Introduction:
Nanotechnology in the Pharmaceutical Industry
Part 2 of 4: Polymer-Drug Conjugates
Although the FDA does not have an established definition of “nanotechnology” or “nanoparticles”, it is generally understood this term relates to the deliberate manipulation of pharmaceutical materials to yield particles with at least one dimension in the size range of approximately 1 and 100 nanometers. Said another way, just because your drug formulation has particles between 1-100 nm, doesn’t mean it’s nanotechnology—the particles need to be deliberately engineered to exhibit particular properties.
We love nanotechnologies and want you to love them too. In this 4-part series, we will introduce some of the well-established nanoparticle technologies, highlighting their benefits. We’ll conclude each part of the series discussing emerging technologies we think are noteworthy. Today in Part 2, we’ll discuss Polymer-drug Conjugates.
Part 2: Polymer-Drug Conjugates
This broad category of nanotechnology describes a single, unified molecule comprised of a polymer covalently linked to a drug, and in some situations a targeting molecule. The most prevalent polymer in this technology is poly(ethylene) glycol (PEG)—with the linkage commonly referred to as “PEGylation”. All the predominant drug types utilize this technology to solve challenges in drug delivery that the drug by itself cannot meet:
- Polymer-Small Molecule Conjugates – linking a polymer to a small molecule can overcome several limitations of a conventional drug, including; (a) poor solubility: attaching a water-soluble polymer to a hydrophobic drug, (b) rapid clearance: increasing the size to reduce renal clearance or add steric shielding to hinder enzymatic drug metabolism, and (c) lack of target specificity: excluding ADCs (active targeting) for now, this strategy aims to take advantage of the enhanced permeability and retention (EPR) effect, and avoid non-specific cellular uptake. An example in this category is the PEGylation of the opioid antagonist naloxol (MOVANTIK®) which prevents the drug from crossing the blood-brain barrier helping to target the opioid-receptors in the gastrointestinal tract to treat opioid-induced constipation.
- Protein-Polymer conjugates– covalently linking a protein with a synthetic or natural polymer combines the inherent activity of the protein with the advantageous properties of polymers. This can dramatically increase the circulation half-life of a protein by masking antigenic sites, preventing recognition and uptake by macrophages. Decorating a protein with polymers can also act as a steric barrier and prevent enzymatic degradation. Perhaps the most famous member of this class is Pegfilgrastim (NEULASTA®), which is the PEGylated version of the colony stimulating factor filgrastim. The PEG modification was designed to increases size, reducing renal clearance and dramatically extending circulation time.
- Peptide-Polymer Conjugates – peptides (i.e., < 50 amino acids) are more vulnerable to enzymatic degradation than proteins. For this reason, a key reason for linkage to a polymer is to shield the peptide from degradation. Other purposes for polymer linkage include the enhancement of cellular uptake, and solubility. Zilbrysq® (Zilucoplan) is an example in this class. It’s a small macrocyclic peptide that functions as complement inhibitor (C5) used in the treatment of generalized myasthenia gravis. This peptide is conjugated to a C16 lipid via a short PEG linker which enhances pharmacokinetics, and stability by increasing the size and adding a steric shield.
- Antibody-Drug Conjugates (ADC) – this category is the most complex structurally as it comprises 3 different components, (a) a monoclonal antibody (mAb): for specific targeting of an antigen, (b) a payload: the warhead of the ADC, often a cytotoxic drug, and (c) a linker: this is typically a polymer that covalently connects the mAb to the payload. Not all, but most ADCs are designed such that the polymer linker is cleavable via acid hydrolysis, enzymatic activity, or disulfide reduction. Trodelvy® (Sacituzumab govitecan-hziy) is a breast cancer ADC comprised of an anti-Trop-2 mAb, and the topoisomerase I inhibitor SN-38, linked by a PEG-based, hydrolytically labile carbonate.
Emerging technologies: Nucleic Acid-Polymer Conjugates
Currently, no approved products contain a nucleic acid-polymer conjugate. However, this is a rapidly growing area of research with several reaching the clinical stage. The fragility of nucleic acids—especially RNA—is the motivation to attach polymers in the hope of reducing enzymatic degradation and thus increasing circulation time and cellular uptake. Another purpose is to connect a nucleic acid to a ligand, as is the case with Silence Therapeutics’ mRNAi GOLD™ platform. Their drug candidate Zerlasiran (SLN360) uses a PEG linker to connect siRNA to a GalNAc ligand, which facilities uptake into liver cells to reduce lipoprotein(a) expression in patients at risk for cardiovascular disease.
