Dynamic Core–Shell Bioconjugates for Targeted Protein Delivery and Release

Seidler, Christiane; Zegota, Maksymilian Marek; Raabe, Marco; Kuan, Seah Ling; Ng, David Y. W.; Weil, Tanja

doi:10.1002/asia.201800843

Cited by 12 publications

(12 citation statements)

References 33 publications

(45 reference statements)

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“…The result is consistent with previous findings where the SHA-boronic acid interactions are in the low µM range. [43,44] As expected, there was no binding under acidic conditions showing the pH-dependence of the system, which is attractive for the release of molecular cargoes in acidic endolysozomes of cancer cells or in acidic cancer microenvironment. Next, we proceeded to prepare various pH-responsive S3-Avi-Cargo assemblies (Cargo = Dox, BDP, and Rho).…”

Section: Preparation Of Ph Responsive S3-avi-cargo Binding and Stability Studiessupporting

confidence: 59%

Assembly of pH-Responsive Antibody-Inspired Protein-Drug Conjugates

Raabe

Heck

Pieszka

et al. 2021

Preprint

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With the advent of chemical strategies that allow the design of smart bioconjugates, peptide- and protein-drug conjugates are emerging as highly efficient therapeutics to overcome limitations of conventional treatment, as exemplified by antibody-drug conjugates. While targeting peptides serve similar roles as antibodies to recognize overexpressed receptors on diseased cell surfaces, peptide-drug conjugates suffer from poor stability and bioavailability due to their low molecular weights. Through a combination of a supramolecular protein-based assembly platform and a pH-responsive dynamic covalent linker, we devise herein the convenient assembly of a trivalent protein-drug conjugate. The conjugate mimics key features of antibody-drug conjugates such as (1) a multipartite structure, (2) peptide recognition sites arranged at distinct locations and at defined distances, (3) a high molecular weight protein scaffold, and (4) an attached drug molecule. These antibody-inspired protein-drug conjugates target cancer cells that overexpress somatostatin receptors, enable controlled release in the microenvironment of cancer cells through an entirely new dynamic covalent biotin linker and exhibit stability in biological media.

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Section: Preparation Of Ph Responsive S3-avi-cargo Binding and Stability Studiessupporting

confidence: 59%

Assembly of pH-Responsive Antibody-Inspired Protein-Drug Conjugates

Raabe

Heck

Pieszka

et al. 2021

Preprint

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“…22 The binding complex is equipped with (1) small spatial requirement, (2) fast binding kinetics and (3) pH-responsiveness within the physiological range (5.0–7.4). 23 Hence, its dynamic covalent binding capabilities have been applied broadly in therapeutics, 24 biosensors, 25,26 stimulus responsive ligation tools 27 and as self-regenerative materials. 28,29 Herein, we propose that BA/CA motifs in a binary sequence would encode molecular recognition in a stimulus responsive fashion.…”

mentioning

confidence: 99%

Sequence Programming with Dynamic Boronic Acid/Catechol Binary Codes

et al. 2019

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The development of a synthetic code that enables a sequence programmable feature like DNA represents a key aspect toward intelligent molecular systems. We developed herein the well-known dynamic covalent interaction between boronic acids (BAs) and catechols (CAs) into synthetic nucleobase analogs. Along a defined peptide backbone, BA or CA residues are arranged to enable sequence recognition to their complementary strand. Dynamic strand displacement and errors were elucidated thermodynamically to show that sequences are able to specifically select their partners. Unlike DNA, the pH dependency of BA/CA binding enables the dehybridization of complementary strands at pH 5.0. In addition, we demonstrate the sequence recognition at the macromolecular level by conjugating the cytochrome c protein to a complementary polyethylene glycol chain in a site-directed fashion.

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“…Amongst these are drug carriers responding to internal stimuli, such as pH, ionic strength, and biomolecules. Drug delivery systems can be also responsive to external stimuli, like ultrasound, light, magnetic fields, or chemical agents [3,4,5,6,7,8,9,10,11]. Herein, we report on the possibility of utilizing biomolecules like enzymes to trigger a specific drug release.…”

Section: Introductionmentioning

confidence: 99%

Biocompatible Coatings from Smart Biopolymer Nanoparticles for Enzymatically Induced Drug Release

et al. 2018

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Nanoparticles can be used as a smart drug delivery system, when they release the drug only upon degradation by specific enzymes. A method to create such responsive materials is the formation of hydrogel nanoparticles, which have enzymatically degradable crosslinkers. Such hydrogel nanoparticles were prepared by ionotropic gelation sodium alginate with lysine-rich peptide sequences—either α-poly-L-lysine (PLL) or the aggrecanase-labile sequence KKKK-GRD-ARGSV↓NITEGE-DRG-KKKK. The nanoparticle suspensions obtained were analyzed by means of dynamic light scattering and nanoparticle tracking analysis. Degradation experiments carried out with the nanoparticles in suspension revealed enzyme-induced lability. Drugs present in the polymer solution during the ionotropic gelation can be encapsulated in the nanoparticles. Drug loading was investigated for interferon-β (IFN-β) as a model, using a bioluminescence assay with MX2Luc2 cells. The encapsulation efficiency for IFN-β was found to be approximately 25%. The nanoparticles suspension can be used to spray-coat titanium alloys (Ti-6Al-4V) as a common implant material. The coatings were proven by ellipsometry, reflection-absorption infrared spectroscopy, and X-ray photoelectron spectroscopy. An enzyme-responsive decrease in layer thickness is observed due to the degradation of the coatings. The Alg/peptide coatings were cytocompatible for human gingival fibroblasts (HGFIB), which was investigated by CellTiterBlue and lactate dehydrogenase (LDH) assay. However, HGFIBs showed poor adhesion and proliferation on the Alg/peptide coatings, but these could be improved by modification of the alginate with a RGD-peptide sequence. The smart drug release system presented can be further tailored to have the right release kinetics and cell adhesion properties.

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Dynamic Core–Shell Bioconjugates for Targeted Protein Delivery and Release

Cited by 12 publications

References 33 publications

Assembly of pH-Responsive Antibody-Inspired Protein-Drug Conjugates

Assembly of pH-Responsive Antibody-Inspired Protein-Drug Conjugates

Sequence Programming with Dynamic Boronic Acid/Catechol Binary Codes

Biocompatible Coatings from Smart Biopolymer Nanoparticles for Enzymatically Induced Drug Release

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