Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles

Abstract

Effective treatment for glioblastoma (GBM) is limited by the presence of the blood–brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1.5- to 2-fold decrease in tumor burden and corresponding increase in survival compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to gliomas and other central nervous system tumors.

Intelligent Nanocomposites with Intrinsic Blood–Brain‐Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma

“…to the cerebrum, thereby compromising the outcomes of diagnosis and therapy . With the increasing development of nanomaterials, receptor‐mediated transcytosis (RMT) has become one of the most promising protocols to overcome the BBB through receptors that are highly expressed on BBB endothelial cells, among which transferrin receptor (TfR) is a promising candidate . Moreover, TfR is also present in substantial quantities on GBM cells due to their high proliferation rate and iron demand .…”

“…Correspondingly, transferrin (Tf), an important glycoprotein in the human body, has been extensively employed to traverse the BBB owing to its ability to combine with TfR to form the Tf‐TfR complex . In those studies, Tf has mostly served only as the targeting moiety by modification onto the surface of nanocarriers, such as liposomes, poly‐ l ‐lysine, PLGA, and Au nanoparticles . However, the complicated fabrication procedures and unavoidable latent immunogenicity of exogenous nanocarriers, among other inevitable issues, seriously impede their further applications.…”

Harnessing CURATE.AI as a Digital Therapeutics Platform by Identifying N‐of‐1 Learning Trajectory Profiles

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] Conventional approaches toward therapeutic intervention, both pharmacologic www.advancedsciencenews.com www.advtherap.com they can lead to the incorrect presumption that if a subject did not respond to a given intervention, they would never respond to that intervention. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] Conventional approaches toward therapeutic intervention, both pharmacologic www.advancedsciencenews.com www.advtherap.com they can lead to the incorrect presumption that if a subject did not respond to a given intervention, they would never respond to that intervention.…”

Harnessing an Artificial Intelligence Platform to Dynamically Individualize Combination Therapy for Treating Colorectal Carcinoma in a Rat Model

“…This is due to the fact that drug synergy is dose dependent and as such, delivering what are perceived to be suitable drugs at the wrong dose ratios can lead to suboptimal responses . Promising strategies to design novel drug combinations have included pairwise drug predictions, systems biology‐guided drug combination design, as well as ex vivo and disease modeling approaches, among others, in an effort to estimate how diseased systems will respond to multi‐drug inputs . Furthermore, delivering drugs that may have never been considered at the right dose ratios can lead to treatment responses that markedly exceed conventional regimens .…”