Engineering endosomolytic nanocarriers of diverse morphologies using confined impingement jet mixing

Pagendarm, Hayden M.; Stone, Payton T.; Kimmel, Blaise R.; Baljon, Jessalyn J.; Aziz, Mina H.; Pastora, Lucinda E.; Hubert, Lauren; Roth, Eric W.; Almunif, Sultan; Scott, Evan A.; Wilson, John T.

doi:10.1039/d3nr02874g

Engineering endosomolytic nanocarriers of diverse morphologies using confined impingement jet mixing

Journal Article · Tue Sep 19 00:00:00 EDT 2023 · Nanoscale

DOI:https://doi.org/10.1039/d3nr02874g· OSTI ID:2470214

^[1]; ^[1]; ^[1]; Baljon, Jessalyn J. ^[1]; Aziz, Mina H. ^[1]; Pastora, Lucinda E. ^[1]; Hubert, Lauren ^[2]; Roth, Eric W. ^[3]; Almunif, Sultan ^[3]; ^[4]; ^[5]

Vanderbilt University, Nashville, TN (United States)
The University of Rhode Island, Kingston, RI (United States)
Northwestern University, Evanston, IL (United States)
Northwestern University, Evanston, IL (United States); Northwestern University, Chicago, IL (United States)
Vanderbilt University, Nashville, TN (United States); Vanderbilt University Medical Center, Nashville, TN (United States)

The clinical translation of many biomolecular therapeutics has been hindered by undesirable pharmacokinetic (PK) properties, inadequate membrane permeability, poor endosomal escape and cytosolic delivery, and/or susceptibility to degradation. Overcoming these challenges merits the development of nanoscale drug carriers (nanocarriers) to improve the delivery of therapeutic cargo. Herein, we implement a flash nanoprecipitation (FNP) approach to produce nanocarriers of diverse vesicular morphologies by using various molecular weight PEG-bl-DEAEMA-co-BMA (PEG-DB) polymers. We demonstrated that FNP can produce uniform (PDI < 0.1) particles after 5 impingements, and that by varying the copolymer hydrophilic mass fraction, FNP enables access to a diverse variety of nanoarchitectures including micelles, unilamellar vesicles (polymersomes), and multi-compartment vesicles (MCVs). We synthesized a library of 2 kDa PEG block copolymers, with DEAEMA-co-BMA second block molecular weights of 3, 6, 12, 15, 20, and 30 kDa. All formulations were both pH responsive, endosomolytic, and capable of loading and cytosolically delivering small negatively charged molecules – albeit to different degrees. Using a B16.F10 melanoma model, we showcased the therapeutic potential of a lead FNP formulated PEG-DB nanocarrier, encapsulating the cyclic dinucleotide (CDN) cGAMP to activate the stimulator of interferon genes (STING) pathway in a therapeutically relevant context. Collectively, these data demonstrate that an FNP process can be used to formulate pH-responsive nanocarriers of diverse morphologies using a PEG-DB polymer system. As FNP is an industrially scalable process, these data address the critical translational challenge of producing PEG-DB nanoparticles at scale. Furthermore, the diverse morphologies produced may specialize in the delivery of distinct biomolecular cargos for other therapeutic applications, implicating the therapeutic potential of this platform in an array of disease applications.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: European Union's Horizon 2020 Research and Innovation Programme; National Institutes of Health (NIH); National Science Foundation (NSF); Stand Up To Cancer (SU2C); Susan G. Komen Foundation; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); Vanderbilt Institute of Chemical Biology and the Vanderbilt Ingram Cancer Center

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470214

Journal Information:: Nanoscale, Journal Name: Nanoscale Journal Issue: 39 Vol. 15; ISSN 2040-3364

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United States

Language:: English

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Engineering endosomolytic nanocarriers of diverse morphologies using confined impingement jet mixing

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