Editors' ChoiceDrug Delivery

Drug delivery in stealth mode

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Science Translational Medicine  12 Dec 2018:
Vol. 10, Issue 471, eaaw0523
DOI: 10.1126/scitranslmed.aaw0523


Zwitterionic polypeptides with high chemical specificity and “stealth”-like behavior have superior pharmacokinetics compared with uncharged polypeptides in mice.

Drug delivery is often limited by the short half-lives and circulation times of peptide- and protein-based drugs. A common approach to overcoming this challenge conjugates drugs to poly(ethylene glycol) (PEG), a process also known as PEGylation. PEG serves as a “stealth” drug carrier that protects the drug and prolongs bioactivity during circulation. Unfortunately, PEG has several limitations, including that (i) a large portion of the human population has developed anti-PEG antibodies, (ii) PEG is not biodegradable and can accumulate in the body, and (iii) PEG’s polydispersity limits the ability to tune its in vivo behavior. In comparison with synthetic polymers, polypeptides have emerged as a new class of materials with high sequence specificity and monodispersity. Recently, researchers have discovered that zwitterionic polymers—neutral polymers that contain both positive and negative charges—have similar “stealth” properties as PEG. Here, the authors propose using zwitterionic polypeptides as a new drug carrier that offers increased control over the chemical structure and “stealth”-like behavior.

Banskota et al. synthesized a small library of zwitterionic polypeptides with different combinations of oppositely charged amino acid residues and different numbers of repeat units. A similar amino acid sequence with uncharged amino acid residues was also synthesized and served as the uncharged polypeptide control. To evaluate the influence of zwitterionic polypeptides on pharmacokinetics, polypeptide half-life and circulation time were measured after intravenous and subcutaneous injection in mice. In both cases, the zwitterionic polypeptides resulted in improved pharmacokinetics, with the best performing zwitterionic polypeptide displaying a half-life and total exposure time twofold greater than the uncharged polypeptide control. To evaluate clinical potential, glucagon like peptide-1 (GLP1)—a peptide used clinically to treat type 2 diabetes (T2D)—was conjugated to the best performing zwitterionic polypeptide and delivered in a mouse model of T2D. Subcutaneous injection of GLP1-conjugated zwitterionic polypeptide reduced blood glucose levels for three days, 70 times longer than the drug alone and 1.5 times longer than the uncharged polypeptide control.

A new class of drug carriers with high specificity and “stealth”-like behavior would be broadly applicable to a range of diseases and treatments that require sustained drug delivery. Nonetheless, ongoing research is needed to evaluate the zwitterionic polypeptides against the current gold standard of PEGylation and in larger animal models.

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