Tuning Net Charge in Aliphatic Polycarbonates Alters Solubility and Protein Complexation Behavior.

Nicholas D Posey,Julia Danischewski,Michael Lueckheide,Vivek M Prabhu,Yuanchi Ma,Jeffrey A Fagan

doi:10.1021/acsomega.1c02523

Nicholas D Posey, Julia Danischewski + Show 4 more

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https://doi.org/10.1021/acsomega.1c02523

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Abstract

A synthetic strategy yielded polyelectrolytes and polyampholytes with tunable net charge for complexation and protein binding. Organocatalytic ring-opening polymerizations yielded aliphatic polycarbonates that were functionalized with both carboxylate and ammonium side chains in a post-polymerization, radical-mediated thiol–ene reaction. Incorporating net charge into the polymer architecture altered the chain dimensions in phosphate buffered solution in a manner consistent with self-complexation and complexation behavior with model proteins. A net cationic polyampholyte with 5% of carboxylate side chains formed large clusters rather than small complexes with bovine serum albumin, while 50% carboxylate polyampholyte was insoluble. Overall, the aliphatic polycarbonates with varying net charge exhibited different macrophase solution behaviors when mixed with protein, where self-complexation appears to compete with protein binding and larger-scale complexation.

Highlights

An aliphatic polycarbonate backbone was selected for the polyampholyte design because of its biodegradability, which is relevant to its intended application as a potential protein carrier
aliphatic polycarbonates (APCs) precursors were synthesized by the ring-opening polymerization (ROP) of MAC, catalyzed by an organo-urea catalyst developed by Lin and Waymouth.[39]
Organo-catalytic ROP of a commercial carbonate monomer was combined with post-polymerization modification using thiol−ene chemistry to synthesize a series of polyelectrolytes

Summary

■ INTRODUCTION

Biodegradable polymers and aliphatic polycarbonates (APCs) are used in the development of drug delivery strategies for many types of therapeutics and biopharmaceuticals.[1,2]. Our speculation is supported by the experimental results by Andrianov et al that increasing the protein/ polymer molar ratio of their highly charged polyphosphazene/ avidin complexes, that is, moving toward charge stoichiometry, led to the formation of an insoluble precipitate and the study by Burova et al with polyphosphazene/lysozyme.[68,69] Dubin and co-workers have determined that there are distinct conditions where soluble complexes are favored over aggregates of complexes that phase-separate; these phase regions were identified by altering pH which changed the ionization states of charges on the protein surface in relation to its polycation partner.[10] Along these lines, the adsorption of linear polyelectrolytes to uniformly charged spheres has been studied theoretically.[70] A critical adsorption line can be determined based upon several molecular parameters including the polymer linear charge density, sphere radius, surface charge density, and Debye screening length. The large aggregation may be further enabled by the presence of hydrophobic ene groups which distinguishes from the binding with APC(+)[100]

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES