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

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 <i>in vivo</i>. This was achieved by developing two parallel polymers with <i>trans</i>-cyclooctene (<i>t</i>CO) in positions differing in terms of the accessibility to the tetrazine-containing moiety. Both <i>in vitro</i> assessment of reaction kinetics and the <i>in vivo</i> distribution behavior demonstrated that <i>t</i>CO conjugated at the chain end of the polymer (PT<i>t</i>CO_ext) instead of those within chains (PT<i>t</i>CO_int) exhibited better accessibility to the tetrazine-modified material ([¹⁷⁷Lu]Lu-DPT). This then led to a more efficient click reaction <i>in vivo</i> 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.