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Abstract Drug nanoaggregates are particles that can deleteriously cause false positive results during drug screening efforts, but alternatively, they may be used to improve pharmacokinetics when developed for drug delivery purposes. The structural features of molecules that drive nanoaggregate formation remain elusive, however, and the prediction of intracellular aggregation and rational design of nanoaggregate-based carriers are still challenging. We investigate nanoaggregate self-assembly mechanisms using small molecule fragments to identify the critical molecular forces that contribute to self-assembly. We find that aromatic groups and hydrogen bond acceptors/donors are essential for nanoaggregate formation, suggesting that both π-π stacking and hydrogen bonding are drivers of nanoaggregation. We apply structure-assembly-relationship analysis to the drug sorafenib and discover that nanoaggregate formation can be predicted entirely using drug fragment substructures. We also find that drug nanoaggregates are stabilized in an amorphous core-shell structure. These findings demonstrate that rational design can address intracellular aggregation and pharmacologic/delivery challenges in conventional and fragment-based drug development processes.
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Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines
Abstract Amphiphilic drugs are molecular drugs or drug conjugates possessing both hydrophilic and lipophilic properties. Representative amphiphilic drugs are composed of a pharmaceutical payload, a linker, and an appropriate amphiphilic modification. The physicochemical properties of amphiphilic drugs can be tailored by structure‐based engineering, which ultimately determine the drug molecules’ self‐assemble ability, bioavailability, protein binding, membrane anchoring, organ and intracellular distributions, side effects, and biological efficacy. Unlike the traditional carrier‐assistant drug delivery system, many of the amphiphilic drugs are carrier‐free and can self‐deliver to target sites/cells and access intracellular organelles without an external delivery carrier. This is achieved by molecular designs that control the delivery pathways of amphiphilic drugs at organ/tissue, cellular, and intracellular levels. In this review the recent advances in self‐delivery amphiphilic drugs and vaccines are highlighted, with emphasis on the underlying design principles and emerging applications.
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- Award ID(s):
- 1750607
- PAR ID:
- 10373244
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Therapeutics
- Volume:
- 3
- Issue:
- 2
- ISSN:
- 2366-3987
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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