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Synthesis of Biomimetic Phosphorus-Containing Polypeptides

  • Author(s): Yakovlev, Ilya
  • Advisor(s): Deming, Timothy J
  • et al.
Abstract

Immune response has historically been a major issue in the drug delivery field. In order to combat this problem, drug carriers have been designed to avoid the body's innate defenses. Following decades of research, it was found that an ideal drug delivery vehicle should enter the body, evade the immune system, stay in circulation long enough to seek out affected cells, and release the payload selectively. Furthermore, the vehicle should be comprised of materials that are non-toxic and biodegradable. While a number of potentially viable materials have been produced, there has arguably not been one which encompasses all these properties.

Using phosphocholine-containing vesicles or micelles as drug delivery vehicles is one potential solution. Phospholipids, the major components of biological membranes, have also been explored for drug delivery purposes; however, their use has not been successful due to the low stability of phospholipid vesicles. Thus, biomimetic polymers with pendant phosphocholine groups were used to increase drug delivery vehicle stability. Much like other polymers, polypeptides may serve as a superior alternative due to the biodegradability of their backbone. Polypeptide synthesis has been thoroughly explored in the previous decades; however no reliable method for the preparation of phosphorus- and phosphatidylcholine-containing polypeptides has been published by the inception of this work.

Herein we discuss methods for preparation of phosphonate and phosphatidylcholine containing polypeptides. Synthesis of these materials builds on robust methods often employed in solution phase DNA synthesis. Protecting group strategies as well as the failures leading up to the polymers' successful synthesis are described. The polymers are synthesized via Co(PMe3)4 initiated polymerization of NCAs and are incorporated into diblock copolypeptides. The resultant products display interesting solution and calcium-binging properties.

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