Pretargeted Polymeric Systems for Conducting Chemo-Radiotherapy on Glioblastoma: An Evaluation of the Impact of Nanomedicine Structure on Bioorthogonal Chemistry In Vivo

This study developed a nanoscaled system combining chemotherapeutic (Temozolomide, TMZ) and radionuclide (¹⁷⁷Lu) for targeted glioblastoma (GBM) treatment. Bioorthogonal click chemistry was utilized to produce a selective delivery platform, and the impacts of nanomedicine structure on the efficiency of bioorthogonal reactions were explored in vivo. This was achieved by developing two parallel polymers with trans-cyclooctene (tCO) in positions differing in terms of the accessibility to the tetrazine-containing moiety. Both in vitro assessment of reaction kinetics and the in vivo distribution behavior demonstrated that tCO conjugated at the chain end of the polymer (PTtCOext) instead of those within chains (PTtCOint) exhibited better accessibility to the tetrazine-modified material ([¹⁷⁷Lu]Lu-DPT). This then led to a more efficient click reaction in vivo and higher ¹⁷⁷Lu accumulation in the tumor. This study provides key information on design considerations for optimal positioning of bioorthogonal reactive species in nanomedicine and a potential treatment approach for GBM.