Project Description: Background: Polylactic acid-polyethylene glycol (PLA-PEG) block copolymers have been widely used to fabricate nanoparticle (NP) drug delivery vehicles due to their ability to self-assemble and facilitate prolonged circulation. The step growth chemistry of polymerization makes these materials challenging to chemically functionalize, as is desirable for targeting and/or tuning drug release kinetics. Herein, we assessed the drug delivery potential of brush-brush and linear-brush copolymer analogues of PLA-PEG, specifically incorporating poly(oligo(lactic acid) methacrylate) (POLAMA, PLA-mimetic) and/or poly(oligo(ethylene glycol) methacrylate) (POEGMA, PEG-mimetic) in one or both blocks, compared to linear PLA-PEG.
Methods: Activator regenerator by electron transfer (ARGET) ATRP were used to synthesize the copolymer analogues POEGMA-POLAMA and PLA-POEGMA. In vivo stability and biodistribution was assessed using BALB/c mice implanted with CT26 tumors. 10 days after implanting the tumor, mice were intravenously injected with Cy5-labelled NPs. The biodistribution of the nanoparticles as a function of block type was monitored at 2-, 8-, and 24-hour timepoints using an IVIS imaging system on various organs.
Results: Fabricated NPs ranged from 60-500 nm in size, with the size tunable based on the fabrication technique used (i.e. solvent type, mixer shear) and the block morphology/block length used for fabrication. The comonomer tert-butyl methacrylate (tBMA) was incorporated in varying ratios to either block, the subsequent hydrolysis can generate any number of derivatizable -COOH groups in either block; this represents a clear advantage over conventional PEG-PLA materials. Biodistribution studies showed significant concentrations of NPs in the tumor, liver, and kidneys, with PLA-POEGMA NPs showing significant accumulation between the 2 and 24 hour timepoints compared to the PEG-PLA control.
Conclusions: PLA-PEG brush copolymer analogues prepared through ATRP or ARGET ATRP are viable alternatives to their linear counterparts while providing superior tunability. NPs fabricated from PLA-PEG analogues have been shown to be cytocompatible and can bioaccumulate in tumors without any modification."