Treatment of glioblastoma is complicated by the tumors’ high resistance to chemotherapy, poor penetration of drugs across the blood brain barrier, and damaging effects of chemotherapy and radiation to normal neural tissue. To overcome these limitations, a thermally responsive polypeptide was developed for targeted delivery of therapeutic peptides to brain tumors using focused hyperthermia. The peptide carrier is based on elastin-like polypeptide (ELP), which is a thermally responsive biopolymer that forms aggregates above a characteristic transition temperature. ELP was modified with cell penetrating peptides (CPPs) to enhance delivery to brain tumors and mediate uptake across the tumor cells’ plasma membranes and with a peptide inhibitor of c-Myc (H1). In rats with intracerebral gliomas, brain tumor targeting of ELP following systemic administration was enhanced up to 5-fold by the use of CPPs. When the lead CPP-ELP-fused c-Myc inhibitor was combined with focused hyperthermia of the tumors, an additional 3 fold increase in tumor polypeptide levels was observed, and 80% reduction in tumor volume, delayed onset of tumor-associated neurological deficits, and at least doubled median survival time including complete regression in 80% of animals was achieved. This work demonstrates that a c-Myc inhibitory peptide can be effectively delivered to brain tumors.

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Introduction Magnetic Resonance Elastography (MRE) analyzes shear waves’ movement thorough tissue to determine stiffness. In a prior study, measurements using first-generation brain MRE techniques correlated with intraoperative observations regarding overall meningioma stiffness. We evaluated the diagnostic accuracy of a higher-resolution MRE technique to preoperatively detect intratumoral variations as compared to surgeon assessment. Methods Fifteen meningiomas in fourteen patients underwent MRE. Tumors with regions of distinctly different stiffness were considered heterogenous. Intratumoral portions were considered hard if there was a significant area ≥ 6 kiloPascals. A 5-point scale graded intraoperative consistency. A durometer semi-quantitatively measured surgical specimen hardness. Statistics included Chi-squared, sensitivity, specificity, positive and negative predicative values (PPV and NPV), and Spearman’s rank correlation coefficient. Results Between MRE and surgery respectively, 9(60%) vs 7(47%) tumors were homogenous; 6(40%) vs 8(53%) tumors were heterogenous; 6(40%) vs 10(67%) tumors had hard portions; and 14(93%) vs 12(80%) tumors had soft portions. MRE sensitivity, specificity, PPV and NPV were: for heterogeneity, 75%, 100%, 100%, and 87%; for hardness, 60%, 100%, 100%, and 56%; and for softness, 100%, 33%, 86%, and 100%. Overall, 10(67%) tumors matched well with MRE and intraoperative consistency and correlated between intraoperative observations (p=0.018) and durometer readings (p=0.046). Tumor size ≤3.5 cm or vascular tumors were more likely to be inconsistent (p<0.05). Conclusions MRE was excellent at ruling-in heterogeneity with hard portions, but less effective in ruling-out heterogeneity and hard portions, particularly in tumors more vascular or <3.5 cm. MRE is the first technology capable of prospectively evaluating intratumoral stiffness and, with further refinement, will likely prove useful in preoperative planning.

Purpose To test the clinical feasibility and usefulness of slip interface imaging (SII), a novel magnetic resonance elastography (MRE)-based method to identify and quantify the degree of tumor brain adhesion in patients with vestibular schwannomas. Materials and Methods With Institutional Review Board approval and after obtaining written informed consent, SII examinations were performed on nine patients with vestibular schwannomas. During the SII acquisition, a low-amplitude mechanical vibration is applied to the head with a pillow-like device placed in the head coil and the resulting shear waves are imaged by using a phase-contrast pulse sequence with motion-encoding gradients synchronized with the applied vibration. Imaging was performed on a 3-T MR system in less than 7 minutes. The acquired shear motion data were processed with two different algorithms (shear line analysis and calculation of octahedral shear strain [OSS]) to identify the degree of tumor-brain adhesion. Blinded to the SII results, neurosurgeons qualitatively assessed tumor adhesion at the time of tumor resection. Standard T2-weighted (T2W), FIESTA, and T2-FLAIR imaging were reviewed to identify the presence of cerebral spinal fluid (CSF) clefts around the tumors. The performance of the use of the CSF cleft and SII for predicting the degree of tumor adhesion was evaluated by using the kappa coefficient and McNemar's test. Results Of the nine patients, SII agreed with the intraoperative assessment of the degree of tumor adhesion in 8 cases (88.9%, [eight of nine], 95% confidence interval [CI]: 57%-98%), with 4/4, 3/3, and 1/2 cases correctly predicted as no adhesion, partial adhesion, and complete adhesion, respectively. However, the T2W, FIESTA, and T2-FLAIR images that used the CSF cleft sign to predict adhesion agreed with surgical findings in only 4 cases (44.4%, [four of nine], 95% CI: 19%-73%). The kappa coefficients indicate good agreement (0.82, 95% CI: 0.5-1) for the SII prediction versus surgical findings, but only fair agreement (0.21, 95% CI: −0.21-0.63) between the CSF cleft prediction and surgical findings. However, the difference between the SII prediction and the CSF cleft prediction was not significant (p=0.103, McNemar), likely because of the small sample size in this study. Conclusion SII can be used to predict the degree of tumor-brain adhesion of vestibular schwannomas and may provide a method to improve preoperative planning and determination of surgical risk in these patients.