Intravitreal Topotecan for Vitreous Seeds in Retinoblastoma: A Long-term Review of 91 Eyes.

PURPOSE: To study the long-term efficacy of intravitreal topotecan (IVT) for vitreous seeds in eyes with retinoblastoma and risk factors for their recurrence. DESIGN: Retrospective, non-comparative, interventional study. PARTICIPANTS: Ninety-one eyes of 90 patients with retinoblastoma treated between January 2013 and April 2019. METHODS: Patients with recurrent or refractory vitreous seeds after completion of intravenous or intra-arterial chemotherapy were treated with IVT (30 µg/0.15 ml) by the safety-enhanced technique. The injection was repeated every 4 weeks until the regression of seeds. Patients with a minimum follow-up of 12 months were included in the analysis. MAIN OUTCOME MEASURES: Primary outcome measures were vitreous seed regression and eye salvage. Secondary outcomes were risk factors for vitreous seed recurrence after treatment with IVT, vision salvage, and complications of IVT. RESULTS: The median age of the patients was 18 months, with most having group D (n = 58 [64%]) and group E (n = 26 [29%]) retinoblastoma. Vitreous seeds were refractory in 46 eyes (51%) and recurrent in 45 eyes (49%). A total of 317 IVT injections were administered, with the median being 3 injections. The median number of IVT injections required was 2.5 injections for dust, 3 injections for sphere, and 5 injections for cloud morphologic features. Recurrence of vitreous seeds after IVT was seen in 17 eyes (19%) at a mean follow-up of 7.9 months. At a mean follow-up 34 months, vitreous seed regression was achieved in 88 eyes (97%) and eye salvage was achieved in 77 eyes (85%). Older age (P = 0.018) and recurrence of retinal tumor (15/17 eyes; P < 0.01) significantly increased the risk of vitreous seed recurrence. Cataract was the most common complication seen in 17 eyes (9%). CONCLUSIONS: Intravitreal topotecan at an every 3- to 4-week regimen is effective against both refractory and recurrent vitreous seeds. The vitreous seed morphologic features correspond to the number of injections required for regression. Increasing age and recurrence of retinal tumor increase the risk of vitreous seed recurrence after treatment with IVT. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Synergistic Nanomedicine Delivering Topoisomerase I Toxin (SN-38) and Inhibitors of Polynucleotide Kinase 3'-Phosphatase (PNKP) for Enhanced Treatment of Colorectal Cancer.

Inhibitors of a DNA repair enzyme known as polynucleotide kinase 3'-phosphatase (PNKP) are expected to show synergistic cytotoxicity in combination with topoisomerase I (TOP1) inhibitors in cancer. In this study, the synergistic cytotoxicity of a novel inhibitor of PNKP, i.e., A83B4C63, with a potent TOP1 inhibitor, i.e., SN-38, against colorectal cancer cells was investigated. Polymeric micelles (PMs) for preferred tumor delivery of A83B4C63, developed through physical encapsulation of this compound in methoxy poly(ethylene oxide)-poly(α-benzyl carboxylate-ε-caprolactone) (mPEO-b-PBCL) micelles, were combined with SN-38 in free or PM form. The PM form of SN-38 was prepared through chemical conjugation of SN-38 to the functional end group of mPEO-b-PBCL and further assembly of mPEO-b-PBCL-SN-38 in water. Moreover, mixed micelles composed of mPEO-b-PBCL and mPEO-b-PBCL-SN-38 were used to co-load A83B4C63 and SN-38 in the same nanoformulation. The loading content (% w/w) of the SN-38 and A83B4C63 to mPEO-b-PBCL in the co-loaded formulation was 7.91 ± 0.66 and 16.13 ± 0.11% (w/w), respectively, compared to 15.67 ± 0.34 (% w/w) and 23.06 ± 0.63 (% w/w) for mPEO-b-PBCL micelles loading individual drugs. Notably, the average diameter of PMs co-encapsulating both SN-38 and A83B4C63 was larger than that of PMs encapsulating either of these compounds alone but still lower than 60 nm. The release of A83B4C63 from PMs co-encapsulating both drugs was 76.36 ± 1.41% within 24 h, which was significantly higher than that of A83B4C63-encapsulated micelles (42.70 ± 0.72%). In contrast, the release of SN-38 from PMs co-encapsulating both drugs was 44.15 ± 2.61% at 24 h, which was significantly lower than that of SN-38-conjugated PMs (74.16 ± 3.65%). Cytotoxicity evaluations by the MTS assay as analyzed by the Combenefit software suggested a clear synergy between PM/A83B4C63 (at a concentration range of 10-40 µM) and free SN-38 (at a concentration range of 0.001-1 µM). The synergistic cytotoxic concentration range for SN-38 was narrowed down to 0.1-1 or 0.01-1 µM when combined with PM/A83B4C63 at 10 or 20-40 µM, respectively. In general, PMs co-encapsulating A83B4C63 and SN-38 at drug concentrations within the synergistic range (10 µM for A83B4C63 and 0.05-1 µM for SN-38) showed slightly less enhancement of SN-38 anticancer activity than a combination of individual micelles, i.e., A83B4C63 PMs + SN-38 PMs at the same molar concentrations. This was attributed to the slower release of SN-38 from the SN-38 and A83B4C63 co-encapsulated PMs compared to PMs only encapsulating SN-38. Cotreatment of cells with TOP1 inhibitors and A83B4C63 formulation enhanced the expression level of γ-HA2X, cleaved PARP, caspase-3, and caspase-7 in most cases. This trend was more consistent and notable for PMs co-encapsulating both A83B4C63 and SN-38. The overall result from the study shows a synergy between PMs of SN-38 and A83B4C63 as a mixture of two PMs for individual drugs or PMs co-encapsulating both drugs.

Efficacy of topotecan nanoparticles for intravitreal chemotherapy of retinoblastoma.

Retinoblastoma (Rb) is the most common intraocular malignancy in children that accounts for approximately 4% of all pediatric malignancies. Since chemotherapy is a widely practiced treatment for Rb, there is a growing interest in developing new and effective drugs to overcome systemic and local side effects of chemotherapy to improve the quality of life and increase the chances of survival. This study sought to fabricate thiolated chitosan nanoparticles containing topotecan (TPH-TCs-NPs) with a view of enhancing drug loading and release control. This research was also designed to assess the ability of TPH-TCs-NPs to improve cell association, increase treatment efficacy in retinoblastoma cells and xenograft-rat-model of retinoblastoma, and overcome current topotecan hydrochloride (TPH) intravitreal administration challenges, including stability loss and poor cellular uptake. Modified ionic gelation method was optimized to fabricate TPH-TCs-NPs and TPH-TMC-NPs (N-trimethyl chitosan nanoparticles containing TPH). We characterized the NPs and quantified topotecan loading and release against a free TPH standard. The efficacy of TPH-NPs was quantified in human retinoblastoma cells (Y79) by XTT and flow cytometry measurement. In addition, Y79 cells were injected intravitreally in both eyes of immunodeficient wistar albino rats to create a xenograft-rat-model to compare the antitumor effectiveness of TPH-NPs and TPH by intravitreal administration. TPH-NPs complexation was confirmed by EDX, FTIR, and DSC techniques. TPH-TCs-NPs and TPH-TMC-NPs had high encapsulation efficiency (85.23 ± 2 and 73.34 ± 2% respectively). TPH-TCs-NPs showed a mean diameter, polidispersity index, and zeta potential of 25±2 nm, 0.21 ± 0.03 and +12 ± 2 mV, respectively. As a function of dose, TCs and TMC NPs were more efficacious than free topotecan (IC50s 53.17 and 85.88 nM, relative to 138.30 nM respectively, P = 0.012). Kruskal-Wallis test showed a statistically significant difference between the groups. Additionally, a significant difference between the tumor control and TPH-TCs-NPs treated group in xenograft-rat-model ( Range of P-value: 0.026 to 0.035) was shown by Bonferroni post hoc test. The current investigation demonstrated enhanced efficacy and association of TPH-TCs-NPs relative to free TPH in retinoblastoma cells and tumor in vitro and in vivo.

Feasibility and Safety of CT-Guided High-Dose-Rate Brachytherapy Combined with Transarterial Chemoembolization Using Irinotecan-Loaded Microspheres for the Treatment of Large, Unresectable Colorectal Liver Metastases.

PURPOSE: To evaluate feasibility and safety of combined irinotecan chemoembolization and CT-guided high-dose-rate brachytherapy (HDRBT) in patients with unresectable colorectal liver metastases > 3 cm in diameter. MATERIALS AND METHODS: This prospective study included 23 patients (age, 70 y ± 11.3; 16 men) with 47 liver metastases (size, 62 mm ± 18.7). Catheter-related adverse events were reported per Society of Interventional Radiology classification, and treatment toxicities were reported per Common Terminology Criteria for Adverse Events. Liver-related blood values were analyzed by Wilcoxon test, with P < .05 as significant. Time to local tumor progression, progression-free survival (PFS), and overall survival (OS) were estimated by Kaplan-Meier method. RESULTS: No catheter-related major or minor complications were recorded. Significant differences vs baseline levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT; both P < .001), γ-glutamyltransferase (GGT; P = .013), and hemoglobin (P = .014) were recorded. After therapy, 11 of 23 patients (47.8%) presented with new grade I/II toxicities (bilirubin, n = 3 [13%]; AST, n = 16 [70%]; ALT, n = 18 [78%]; ALP, n = 12 [52%] and hemoglobin, n = 15 [65%]). Moreover, grade III/IV toxicities developed in 10 (43.5%; 1 grade IV): AST, n = 6 (26%), grade III, n = 5; grade IV, n = 1; ALT, n = 3 (13%); GGT, n = 7 (30%); and hemoglobin, n = 1 (4%). However, all new toxicities resolved within 3 months after therapy without additional treatment. Median local tumor control, PFS, and OS were 6, 4, and 8 months, respectively. CONCLUSIONS: Combined irinotecan chemoembolization and CT-guided HDRBT is safe and shows a low incidence of toxicities, which were self-resolving.

Combination of Bronchial Arterial Infusion Chemotherapy plus Drug-Eluting Embolic Transarterial Chemoembolization for Treatment of Advanced Lung Cancer-A Retrospective Analysis of 23 Patients.

PURPOSE: To determine the efficacy and safety of the combination of bronchial arterial infusion (BAI) chemotherapy and transarterial chemoembolization with the use of drug-eluting embolic (DEE) particles in the treatment of unresectable advanced lung cancer. MATERIALS AND METHODS: A retrospective review was performed of 23 patients with unresectable lung cancer (stage III/IV) who received BAI chemotherapy and DEE chemoembolization. Treatment response was assessed by enhanced CT and evaluated on the basis of Response Evaluation Criteria In Solid Tumors at 30 d after the last combination treatment. Patients were followed up until death or March 15, 2020, whichever was first. Overall survival (OS) was estimated by Kaplan-Meier analysis, and factors associated with OS were evaluated by Cox proportional-hazards test. RESULTS: Complete response, partial response, stable disease, and progressive disease were seen in 2, 16, 5, and 0 patients at 30 d after the last combination treatment, respectively; therefore, the overall response rate was 78.3% and the disease control rate was 100%. Preprocedure symptoms (hemoptysis in 7 patients and dyspnea in 10) resolved in all cases after combination therapy. Nineteen patients died during follow-up, and 4 survived. Median OS was 15.6 mo (95% confidence interval, 10.1-21.1 mo). On univariate analysis and multivariate analysis, tumor/node/metastasis staging was an independent risk factor for prognosis. There were no serious adverse events during the procedures. CONCLUSIONS: The combination of BAI chemotherapy plus DEE chemoembolization appears to be a promising method for treatment of advanced lung cancer.

Reduction-responsive sulfur dioxide polymer prodrug nanoparticles loaded with irinotecan for combination osteosarcoma therapy.

Combination therapy can boost the therapeutic effectiveness of monotherapies by achieving synergy between therapeutic agents. Herein, a reduction-responsive sulfur dioxide (SO2) polymer prodrug was synthesized as a nanocarrier to load irinotecan (IRN) to be used in combination osteosarcoma therapy. The SO2 prodrug (denoted as mPEG-PLG (DNs)) was synthesized by coupling a small-molecule SO2 donor, N-(3-azidopropyl)-2,4-dinitrobenzenesulfonamide (AP-DNs), to the side chains of methoxy poly (ethylene glycol)-block-poly (γ-propargyl-L-glutamate) block copolymer. The mPEG-PLG (DNs) had the ability to self-assemble into micelles while simultaneously encapsulating IRN in aqueous media. The formed micelles led to enhanced SO2 and IRN release in reductive conditions. Using nile red as a model drug, the loaded micelles were efficiently internalized by cancer cells, demonstrated by confocal laser scanning microscopy and flow cytometry. The release of SO2 within nanoparticles (NPs) in tumor cells led to enhanced intracellular reactive oxygen species amounts together with induced oxidative destruction to cancer cells. Furthermore, the IRN-loaded SO2 polymer prodrug NPs mediated synergistic therapeutic effects against osteosarcoma cells, leading to improved biodistribution and enhanced tumor growth inhibition over control groups in a murine osteosarcoma model. Taken together, this work highlights the potential of SO2 polymer prodrugs as reduction-responsive nanocarriers to load chemotherapeutics for effective combination osteosarcoma therapy.

Phase Ib/II study of weekly topotecan and daily gefitinib in patients with platinum resistant ovarian, peritoneal, or fallopian tube cancer.

INTRODUCTION: 50-70% of epithelial ovarian cancers overexpress epidermal growth factor receptor, and its expression has been correlated with poor prognosis. We conducted a phase Ib/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with epidermal growth factor receptor positivity. METHODS: Patients with measurable recurrent or persistent cancer after treatment with a platinum containing regimen with positive epidermal growth factor receptor expression, as determined by immunohistochemistry, were eligible for the study. Initial treatment was 250 mg/day gefitinib (oral) and 2.0 mg/m2 topotecan (intravenous) on days 1, 8, and 15, on a 28 day cycle. Dose escalations were planned for topotecan (dose levels 1-3: 2, 3, and 4 mg/m2) until the maximum tolerated dose was reached. RESULTS: 19 patients received a total of 61 cycles. Median age was 59.8 years (range 42-76 years). Histologic types in treated patients included 74% serous (n=14), 11% mixed (n=2), 11% transitional (n=2), and 5% clear cell (n=1). For phase Ib, three patients were treated at dose level 1, three at dose level 2, and three at dose level 3 for topotecan. The maximum tolerated dose was 4.0 mg/m2 (days 1, 8, and 15) for topotecan and 250 mg (daily) for gefitinib. Therefore, dose level 3 was used for phase II. Among the 19 patients, 63.2% (n=12) had progressive disease, 15.8% (n=3) had stable disease, 10.5% (n=2) had a partial response, and 10.5% (n=2) were not evaluable. The most serious adverse events of any grade attributed to the therapy were anemia (89.4%), neutropenia (68.4%), abdominal pain (84%), constipation (78.9%), and diarrhea (78.9%). CONCLUSION: Although the drug combination was relatively well tolerated, this prospective phase Ib/II clinical trial did not show sufficient clinical activity of topotecan combined with gefitinib in patients with epidermal growth factor receptor positive recurrent ovarian, fallopian tube, or peritoneal cancers.

Irinotecan-Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview.

Irinotecan has been used in the treatment of various malignancies for many years. Still, the knowledge regarding this drug is expanding. The pharmacogenetics of the drug is the crucial component of response to irinotecan. Furthermore, new formulations of the drug are introduced in order to better deliver the drug and avoid potentially life-threatening side effects. Here, we give a comprehensive overview on irinotecan's molecular mode of action, metabolism, pharmacogenetics, and toxicity. Moreover, this article features clinically used combinations of the drug with other anticancer agents and introduces novel formulations of drugs (e.g., liposomal formulations, dendrimers, and nanoparticles). It also outlines crucial mechanisms of tumor cells' resistance to the active metabolite, ethyl-10-hydroxy-camptothecin (SN-38). We are sure that the article will constitute an important source of information for both new researchers in the field of irinotecan chemotherapy and professionals or clinicians who are interested in the topic.

Topoisomerase 1 inhibitor topotecan delays the disease progression in a mouse model of Huntington's disease.

Huntington's disease (HD) is a dominantly inherited progressive neurodegenerative disorder caused by the accumulation of polyglutamine expanded mutant huntingtin as inclusion bodies primarily in the brain. After the discovery of the HD gene, considerable progress has been made in understanding the disease pathogenesis and multiple drug targets have been identified, even though currently there is no effective therapy. Here, we demonstrate that the treatment of topotecan, a brain-penetrating topoisomerase 1 inhibitor, to HD transgenic mouse considerably improved its motor behavioural abnormalities along with a significant extension of lifespan. Improvement of behavioural deficits are accompanied with the significant rescue of their progressively decreased body weight, brain weight and striatal volume. Interestingly, topotecan treatment also significantly reduced insoluble mutant huntingtin load in the HD mouse brain. Finally, we show that topotecan treatment to HD mouse not only inhibits the expression of transgenic mutant huntingtin, but also at the same time induces the expression of Ube3a, an ubiquitin ligase linked to the clearance of mutant huntingtin. These findings suggest that topotecan could be a potential therapeutic molecule to delay the progression of HD.

Click chemistry-mediated tumor-targeting of SN38-loaded nanoparticles using trastuzumab.

For efficient drug delivery, we introduce a click-chemistry-mediated two-step tumor-targeting strategy for nanoparticles (NPs). We modified HER2-binding trastuzumab with trans-cyclooctene (TCO-Trb), and fabricated tetrazine-modified NPs containing the anticancer drug, SN38 (SN38-Tz-NPs). To target tumor cells with the Tz-NPs, the tumor cells are first treated with TCO-Trb. The TCO-Trb binds HER2s and presents multiple TCO groups on the cell surface. Subsequently, the cells are treated with SN38-Tz-NPs that can bind the cell surface via click chemistry between Tz and TCO. This click chemistry-mediated binding resulted in enhanced tumor-targeting of Tz-NPs to the target tumor cells. In our study, this strategy was performed and analyzed in vitro and in vivo, and the results show that this is a promising strategy for tumor-targeted drug delivery by NPs.

Clinical outcomes and prognostic factors to predict treatment response in high risk neuroblastoma patients receiving topotecan and cyclophosphamide containing induction regimen: a prospective multicenter study.

BACKGROUND: Neuroblastoma is the most common extra-cranial solid tumor among children. Despite intensive treatment, patients with advanced disease mostly experience dismal outcomes. Here, we proposed the use of topotecan and cyclophosphamide containing induction regimen as an upfront therapy to high risk neuroblastoma patients. METHODS: Patients with high risk neuroblastoma undergoing ThaiPOG high risk neuroblastoma protocol from 2016 to 2017 were studied. All patients received 6 cycles of induction regimen consisting of 2 cycles topotecan (1.2 mg/m2/day) and cyclophosphamide (400 mg/m2/day) for 5 days followed by cisplatin (50 mg/m2/day) for 4 days combined with etoposide (200 mg/m2/day) for 3 days on the third and fifth cycles and cyclophosphamide (2100 mg/m2/day) for 2 days combined with doxorubicin (25 mg/m2/day) and vincristine (0.67 mg/m2/day) for 3 days on the fourth and sixth cycles. Treatment response after the 5th cycle before surgery and treatment-related toxicities after each topotecan containing induction cycle were evaluated. Relevant prognostic factors were analyzed to measure the treatment response among those patients. RESULTS: In all, 107 high risk neuroblastoma patients were enrolled in the study. After the 5th cycle of induction regimen, the patients achieved complete response (N = 2), very good partial response (N = 40), partial response (N = 46) and mixed response (N = 19). None of the patients experienced stable disease or disease progression. The most significant prognostic factor was type of healthcare system. The most common adverse effect was febrile neutropenia followed by mucositis, diarrhea and elevated renal function. CONCLUSION: The topotecan and cyclophosphamide containing induction regimen effectively provides favorable treatment response. The regimen is well tolerated with minimal toxicity among patients with high risk neuroblastoma in Thailand.

Pilot Study Comparing Systemic and Tissue Pharmacokinetics of Irinotecan and Metabolites after Hepatic Drug-Eluting Chemoembolization.

Differences in drug metabolism associated with UGT1A1 polymorphism could result in individualized local response to hepatic chemoembolization with irinotecan-eluting beads (DEBIRI) or predictable toxicities. Five patients with inoperable hepatic metastases from colorectal or anal malignancies treated with DEBIRI were assessed for UGT1A1 mutations. No difference in area under the curve (AUC) for SN38 in normal liver and tumor tissue samples was noted with variant or wild-type UBT1A1 (P = .16 and P = .05, respectively). Plasma SN-38 AUC was significantly lower in wild-type compared to variant patients (P < .0001). UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI.

Prediction of irinotecan toxicity in metastatic colorectal cancer patients based on machine learning models with pharmacokinetic parameters.

Irinotecan (CPT-11) is a drug used against a wide variety of tumors, which can cause severe toxicity, possibly leading to the delay or suspension of the cycle, with the consequent impact on the prognosis of survival. The main goal of this work is to predict the toxicities derived from CPT-11 using artificial intelligence methods. The data for this study is conformed of 53 cycles of FOLFIRINOX, corresponding to patients with metastatic colorectal cancer. Supported by several demographic data, blood markers and pharmacokinetic parameters resulting from a non-compartmental pharmacokinetic study of CPT-11 and its metabolites (SN-38 and SN-38-G), we use machine learning techniques to predict high degrees of different toxicities (leukopenia, neutropenia and diarrhea) in new patients. We predict high degree of leukopenia with an accuracy of 76%, neutropenia with 75% and diarrhea with 91%. Among other variables, this study shows that the areas under the curve of CPT-11, SN-38 and SN-38-G play a relevant role in the prediction of the studied toxicities. The presented models allow to predict the degree of toxicity for each cycle of treatment according to the particularities of each patient.

ATTAIN: Phase III study of etirinotecan pegol versus treatment of physician's choice in patients with metastatic breast cancer and brain metastases.

The increasing incidence of breast cancer brain metastases is a major clinical problem with its associated poor prognosis and limited treatment options. The long-acting topoisomerase-1 inhibitor, etirinotecan pegol, was designed to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Motivated by improved survival findings from subgroup analyses from the Phase III BEACON trial, this ongoing randomized, Phase III trial compares etirinotecan pegol to drugs commonly used for advanced breast cancer in patients with stable, treated breast cancer brain metastases who have been previously treated with an anthracycline, taxane and capecitabine. The primary end point is overall survival. Secondary end points include objective response rate, progression-free survival and time to CNS disease progression or recurrence in patients with/without CNS lesions present at study entry. Trial registration number: NCT02915744.

Irinotecan hydrochloride trihydrate loaded folic acid-tailored solid lipid nanoparticles for targeting colorectal cancer: development, characterization, and in vitro cytotoxicity study using HT-29 cells.

Aim: The aim of this investigation was to evaluate the potential of folic acid-tailored solid lipid nanoparticles (SLNs) for encapsulation as well as for in vitro cytotoxicity study of irinotecan hydrochloride trihydrate (IHT) against colorectal cancer (CRC) by using HT-29 cells. Methods: Solvent diffusion technique was employed for the preparation of SLNs. Further, the formulations were optimised via three-level, three-factor Box-Behnken design (BBD). Results: The uncoupled SLNs (IRSLNs) and folic acid-coupled SLNs (IRSLNFs) formulations revealed not only high %entrapment efficiency but also small particle size. Moreover, in vitro drug release results from IRSLNs and IRSLNFs confirmed that they followed sustained-release effect for up to 144 h. Whereas, in vitro cell viability study against HT-29 cell line suggested significantly (p < 0.05) higher cytotoxicity (IC50 = 15 µg/ml) of IRSLNFs over IRSLNs and IHT solution. Conclusions: Outcomes suggested that the engineered IRSLNFs hold great potential for targeting CRC for an extended period of time.

Preparation and Evaluation of Irinotecan Poly(Lactic-co-Glycolic Acid) Nanoparticles for Enhanced Anti-tumor Therapy.

Irinotecan (IRT), the pro-drug of SN-38, has exhibited potent cytotoxicity against various tumors. In order to enhance the anti-tumor effect of IRT, we prepared IRT-loaded PLGA nanoparticles (IRT-PLGA-NPs) by emulsion-solvent evaporation method. Firstly, IRT-PLGA-NPs were characterized through drug loading (DL), entrapment efficiency (EE), particle size, zeta potential, transmission electron microscopy (TEM), and differential scanning calorimetry (DSC). We next studied the in vitro release characteristics of IRT-PLGA-NPs. Finally, the pharmacokinetics and pharmacodynamics profiles of IRT-PLGA-NPs were investigated. The results revealed that IRT-PLGA-NPs were spherical with an average size of (169.97 ± 6.29) nm and its EE and DL were (52.22 ± 2.41)% and (4.75 ± 0.22)%, respectively. IRT-PLGA-NPs could continuously release drug for 14 days in vitro. In pharmacokinetics studies, for pro-drug IRT, the t1/2ß of IRT-PLGA-NPs was extended from 0.483 to 3.327 h compared with irinotecan solution (IRT-Sol), and for its active metabolite SN-38, the t1/2ß was extended from 1.889 to 4.811 h, which indicated that IRT-PLGA-NPs could prolong the retention times of both IRT and SN-38. The pharmacodynamics results revealed that the tumor doubling time, growth inhibition rate, and specific growth rate of IRT-PLGA-NPs were 2.13-, 1.30-, and 0.47-fold those of IRT-Sol, respectively, which demonstrated that IRT-PLGA-NPs could significantly inhibit the growth of tumor. In summary, IRT-PLGA-NPs, which exhibited excellent therapeutic effect against tumors, might be used as a potential carrier for tumor treatment in clinic.

Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. METHODS: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1-5) plus either oral sorafenib 400 mg or placebo twice daily on days 6-15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01047891. FINDINGS: Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43-0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8-7·6) with sorafenib versus 4·4 months (3·7-5·0) with placebo. The most common grade 3-4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]). INTERPRETATION: Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies. FUNDING: Bayer, Amgen, and GlaxoSmithKline.

New therapeutic approaches for brainstem tumors: a comparison of delivery routes using nanoliposomal irinotecan in an animal model.

Despite the advances in imaging, surgery and radiotherapy, the majority of patients with brainstem gliomas die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which prevents total surgical resection and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. The development of new therapeutic approaches which can circumvent the BBB is a potential path to improve outcomes for these children. Convection-enhanced delivery (CED) and intranasal delivery (IND) are strategies that permit direct drug delivery into the central nervous system and are an alternative to intravenous injection (IV). We treated rats bearing human brainstem tumor xenografts with nanoliposomal irinotecan (CPT-11) using CED, IND, and IV. A single treatment of CED irinotecan had a similar effect on overall survival as multiple treatments by IV route. IND CPT-11 showed significantly increased survival of animals with brainstem tumors, and demonstrated the promise of this non-invasive approach of drug delivery bypassing the BBB when combined with nanoliposomal chemotherapy. Our results indicated that using CED and IND of nanoliposomal therapy increase likelihood of practical therapeutic approach for the treatment of brainstem gliomas.

Intratumoral Injection Administration of Irinotecan-Loaded Microspheres: In Vitro and In Vivo Evaluation.

To reduce the toxic and side effects of intravenous chemotherapeutic drugs on the tumor-patients, the aims of this study were to design and study intratumor-administrated irinotecan-loaded PLGA microspheres (CPT-11-PLGA-MS) in vitro and in vivo according to the structure characteristics of CPT-11. PLGA microspheres containing irinotecan were prepared by emulsion solvent evaporation method and evaluated in terms of their morphology, particle size analysis, in vitro drug release, drug retention and leakage studies in vivo, and pharmacodynamics studies. The CPT-11-PLGA-MS were spherical with mean size of 9.29 ± 0.02 µm, and average encapsulation efficiency were measured of 77.97 ± 1.26% along with the average drug loading of 7.08 ± 0.11%. DSC results indicated that the drug existed in the phase of uncrystallization in the microspheres. The formulation of CPT-11-PLGA-MS could prolong the in vitro drug release to 16 days following Weibull equation. In CPT-11-PLGA-MS after intratumor injection administration was significantly improved. The results demonstrated that the slow-sustained release of CPT-11-PLGA-MS in tumor tissue after intratumor injection of microspheres can reduce the drug leakage to the circulation system, maintain the drug retention, and improve the therapeutic effect, which could become a promising drug delivery system for CPT-11 and could maintain the most effective concentration at the target site to maximum limit.

The combination of A-966492 and Topotecan for effective radiosensitization on glioblastoma spheroids.

Radiotherapy is one of the modalities in the treatment of glioblastoma patients, but glioma tumors are resistant to radiation and also chemotherapy drugs. Thus, researchers are investigating drugs which have radiosensitization capabilities in order to improve radiotherapy. PARP enzymes and topoisomerase I enzymes have a critical role in repairing DNA damage in tumor cells. Thus, inhibiting activity of these enzymes helps stop DNA damage repair and increase DSB lethal damages. In the current study, we investigated the combination of TPT as a topoisomerase I inhibitor, and A-966492 as a novel PARP inhibitor for further radiosensitization. U87MG cells (a human glioblastoma cell line) were cultured in Poly-Hema coated flasks to reach 300 µm-diameter spheroids. Treatments were accomplished by using non-toxic concentrations of A-966492 and Topotecan. The surviving fraction of treated cells was determined by clonogenic assay after treatment with drugs and 6 MV X-ray. The γ-H2AX expression was measured by an immunofluorescence staining method to examine the influence of A-966492, TPT and radiation on the induction of double stranded DNA breaks. Treatments using the A-966492 drug were conducted in concentration of 1 µM. Combining A-966492 and TPT with radiation yielded enhanced cell killing, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER50) 1.39 and 1.16 respectively. Radio- and chemo-sensitization was further enhanced when A-966492 was combined with both X-ray and TPT, with SER50 of 1.53. Also γ-H2AX expression was higher in the group treated with a combination of drugs and radiation. A-966492 is an effective PARP inhibitor and has significant radio-sensitivity on U87MG spheroids. By accumulating cells in the S phase and by inhibiting the DNA damage repair, TPT enhanced radio-sensitivity. A-966492 combined with TPT as a topoisomerase I inhibitor had additive radio-sensitizing effects. As a result, applying PARP and topoisomerase I inhibitors can be a suitable strategy for improving radiotherapy in clinics.