Apoorvi Chaudhri, Molli Garifo, Pranavi Thatavarthi, Torrick Fletcher, Jessica Larsen
Glioblastoma represents a highly aggressive brain tumor with low survival and no response to chemotherapy and radiation therapy. Temozolomide, the current standard of care chemotherapy, improves patient survival by only about 6 months because of several resistance mechanisms, including unmethylated MGMT, which enables repair of chemotherapy-induced DNA damage. Thus, additional treatment strategies are necessary to investigate efficient responses towards glioblastoma. Doxorubicin (DOX) is a chemotherapeutic agent that is independent of MGMT methylation and instead works through inhibition of topoisomerase (TOPO) II, an enzyme necessary for DNA replication of the tumor. The inability of doxorubicin to cross the blood-brain barrier (BBB) precludes its use in glioblastoma. Polymersome nanoparticles have the potential to transport agents across the BBB. Here, we develop hyaluronic acid-b-polylactic acid (HA-PLA) polymeric nanoparticles called polymersomes, encapsulate them with DOX and investigate the ability of our system to induce apoptosis in a human glioblastoma cell line. HA-PLA polymersomes encapsulated with DOX at 6 µg mL-1 showed an encapsulation efficiency of 99 ± 1% and a PDI of 0.70 ± 0.02 with diameter of 122.1 ± 2.9 nm, with encapsulation efficiency decreasing and diameter increasing as additional DOX is added. Release studies showed an increase in DOX released from HA-PLA-based polymersomes due to acid-mediated hydrolysis of the PLA ester bonds. The HA-PLA polymersomes show specificity and receptor-mediated endocytosis towards CD44-positive U87 glioblastoma cells with ∼42% uptake due to the natural affinity of HA (hyaluronic acid) to CD44. This receptor-mediated and additional mode of endocytosis was greatly stunted at 4 °C. Jurkat cells that are CD44 negative did not show uptake. Our HLA-PLA-DOX system promotes apoptosis of glioblastoma through inhibition of topoisomerase (TOPO) II. Thus, our system could allow tumor specificity through HA-CD44 affinity and slow drug release through pH sensitivity of PLA in the acidic tumor microenvironment.