Bioactive Phosphorus Dendrimers as a Universal Protein Delivery System for Enhanced Anti-inflammation Therapy

Abstract

Nanocarrier-based cytoplasmic protein delivery offers opportunities to develop protein therapeutics; however, many delivery systems are positively charged, causing severe toxic effects. For enhanced therapeutics, it is also of great importance to design nanocarriers with intrinsic bioactivity that can be integrated with protein drugs due to the limited bioactivity of proteins alone for disease treatment. We report here a protein delivery system based on anionic phosphite-terminated phosphorus dendrimers with intrinsic anti-inflammatory activity. A phosphorus dendrimer termed AK-137 with optimized anti-inflammatory activity was selected to complex proteins through various physical interactions. Model proteins such as bovine serum albumin, ribonuclease A, ovalbumin, and fibronectin (FN) can be transfected into cells to exert their respective functions, including cancer cell apoptosis, dendritic cell maturation, or macrophage immunomodulation. Particularly, the constructed AK-137@FN nanocomplexes display powerful therapeutic effects in acute lung injury and acute gout arthritis models by integrating the anti-inflammatory activity of both the carrier and protein. The developed anionic phosphite-terminated phosphorus dendrimers may be employed as a universal carrier for protein delivery and particularly utilized to deliver proteins and fight different inflammatory diseases with enhanced therapeutic efficacy.

Brain Delivery of Biomimetic Phosphorus Dendrimer/Antibody Nanocomplexes for Enhanced Glioma Immunotherapy via Immune Modulation of T Cells and Natural Killer Cells

“…It is noteworthy that the size of the AK128-aPD1@M1m NCs measured by TEM is smaller than their hydrodynamic size, measured by dynamic light scattering (DLS). It is likely due to the fact that TEM measures the size of single AK128-aPD1@M1m NCs in a dry state, while DLS measures the hydrodynamic size of the NCs in aqueous solution, which usually reflects a certain degree of aggregation of single particles …”

“…Efficient release of aPD1 from the AK128-aPD1@M1m NCs is necessary to exert its functions. Then, we attempted to illustrate the possible mechanism of protein release by investigating the hydrodynamic size change of the NCs at different pHs. , As shown in Figure S3A, two peaks appear in the hydrodynamic size distribution histogram of the AK128-aPD1 NCs at pH 6.5 (simulated tumor microenvironment), which is very different from that at pH 7.4. This may be because the pH affects the weak interaction forces between phosphorus dendrimers and aPD1.…”

“…What’s more, phosphite-terminated anionic phosphorus dendrimers have been proven to be a universal protein delivery system, since they possess terminal phosphate anionic groups and a benzene ring-rich branched scaffold structure, and can complex proteins through electrostatic interaction, hydrogen bonding, cation-Π, and hydrophobic interaction. This is because the guanidinium or amino groups of proteins can electrostatically interact phosphate groups of phosphorus dendrimers, the phenyl of phosphorus dendrimers and aromatic amino acids of protein may be π–π stacked in aqueous solution, hydrogen bonding between phosphorus dendrimer and proteins may exist, and the remaining positively or negatively charged side chains of proteins can interact with the benzene ring of phosphorus dendrimers through ionic-π interactions .…”

Phosphorus-Based Nanomaterials for Biomedical Applications: A Review

“…As a representative of p-type direct bandgap semiconductors, BLK-P exhibits unique physical properties (Figure a). These include high carrier mobility (∼10 3 cm 2 /(V s) at room temperature), an adjustable bandgap width ranging from 0.3 to 2.0 eV based on the number of layers, a spectral response covering the visible to mid-infrared region, strong light-matter interactions, and distinctive intraplanar anisotropy in optical and electrical properties. , BLK-P has demonstrated significant potential for use in transistors, mid-infrared optoelectronic devices, optical communications, and highly sensitive thermal imaging. , Consequently, BLK-P, as a potential biomedical functional material with excellent biocompatibility and degradability, offers unique advantages for biomedical applications. , However, BLK-P is not stable enough and the precise structure is difficult to regulate …”

“…A study developed a protein delivery system using a phosphorus dendritic polymer capped with an anionic phosphite. This system can serve as a versatile carrier for delivering proteins, particularly for addressing various inflammatory diseases with improved therapeutic effectiveness . BLK-P quantum dots (BPQDs) were incorporated into polyethylene glycol-modified chitosan nanospheres containing the antibiotic amikacin, termed PEG@CS/BPQDs-AM NPs.…”