Block Co-polymer Nanoparticles with Degradable Cross-Linked Core and Low-Molecular-Weight PEG Corona for Anti-tumour Drug Delivery

Biodegradable/bioeliminable, core-cross-linked, block co-polymer nanoparticles have been synthesized as a potential anti-tumour drug-delivery system. Methacrylate-modified poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-b-PDLLA) composed of low-molecular-weight polymer blocks (<5 kg/mol) were synthesized by ring-opening polymerization and post-polymerization chemical modifications. Nanoparticles with a diameter of 110 +/- 20 nm were formed from methacryl ate-modified PEG(45)-b-PDLLA(41) in a THF/water mixture (1:3). The particles were then core-cross-linked using a new, highly acid-labile ketal cross-linker. The cross-linked particles had a hydrodynamic diameter of 104 +/- 20 nm (in THF/water, 1:3), as determined by :DLS. The particles in THF exhibited a similar hydrodynamic diameter. Doxorubicin as a model anti-tumour drug was loaded into the nanoparticles (25-31 wt%). The particles released 50% of the loaded drug slowly approximately in 2 days at pH 5.5 and in 5 days at pH 7.4. The particles degraded to bioeliminable polymer fragments (<40 kg/mol) after the hydrolysis of the ketal cross-links at pH 5.5 in seven days, as determined by GPC. Doxorubicin-loaded cross-linked particles (9.3 mu M doxorubicin/2.5 mu M polymer) inhibited the viability of human neuroblastoma SH-EP cells, whilst the particles without drug at the same concentration were non-toxic, as determined by an Alamar Blue assay. Flow cytometry experiments revealed that the doxorubicin-loaded cross-linked particle.; were taken up by SH-EP cells in quantities comparable with free doxorubicin. Overall the results support the value of the cross-linked particles for further investigation as a carrier for anti-tumour drugs. (c) Koninklijke Brill NV, Leiden, 2011