β-Cyclodextrin Inclusion Complex with Oxazine-4 Derivative for the Treatment of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is the most common type of high-grade glioma and accounts for as much as 50% of all primary brain tumors. With the current standard of care, survival of GBM patients remains poor at 15 months after diagnosis. In this study, the antiproliferative effects of a novel oxazine-4 derivative called 0108 were examined. Delivery of 0108 was accomplished via complexation with (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) to form 0108CD. The association constant, Ka, of 0108CD was determined and stability of 0108CD formulations made with 1, 2.5, 5, 7.5, and 10% HP-β-CD were assessed over 24, 48, and 72 hours. The in vitro toxicity of 0108 and 0108CD was quantified via IC50 in U87-MG, U118-MG, SF298, and SF268 cell lines. The effects of 0108 on cell phase were examined in U87-MG. The 5% HP-β-CD formulation was established as the optimal 0108CD treatment based on maximum 0108 encapsulation without HP-β-CD oversaturation. Stability of the 5% HP-β-CD formulation decreased after 24 hours. Incorporating 0108 in a HP-β-CD vesicle did not change the potency of the drug in SF295-MG and U118-MG, and increased its potency in U87-MG and SF268-MG. 0108 treatment at the highest dose showed a time-independent increase in the number of cells in G0/G1 and S phases and a decrease in G2/M phase

Three-Year Experience of a Multidisciplinary Central Nervous System Clinic Model for Radiation Oncology and Neurosurgery (RADIANS) in a Community Hospital Setting.

Background: As academic centers partner and establish healthcare systems with community hospitals, delivery of subspecialty, multidisciplinary care in community hospital settings remains a challenge. Improving outcomes for central nervous system (CNS) disease is related to integrated care between neurosurgery (NS) and radiation oncology (RadOnc) specialties. Our multidisciplinary community hospital-based clinic, RADIANS, previously reported high patient approval of simultaneous evaluation with NS and RadOnc physicians. Three-year experience is now reported. Methods: Prospectively collected clinical and demographic patient data over three years was done, and surveys administered. Descriptive statistics reported as mean and percentages for patient characteristics, diagnosis, treatment and outcomes. Results: Between August 2016 and August 2019, 101 patients were evaluated. Mean age and distanced traveled was 61.2 years, and 54.9 miles, respectively. Patient Satisfaction Score was 4.79 (0-5 Scale, 5-very satisfied). Most common referral source was medical oncologists. Seventy-two patients had malignant CNS disease (brain mets 28; spine mets 27; both 6; primary brain 9; primary spine 2), 29 had benign CNS disease. Post-evaluation treatment: radiation therapy (RT) only (n=29), neurosurgery (NS) only (n=16), both RT and NS (n=22), and no RT/NS intervention (n=34). Fractionated stereotactic radiosurgery was most common RT delivered; craniotomy with tumor resection was most common NS performed. Treatment outcomes: local control=61/67 (91%); radiation necrosis or radiation-induced myelitis=2/51 (3.9%). Conclusions: The RADIANS multidisciplinary community hospital-based CNS clinic model is first of its kind to be reported, continuing strong patient approval at extended follow-up. Data indicates the model serves as a regional referral center, delivering evidence-based treatment modalities for complex CNS disease in community hospital settings, yielding high rates of local control and low rates of grade 3 or 4 radiation-induced toxicity

Microfluidics Formulated Liposomes of Hypoxia Activated Prodrug for Treatment of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) presents as an unmet clinical challenge for drug delivery due to its unique hypoxic biology. Vinblastine-N-Oxide (CPD100) is a hypoxia-activated prodrug (HAP) that selectively converts to its parent compound, vinblastine, a potent cytotoxic agent, under oxygen gradient. The study evaluates the efficacy of microfluidics formulated liposomal CPD100 (CPD100Li) in PDAC. CPD100Li were formulated with a size of 95 nm and a polydispersity index of 0.2. CPD100Li was stable for a period of 18 months when freeze-dried at a concentration of 3.55 mg/mL. CPD100 and CPD100Li confirmed selective activation at low oxygen levels in pancreatic cancer cell lines. Moreover, in 3D spheroids, CPD100Li displayed higher penetration and disruption compared to CPD100. In patient-derived 3D organoids, CPD100Li exhibited higher cell inhibition in the organoids that displayed higher expression of hypoxia-inducible factor 1 alpha (HIF1A) compared to CPD100. In the orthotopic model, the combination of CPD100Li with gemcitabine (GEM) (standard of care for PDAC) showed higher efficacy than CPD100Li alone for a period of 90 days. In summary, the evaluation of CPD100Li in multiple cellular models provides a strong foundation for its clinical application in PDAC