Overcoming drug delivery barriers to Unlock the therapeutic potential of conventional chemotherapy in glioblastoma.

Glioblastoma (GBM) remains one of the most incurable malignancies, and systemic therapies continue to provide only limited clinical benefit despite encouraging preclinical evidence. Therapeutic failure has traditionally been attributed to insufficient drug efficacy or intrinsic resistance mechanisms. However, increasing evidence suggests that many conventional chemotherapeutic agents retain substantial antitumor activity but fail to achieve sufficient intratumoral exposure because of delivery barriers. This review proposes that inadequate drug delivery represents a major barrier limiting the therapeutic efficacy of conventional chemotherapeutics in GBM, independent of their intrinsic pharmacodynamic activity. We re-evaluate conventional chemotherapeutic agents, including alkylating agents, microtubule-targeting agents, topoisomerase inhibitors, and platinum compounds, from the perspective of blood-brain barrier (BBB) transport, heterogeneous intratumoral drug distribution, and dose-limiting systemic toxicity. We further discuss how emerging drug delivery strategies can restore the therapeutic potential of these agents by improving brain penetration and intratumoral distribution without altering their intrinsic pharmacological properties.By reframing chemotherapy failure in GBM as a consequence of both pharmacodynamic resistance and inadequate drug delivery, this Review highlights drug delivery as an underappreciated determinant of therapeutic efficacy.