Particle Integrity and Size Effect on the Journey of Polymeric Nanocarriers in Zebrafish Model and the Correlation with Mice

Abstract

block (polyethylene glycol (PEG)) and hydrophobic block (such as polycaprolactone (PCL), poly lactic-co-glycolic acid, and poly-d,l-lactic acid) have promising applications to deliver water-insoluble drugs owing to their stealth shell-hydrophobic core structure. However, to date, only a few polymeric NCs (excluding biologics) were approved in clinics, such as GenexolPM/Cynviloq (Samyang Biopharm), Nanoxel (Fresenius Kabi), and Apealea/Paclical (Oasmia Pharmaceuticals). [2] There exists a large gap from basic research to the clinical transformation of polymeric NCs because they cannot offer a significantly improved therapeutic benefit over the free drug. [3][4][5] Once entering the blood circulation, polymeric NCs will face a complex biological environment (e.g., dilution, shear force, and protein adsorption) and various plasma components, which will dramatically affect their biofate. [4] Polymeric NCs may lose their integrity in blood circulation. Intact polymeric NCs may be recognized and rapidly sequestered by reticuloendothelial system (RES) and further eliminated from the systemic circulation. However, due to the lack of sufficient understanding of their biofate and parameters that could regulate in vivo processes, the behaviors of polymeric NCs in vivo could not be well controlled, resulting in unsatisfactory therapeutic benefit.Moreover, the in vivo characterization and optimization of NCs are also challenging in early formulation development in the absence of a proper screening model. The in vivo fate of polymeric NCs not only depends on the biological environment but also relies on their physicochemical properties, such as particle size, shape, surface modification, and charge, which offer enormous possibilities for formulation optimization. [3,6,7] Although in vitro cell models are conventional drug screening tools, they cannot completely reflect or mimic the in vivo biological environment, resulting in formulations screened in cell models that might not work in rodent models. [8] Moreover, rodent experiments are time-consuming and costly, failing to assess a large number of formulations in a short time. Thus, there exists an urgent demand for a suitable preclinical model Polymeric nanocarriers have high biocompatibility for potential drug delivery applications. After entering bloodstream, nanocarriers will circulate, interact with proteins, dissociate, or be cleared by reticuloendothelial system. Zebrafish as a visual animal model, can serve as a tool for screening nanomedicines and monitoring nanocarrier behaviors in vivo. However, a comprehensive correlation between zebrafish and rodent models is currently deficient. Here, different-sized poly(caprolactone) nanocarriers (PCL NCs) are fabricated with or without PEGylation to investigate correlation between zebrafish and mice regarding their biofate via Förster resonance energy transfer technique. Results show that PEGylated PCL NCs have higher integrity in both zebrafish and mice. Small PEG-PCL NCs have longer circulation, while large PEG-PCL NCs have ...

Apoptosis-Sensing Xenograft Zebrafish Tumor Model for Anticancer Evaluation of Redox-Responsive Cross-Linked Pluronic Micelles

“…It was demonstrated that the CPPMs had higher integrity and a longer circulation time than OPPMs in the zebrafish larva model. 21 The long circulation of Dox CPPMs could increase their exposure time and opportunity in the tumor site. Here, we further established the B16F10 xenograft zebrafish tumor model to evaluate their tumor delivery and anti-cancer effect, which provided the in vivo reductive (GSH) tumor microenvironment.…”

“…16−22 We also established the comprehensive correlation between zebrafish and mice models regarding the biofate of polymeric nanocarriers in vivo. 21 However, most of the studies were performed on the normal zebrafish model to evaluate the biological properties and behaviors of nanomedicines in vivo. Few studies worked on the evaluation of nanomedicines on the zebrafish disease models, which could better reflect the true effects in the physiological environment of the disease.…”

FRET Ratiometric Nanoprobes for Nanoparticle Monitoring

“…In contrast, rat serum destabilized the NCs dramatically, as indicated by the rapid decrease in the FRET ratio from 0.46 at 1 min to 0.42 at 30 min (large PCL NCs). Consistently, most of the large PCL NCs quickly dissociated in zebrafish at 1 h post injection, while the large PEG-PCL NCs and small PEG-PCL NCs retained much higher integrity [ 58 ]. FRET imaging combined with zebrafish has also been used to study the in vivo behaviours of polymeric micelles using a co-loaded FRET pair, DiO and DiI [ 35 ].…”

“…Tao et al attempted to correlate the NP elimination in zebrafish with rodents. They synthesized poly(caprolactone) nanocarriers (PCL NCs) with or without PEGylation using FRET [ 58 ]. A FRET pair, DiO and DiI, was co-encapsulated into the PCL NCs to study the NC stability ( Figure 7 ).…”

Responsive Hydrogels Based on Triggered Click Reactions for Liver Cancer

“…Polymeric micelles have high biocompatibility for potential drug delivery applications. [ 83 ] On the one hand, achieving spatially structures is to utilize amphiphilic copolymers with one or two macromolecular backbones so that they can self‐assemble in solution. [ 84 ] Nanocomposite responsive hydrogels are usually hydrated polymeric interactions, so most are assembled through noncovalent linkages or covalent bonds.…”