9 research outputs found
The Transferability from Animal Models to Humans: Challenges Regarding Aggregation and Protein Corona Formation of Nanoparticles
Nanomaterials
are interesting candidates for applications in medicine
as drug delivery or diagnostic agents. For safe application, they
have to be evaluated in in vitro and in vivo models to finally be
translated to human clinical trials. However, often those transfer
processes fail, and it is not completely understood whether in vitro
models leading to these animal models can reliably be compared to
the situation in humans. In particular, the interaction of nanomaterials
with components from different blood plasma sources is difficult to
compare, and the outcomes of those interactions with respect to body
distribution and cell uptake are unclear. Therefore, we investigated
the interactions of differently functionalized polymeric and inorganic
nanoparticles with human, mouse, rabbit, and sheep plasma. The focus
was put on the determination of aggregation events of the nanoparticles
occurring in concentrated plasma and the correlation with the respectively
formed protein coronas. Both the stability in plasma as well as the
types of adsorbed proteins were found to strongly depend on the plasma
source. Thus, we suggest evaluating the potential use of nanocarriers
always in the plasma source of the chosen animal model for in vitro
studies as well as in human plasma to pin down differences and eventually
enable transfer into clinical trials in humans
The Transferability from Animal Models to Humans: Challenges Regarding Aggregation and Protein Corona Formation of Nanoparticles
Nanomaterials
are interesting candidates for applications in medicine
as drug delivery or diagnostic agents. For safe application, they
have to be evaluated in in vitro and in vivo models to finally be
translated to human clinical trials. However, often those transfer
processes fail, and it is not completely understood whether in vitro
models leading to these animal models can reliably be compared to
the situation in humans. In particular, the interaction of nanomaterials
with components from different blood plasma sources is difficult to
compare, and the outcomes of those interactions with respect to body
distribution and cell uptake are unclear. Therefore, we investigated
the interactions of differently functionalized polymeric and inorganic
nanoparticles with human, mouse, rabbit, and sheep plasma. The focus
was put on the determination of aggregation events of the nanoparticles
occurring in concentrated plasma and the correlation with the respectively
formed protein coronas. Both the stability in plasma as well as the
types of adsorbed proteins were found to strongly depend on the plasma
source. Thus, we suggest evaluating the potential use of nanocarriers
always in the plasma source of the chosen animal model for in vitro
studies as well as in human plasma to pin down differences and eventually
enable transfer into clinical trials in humans
Zirconium oxocluster/polymer hybrid nanoparticles prepared by photoactivated miniemulsion copolymerization
The photoactivated free radical miniemulsion copolymerization of methyl methacrylate (MMA) and the zirconium oxocluster Zr4O2(methacrylate)12 is used as an effective and fast preparation method for polymer/inorganic hybrid nanoparticles. The oxoclusters, covalently anchored to the polymer network, act as metal-organic cross-linkers, thus improving the thermomechanical properties of the resulting hybrid nanoparticles. Benzoin carbonyl organic compounds were used as photoinitiators. The obtained materials are compared in terms of cross-linking, effectiveness of cluster incorporation, and size distribution with the analogous nanoparticles produced by using conventional thermally induced free radical miniemulsion copolymerization. The kinetics of the polymerization process in the absence and in the presence of the oxocluster is also investigated
Targeting Cancer Chemotherapy Resistance by Precision Medicine-Driven Nanoparticle-Formulated Cisplatin
Therapy resistance is the major cause of cancer death. As patients respond heterogeneously, precision/personalized medicine needs to be considered, including the application of nanoparticles (NPs). The success of therapeutic NPs requires to first identify clinically relevant resistance mechanisms and to define key players, followed by a rational design of biocompatible NPs capable to target resistance. Consequently, we employed a tiered experimental pipeline from in silico to analytical and in vitro to overcome cisplatin resistance. First, we generated cisplatin-resistant cancer cells and used next-generation sequencing together with CRISPR/Cas9 knockout technology to identify the ion channel LRRC8A as a critical component for cisplatin resistance. LRRC8A’s cisplatin-specificity was verified by testing free as well as nanoformulated paclitaxel or doxorubicin. The clinical relevance of LRRC8A was demonstrated by its differential expression in a cohort of 500 head and neck cancer patients, correlating with patient survival under cisplatin therapy. To overcome LRRC8A-mediated cisplatin resistance, we constructed cisplatin-loaded, polysarcosine-based core cross-linked polymeric NPs (NPCis, Ø ∼ 28 nm) with good colloidal stability, biocompatibility (low immunogenicity, low toxicity, prolonged in vivo circulation, no complement activation, no plasma protein aggregation), and low corona formation properties. 2D/3D-spheroid cell models were employed to demonstrate that, in contrast to standard of care cisplatin, NPCis significantly (p < 0.001) eradicated all cisplatin-resistant cells by circumventing the LRRC8A-transport pathway via the endocytic delivery route. We here identified LRRC8A as critical for cisplatin resistance and suggest LRRC8A-guided patient stratification for ongoing or prospective clinical studies assessing therapy resistance to nanoscale platinum drug nanoformulations versus current standard of care formulations