Drug nanocarrier clearance by the immune system must be mitigated in order to achieve targeted delivery to pathological tissues. We present two parts to the problem: first, the relationship between nanoparticle block copolymer chemistry and passivation against non-specific recognition and clearance; and second, how conjugation to the surface of the nanoparticle can effect targeting.  We have produced hydrophobic nanocarriers with dense PEG layers resulting from block-copolymer-directed assembly during rapid precipitation. Nanocarriers were formed using block copolymers with hydrophobic anchor blocks of polystyrene (PS), poly-e-capralactone (PCL), poly-d,l-lactide (PLA), or poly-lactide-co-glycolide (PLGA), and hydrophilic blocks of polyethylene glycol (PEG) with various molecular weights, from 1.5 kg/mol to 9 kg/mol. Nanocarriers with paclitaxel prodrugs were evaluated in vivo in Foxn 1 nu mice to determine relative rates of clearance, and in vitro complement activation assays were conducted in an effort to correlate the protection of the nanocarrier surface with in vivo circulation. Guidelines for optimizing block copolymer structure to maximize circulation of nanocarriers formed were proposed, relating to the relative size of the hydrophilic and hydrophobic block, the hydrophobicity of the anchoring block, the absolute size of the PEG block, and secondary consideration such as polymer crystallization. The second aspect of the presentation is on targeting. A fraction of PEG chains on the nanoparticle surface can be conjugated with targeting ligands, including small molecules (mannose to target to TB infected macrophages), peptide sequences (LHRH for breast cancer), and full antibodies (anti-EGFR mAb C225). The reactivity of different size ligands onto the PEG brush layer poses interesting challenges to understanding reactions in constrained media. Furthermore, the targeting efficiency is shown to not be a simple function of the density of the ligand on the nanoparticle surface. This opens interesting questions about the role of ligand and receptor density on binding and uptake.

Effects of block copolymer properties on nanocarrier protection from in vivo clearance and targeting

245th National Meeting (2013)

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