Versatile and Finely Tuned Albumin Nanoplatform based on Click Chemistry

Abstract

Albumin is one of the most attractive nanoplatforms for targeted imaging and drug delivery due to its biocompatibility and long circulation half-life. However, previously reported albumin-based nanoplatforms have shown inconsistent blood circulation half-life according to the modified methods, and the affecting factors were not well evaluated, which could hamper the clinical translation of albumin-based nanoplatforms. Herein, we developed a finely tuned click-chemistry based albumin nanoplatform (CAN) with a longer circulation half-life and an efficient tumor targeting ability. Methods: CAN was synthesized in two steps. First, albumin was conjugated with ADIBO-NHS (albumin-ADIBO) by reacting albumin with various molar ratios of ADIBO. The number of attached ADIBO moieties was determined using matrix-assisted laser desorption ionization time of flight (MALDI-TOF). Second, the desired modalities including azide-functionalized chelator, a fluorescence dye, and folate were incorporated into albumin-ADIBO using strain-promoted alkyne-azide cycloaddition reaction (SPAAC reaction). The biodistribution and targeting efficiency of functionalized CANs were demonstrated in mice. Results: The degree of functionalization (DOF) and resulting in vivo biodistribution was controlled precisely using the click chemistry approach. Specifically, the numbers of attached azadibenzocyclooctyne (ADIBO) moieties on albumin, the DOF, were optimized by reacting albumin with varying molar ratios of ADIBO with a high reproducibility. Furthermore, we developed a simple and efficient method to estimate the DOF using UV - visible spectrophotometry (UV-vis), which was further validated by matrix-assisted laser desorption ionization time of flight (MALDI-TOF). The biodistribution of CAN could be controlled by DOF, and CAN with an optimized DOF showed a long circulation half-life (> 18 h). CAN was further functionalized using a simple click chemistry reaction with an azide functionalized chelator, a fluorescence dye, and folate. 64 Cu- and folate-labeled CAN ( 64 Cu-CAN-FA) showed effective and specific folate receptor targeting in vivo , with an over two-fold higher uptake than the liver at 24 h post-injection. Conclusions: Our development from the precisely controlled DOF demonstrates that an optimized CAN can be used as a multifunctional nanoplatform to obtain a longer half-life with radioisotopes and ligands, and provides an effective method for the development of albumin-based tumor theranostic agents.

Anti-Angiogenic Therapy: Albumin-Binding Proteins Could Mediate Mechanisms Underlying the Accumulation of Small Molecule Receptor Tyrosine Kinase Inhibitors in Normal Tissues with Potential Harmful Effects on Health

“…Studies on healthy rats have shown that [ 68 Ga]ABY-028, an albumin-binding domain protein-based imaging tracer for positron emission tomography, binds in vivo to albumin, acquires albumin circulatory behavior, and accumulates in liver, spleen, and in muscle tissues [ 75 ]. Similar data were published by Park and collaborators [ 76 ] who noticed effective accumulation of 64 [Cu]-labeled-click chemistry-based albumin nanoplatform conjugates in normal lung, liver, kidney, intestine, and heart with an over four-fold higher uptake than the tumor at 1 h post-injection. Zhong and collaborators [ 77 ] showed effective accumulation of anlotinib (an oral RTKI targeting VEGFR, PDGFR, FGFR, and c-Kit; Table 1 ) in female tumor-bearing mice.…”

Secreted protein acidic and rich in cysteine mediates active targeting of human serum albumin in U87MG xenograft mouse models

“…We conjugated HSA with FNR648 fluorescence dye following the procedure described in our previous publication 55.…”

<p>Bone-Targeted Extracellular Vesicles from Mesenchymal Stem Cells for Osteoporosis Therapy</p>

“…It’s commonly used in synthesis of functional polymers, cell markers, and biomedical synthesis. 20 , 21 Stefanucci Azzurra’s team reported a new enkephalin analogue with great analgesic, which was constructed via “click chemistry”; 22 Lee’s team used copper-free “click chemistry” to combine growth factors with collagen. 23 “Click chemistry” is a powerful synthetic tool in the discovery of new drugs.…”