The effect of surface PEGylation on nanoparticle transport through an extracellular matrix (ECM) is an important determinant for tumor targeting success. Fluorescent stealth liposomes (base lipid DOPC) were prepared incorporating different proportions of PEG-grafted lipids (2.5, 5 and 10% of the total lipid content) for a series of PEG molecular weights (1000, 2000 and 5000 Da). The ECM was modelled using a collagen matrix. The kinetics of PEGylated liposome adhesion to and transport in collagen matrices were tracked using fluorescence correlation spectroscopy (FCS) and confocal microscopy, respectively.Generalized least square regressions were used to determine the temporal correlations between PEG molecular weight, surface density and conformation, and the liposome transport in a collagen hydrogel over 15 hours. PEG conformation determined the interaction of liposomes with the collagen hydrogel and their transport behaviour. Interestingly, liposomes with mushroom PEG conformation accumulated on the interface of the collagen hydrogel, creating a dense liposomal front with short diffusion distances into the hydrogels. On the other hand, liposomes with dense brush PEG conformation interacted to a lesser extent with the collagen hydrogel and diffused to longer distances. In conclusion, a better understanding of PEG surface coating as a modifier of transport in a model ECM matrix has resulted. This knowledge will improve design of future liposomal drug carrier systems.
Nanoparticles are engineered from materials such as metals, polymers, and different carbon allotropes that do not exist within the body. Exposure to these exogenous compounds raises concerns surrounding toxicity, inflammation, and immune activation. These responses could potentially be mitigated by synthesizing nanoparticles directly from molecules derived from the host. However, efforts to assemble patient-derived macromolecules into structures with the same degree of size and shape tunability as their exogenous counterparts remains a significant challenge. Here we solve this problem by creating a new class of size-and shape-tunable personalized protein nanoparticles (PNP) made entirely from patient-derived proteins. PNPs are built into different sizes and shapes with the same degree of tunability as gold nanoparticles. They are biodegradable and do not activate innate or adaptive immunity following single and repeated administrations in vivo. PNPs can be further modified with specific protein cargos that remain catalytically active even after intracellular delivery in vivo. Finally, we demonstrate that PNPs created from different human patients have unique molecular fingerprints encoded directly into the structure of the nanoparticle. This new class of personalized nanomaterial has the potential to revolutionize how we treat patients and can become an integral component in the diagnostic and therapeutic toolbox.
A nanoparticle can hold multiple
types of therapeutic and imaging
agents for disease treatment and diagnosis. However, controlling the
storage of molecules in nanoparticles is challenging, because nonspecific
intermolecular interactions are used for encapsulation. Here, we used
specific DNA interactions to store molecules in nanoparticles. We
made nanoparticles containing DNA anchors to capture DNA-conjugated
small molecules. By changing the sequences and stoichiometry of DNA
anchors, we can control the amount and ratio of molecules with different
chemical properties in the nanoparticles. We modified the cytotoxicity
of our nanoparticles to cancer cells by changing the ratio of encapsulated
drugs (mertansine and doxorubicin). Specifically controlling the storage
of multiple types of molecules allows us to optimize the properties
of combination drug and imaging nanoparticles.
Nanoparticles travel through blood
vessels to reach disease sites,
but the local environment they encounter may affect their surface
chemistry and cellular interactions. Here, we found that as nanoparticles
transit through injured blood vessels they may interact with a highly
localized concentration of platelet factor 4 proteins released from
activated platelets. The platelet factor 4 binds to the nanoparticle
surface and interacts with heparan sulfate proteoglycans on endothelial
cells, and induces uptake. Understanding nanoparticle interactions
with blood proteins and endothelial cells during circulation is critical
to optimizing their design for diseased tissue targeting and delivery.
Nanobio interaction studies have generated a significant
amount
of data. An important next step is to organize the data and design
computational techniques to analyze the nanobio interactions. Here
we developed a computational technique to correlate the nanoparticle
spatial distribution within heterogeneous solid tumors. This approach
led to greater than 88% predictive accuracy of nanoparticle location
within a tumor tissue. This proof-of-concept study shows that tumor
heterogeneity might be defined computationally by the patterns of
biological structures within the tissue, enabling the identification
of tumor patterns for nanoparticle accumulation.
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