![]() ![]() Successful clinical deployment of DOX-containing constructs for treating CNS malignancies may have also been compromised by the predominant use of models with limited clinical relevance-either using in vitro systems or human GBM xenografts (i.e., U87, U251 refs. The composition of different DOX-encapsulated nanocarriers, as well as free DOX and other selected therapies, used to treat high-grade gliomas, brain metastases, and other solid tumors are summarized in Supplementary Table S1. ![]() For instance, DOX has been encapsulated in a variety of large organic nanocarriers (e.g., liposomes) for the treatment of patients with malignant brain tumor but, in many cases, has shown only modest increases in overall survival ( 11, 12). In this regard, DOX is exemplary of a class of small-molecule drugs that would benefit from the design and advancement of newer-generation drug delivery systems that can be engineered to better navigate complex biological barriers and improve therapeutic efficacy in highly aggressive CNS cancers, which remains a critically important unmet need.Īlthough extensive efforts have led to the development of a diverse array of both clinical and preclinical nanocarrier-based drug delivery systems ( 10), the vast majority of these systems are relatively large in size (i.e., at least 60 nm), which limits their uniform delivery, penetration, diffusion, and accumulation within the tumor interstitium this results in only local responses following their extravasation and concentration along vessel walls ( 11). Potent cytotoxicity of DOX in gliomas has been confirmed in experimental studies leading to significant interest in its clinical potential and efforts to overcome a combination of poor BBB penetrance and narrow therapeutic window ( 8, 9). The anthracycline, doxorubicin (DOX), used in this work, exhibits anti-neoplastic properties against a broad spectrum of tumor types (e.g., breast, lung, sarcoma), but its clinical use is limited by cardiotoxicity, bone marrow depression, nephrotoxicity, and other adverse effects ( 7). These factors contribute to an insufficient therapeutic window between efficacy and dose-limiting toxicities (DLT). In addition to intra- and intertumoral heterogeneity promoting resistance and eventual recurrence ( 4), a principal challenge leading to central nervous system (CNS) treatment failures has been the reduced transport of potentially effective small-molecule drugs (i.e., chemotherapies) across the blood–brain barrier (BBB) and blood–tumor barriers ( 5, 6) accompanied by marked reductions in tumor tissue penetration, diffusion, and accumulation of such drugs. ![]() Despite considerable efforts to develop new classes of small-molecule drugs, prospects for patients with such aggressive tumors have not improved for decades, with approximately 7% of patients surviving 5 years after diagnosis ( 3). Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor prognosis and few available treatment options ( 1, 2). ![]()
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