Development and Characterization of Pi-stacking Filamentous Polymeric Nanocarriers for Applications in NanomedicinePublic
Nanocarriers, structures with at least one dimension on the nanoscale (1-1000 nm), have been engineered for delivery of various cargoes. The shape and flexibility of nanocarriers are important parameters that influence their biological performance. Self-assembling polymeric filamentous nanocarriers, known as filomicelles (FM), are of great interest to nanomedicine due to their structural flexibility, extensive systemic circulation time, and amenability to unique “cylinder-to-sphere” morphological transitions for sustained drug delivery. FM self-assembled from the block copolymer poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) have great potential for drug delivery applications, particularly in immunomodulation. However, current fabrication techniques for FM self-assembly are highly variable and difficult to scale, and the impact on FM flexibility on nanocarrier uptake is not well-understood. In this work, I describe the development and characterization of a pi-stacking filamentous nanocarrier platform with controlled flexibility, enhanced stability, and scalable formation for drug delivery. First, I demonstrate that co-assembly of PEG-b-PPS diblocks with tetrablock copolymers composed of PEG-b-PPS linked by a pi-stacking perylene bisimide (PBI) moiety permits rapid, scalable, and facile assembly of FM with control over length and flexibility. Secondly, I found that the flexibility of filamentous nanocarriers can be optimized to decrease their internalization by macrophages in vitro, modulate their biodistribution on the cellular and organ level, and increase their systemic circulation times in vivo compared to (-)PBI-FM without PBI tetrablocks. Lastly, I investigated the potential utility of this FM nanocarrier platform in various biomedical applications, including passive targeting in a melanoma cancer model and as drug delivery vehicles for an anti-parasitic drug. Thus, my work shows that incorporation of pi-stacking allows for rapid, scalable assembly of FM with tunable flexibility and stability for applications in nanomedicine.
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