive targeting to areas of enhanced vascular permeability (inflammation, infection, and tumors)
    • Active targeting capability
  • Strong IP
  • SC, IV, and IM

to topComparison of PGCTM to Other Systems

PGCTM is Superior to No Carrier PGCTM is Superior to HESylation & PEGylation PGCTM is Superior to Liposomes & Micelles
  • Extends circulation
  • Accumulates in infected, inflamed, and tumor tissues
  • Mitigates non-specific interactions
  • Protects from enzymatic and hydrolytic degradation
  • Improves solubility
  • No modification of API
  • Protection from reactions at SC injection site
  • Smaller MW PEG in PGCTM is safer
  • No loss of activity
  • PGCTM is a discrete molecule, not a complex
  • PGC-APITM traffics to the bloodstream intact from SC site
  • Deeper distribution into infected, inflamed, and tumor tissues
  • PGC-APITM complex is much less dilution dependent

to topSolubility Case Study

Insoluble peptide

    • Solubility < 1 mg/mL in water
    • Evaluated by microscopy

Formulated with PGC-hydrophobic coreTM

  • Insoluble peptide & PGC-HCTM
    • 1:10 weight ratio
  • Co-lyophilized in organic solvent
    • Lyophilizable
    • Miscible in water
  • Dissolved in water
    • 10mg/mL insoluble peptide with 100mg/mL PGC-HCTM

PK

to topPGCTM dramatically extends bioavailability and pharmacokinetics when formulated with peptides

ANP example in dog

Unformulated ANP peptide (red) is cleared in minutes while PGC-formulated-ANPTM (blue) lasts for days.

to topLigand-TerlipressinTM pro-drug example in rats

Unformulated Ligand-Terlipressin peptide (“free”, orange) is cleared in minutes while PGC-formulated-Ligand-TerlipressinTM (green) lasts for days.


Targeting

to topMechanism of Passive Targeting from Enhanced Permeability and Retention

Healthy blood vessels (A)

  • PGCTM carrier flows through healthy blood vessels (A)

Sites of infection, inflammation, and in tumors (B)

  • The blood vessels have openings that make them porous to large molecules
  • PGCTM extravasates through the abnormal openings to interstitial area
  • Carrier with drug payload accumulates in sites of enhanced vascular permeability

to topPGCTM Targets Inflammation and Infection

Enhanced permeability and retention and long circulation enables accumulation of PGCTM loaded with imaging agent to damaged tissue

to topPGCTM Tumor Targeting

Accumulation of PGC-formulated-APITM in tumors is a result of long circulation and enhanced permeability and retention effects

Rat breast tumor model imaged with PGCTM and co-labeled with Gd and 111In; Fisher rat at 48 hrs.

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