University of Groningen
DNA-based drug carriers and dynamic proteoids with tunable properties Liu, Yun
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Publication date: 2017
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Liu, Y. (2017). DNA-based drug carriers and dynamic proteoids with tunable properties. University of Groningen.
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Summary
128
The rapid development of DNA nanotechnology has led to the generation of numerous 1D, 2D and 3D DNA nanostructures with different sizes and shapes. Due to their low toxicity and high biocompatibility, they are exploited in the field of nanomedicine. On the other hand, the application of constitutional dynamic chemistry (CDC) in biopolymer science gives rise to the generation of constitutional dynamic analogues of biopolymers, biodynamers, which can be used as novel adaptive biomaterials. N NH N HN OH OH HO HO 3' 5' 5' 3' a b Foscan
Scheme 1. Structures of a) Foscan and b) lipid-modified DNAs.
In chapter 1, we discuss the development of nucleic acid amphiphiles as drug carriers, including their synthetic approaches, controllable self-assembly behavior, and modification methods.
In chapter 2, we introduce the development of constitutionally dynamic covalent analogues of nucleic acids (DyNAs), polysaccharides (glycodynamers) and proteins (dynamic proteoids) as novel functional biomaterials.
In chapter 3, we designed and synthesized three types of lipid-modified DNA amphiphiles (Scheme 1b) that form micelles at comparatively low critical micelle concentration through solid-phase synthesis. We successfully used them to solubilize the insoluble photosensitizer Foscan (Scheme 1a) used for photodynamic therapy. We obtained novel drug-delivery systems with high drug loading capacities that do not compromise the biological activity of the active pharmaceutical ingredient.
O O HO H H HO O O H H Budesonide
Scheme 2. Structure of budesonide.
budesonide (Scheme 2), a hydrophobic glucocorticoid with high anti-inflammatory activity, with a high loading capacity. The inhibition of interleukin-8 release showed that the new delivery system maintains its inhibitory activity in cell-based assays.
+ pD = 5 N N N O 6 H N O R N n N H O H O O 6 1 N H NH2 H2N O R
Scheme 3. Generation of dynamic proteiods through polycondensation of dialdehyde 1 with α-amino acid hydrazides.
In chapter 5, we designed and synthesized a range of dynamic proteoids through polycondensation of different types of α-amino acid hydrazides with the nonbiological dialdehyde 1 (Scheme 3), through formation of two types of reversible C=N bonds (imine and acylhydrazone). The polymerization reaction is driven by the self-organization/folding of the resulting polymers. We found that the properties of the side chains of the α-amino acid hydrazides, including aromaticity, charge and polarity, have a strong influence on the rate of polymerization, structure and dynamic properties of the resulting biodynamers.
H2N H N N H O O R2 R1 NH2 pD = 5 + N H NH2 H2N O R O OH HO N n O HO OH OH HO HO + pD = 5 N H N O N R O OH HO N n N H N O N H R2 N O R1 b) a) OH O HO OH OH HO HO OH 2 2 N H O H O O 6 H2N H N N H O O R2 R1 NH2 N N N O 6 H N O R2 N H N O R1 n + pD = 5 1 c)
Scheme 4. Generation of dynamic proteoids through polycondensation of a) dialdehyde 1 with dipeptide hydrazides; b) dialdehyde 2 with α-amino acid hydrazides; c) dialdehyde 2 with dipeptide hydrazides.
In chapter 6, we designed and prepared a series of dynamic proteoids through polycondensation of different types of α-amino acid and dipeptide hydrazides with nonbiological aromatic dialdehyde 1 and biological aliphatic dialdehyde 2 (Scheme 4). By using dialdehyde 2, we enhanced the biocompatibility of the resulting
Summary
130
biodynamers. The respective importance of factors that influence the polymerization and structure of the resulting biodynamers was compared, including aromaticity, negative charge and the hydroxyl group in the side chains of α-amino acids.
In conclusion, the first part of the present thesis describes the design and synthesis of DNA-based amphiphiles and their application as solubilizers for hydrophobic drugs without influencing their biological activity. Through hybridizing with complementary DNA bearing functional groups, multi functionalization can be achieved controllably and efficiently. We believe that self-assembled DNA nanocarriers hold great promise to be employed as nanocarriers in nanomedicine. The second part of this thesis describes the design and preparation of constitutionally dynamic analogues of proteins (dynamic proteoids) with different nano-structures through the polycondensation of various α-amino acid and dipeptide hydrazides with two types of dialdehydes, namely a nonbiological aromatic dialdehyde and a biological aliphatic dialdehyde. The results provide a basis for the rational design and synthesis of well-ordered architectures and adaptive dynamic proteoids. The resulting biodynamers combine biocompatibility and functionality of the biological components with adaptability stemming from dynamic covalent bonds. They may find use as functional adaptive biomaterials in both biomedical and bio-engineering areas.
