Ultrasmall Nanoparticle Delivery of Doxorubicin Improves Therapeutic Index for High-Grade Glioma.
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ABSTRACT: Purpose
Despite dramatic growth in the number of small-molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (<8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C' dots), for the efficacious treatment of high-grade gliomas.Experimental design
This work presents first-in-kind renally clearable ultrasmall (<8 nm) multimodal C' dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models.Results
Optimal drug-per-particle ratios of as-developed nanoparticle-drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor-driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model.Conclusions
Ultrasmall C' dot-drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.
SUBMITTER: Aragon-Sanabria V
PROVIDER: S-EPMC9250642 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPrevious studies have shown that endogenous T cells play an important role in the prolonged survival time of high-grade glioma (HGG) patients. Our objectives were to investigate the features of T-cell receptor (TCR) repertoires in HGG patients and to elucidate any potential therapeutic value.MethodsDuring November 2011 and December 2018, tumor tissues and blood samples of 35 patients with HGG who underwent surgery at Beijing Tiantan Hospital or Beijing Shijitan Hospital were selected after surgery. After isolating DNA from samples, multiple rounds of PCR were performed to establish a DNA immune repertoire (IR). Then, the sequences and frequencies of the complementarity-determining 3 (CDR3) region in TCR beta chain (TRB) were identified by high-throughput sequencing and IR analysis. A survival follow-up was conducted monthly thereafter until December 2018. Finally, the t test and Mann-Whitney test were used to compare statistical differences between two sets of data.ResultsThe Shannon diversity index (SHDI) of TRB sequences of HGG patients was significantly lower than that of healthy individuals (7.34 vs. 8.45, P = 0.001). The SHDI of TRB sequences of glioblastoma (GBM) patients with more than 16 months survival time was much higher than that of GBM patients with shorter survival times in both tumor tissues (3.48 ± 0.31 vs. 6.21 ± 0.33, t = -5.49, P = 0.002) and blood cells (6.02 ± 0.66 vs. 7.44 ± 0.32, t = -2.20, P = 0.036). In addition, patients achieved a distinctly higher proportion compared to that of healthy individuals in the proportion of TRBV9 and TRBV5 functional regions (9.83% vs. 6.83%, P = 0.001). Surgical tissue from patients who survived more than 16 months yielded a much higher proportion of TRBV4 and TRBV9 regions (7.14% vs. 3.28%, t = 3.18, P = 0.019). In surgical tissues from two GBM patients who survived for longer than 46 months, we found a potentially therapeutic TCR sequence.ConclusionsHGG patients have less species diversity of TCR repertoires compared with that of healthy individuals. TRBV9 regions in TCRs may be protective factors for long-term survival of GBM patients.
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