Thermosensitive liposomal drug delivery systems: state of the art review

Thermosensitive liposomes are a promising tool for external targeting of drugs to solid tumors when used in combination with local hyperthermia or high intensity focused ultrasound. In vivo results have demonstrated strong evidence that external targeting is superior over passive targeting achieved by highly stable long-circulating drug formulations like PEGylated liposomal doxorubicin. Up to March 2014, the Web of Science listed 371 original papers in this field, with 45 in 2013 alone. Several formulations have been developed since 1978, with lysolipid-containing, low temperature-sensitive liposomes currently under clinical investigation. This review summarizes the historical development and effects of particular phospholipids and surfactants on the biophysical properties and in vivo efficacy of thermosensitive liposome formulations. Further, treatment strategies for solid tumors are discussed. Here we focus on temperature-triggered intravascular and interstitial drug release. Drug delivery guided by magnetic resonance imaging further adds the possibility of performing online monitoring of a heating focus to calculate locally released drug concentrations and to externally control drug release by steering the heating volume and power. The combination of external targeting with thermosensitive liposomes and magnetic resonance-guided drug delivery will be the unique characteristic of this nanotechnology approach in medicine

The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro

Background: Alkylphosphocholines constitute a novel class of antineoplastic synthetic phospholipid derivatives that induce apoptosis of human tumor cell lines by targeting cellular membranes. We could recently show that the first intravenously applicable alkylphosphocholine erucylphosphocholine (ErPC) is a potent inducer of apoptosis in highly resistant human astrocytoma/glioblastoma cell lines in vitro. ErPC was shown to cross the blood brain barrier upon repeated intravenous injections in rats and thus constitutes a promising candidate for glioblastoma therapy. Aim of the present study was to analyze putative beneficial effects of ErPC and its clinically more advanced derivative erucylphosphohomocholine (erucyl-N, N, N-trimethylpropanolaminphosphate, ErPC3, Erufosine (TM) on radiation-induced apoptosis and eradication of clonogenic tumor cells in human astrocytoma/glioblastoma cell lines in vitro. Results: While all cell lines showed high intrinsic resistance against radiation-induced apoptosis as determined by fluorescence microscopy, treatment with ErPC and ErPC3 strongly increased sensitivity of the cells to radiation-induced cell death (apoptosis and necrosis). T98G cells were most responsive to the combined treatment revealing highly synergistic effects while A172 showed mostly additive to synergistic effects, and U87MG cells sub-additive, additive or synergistic effects, depending on the respective radiation-dose, drug-concentration and treatment time. Combined treatment enhanced therapy-induced damage of the mitochondria and caspase-activation. Importantly, combined treatment also increased radiation-induced eradication of clonogenic T98G cells as determined by standard colony formation assays. Conclusion: Our observations make the combined treatment with ionizing radiation and the membrane targeted apoptosis modulators ErPC and ErPC3 a promising approach for the treatment of patients suffering from malignant glioma. The use of this innovative treatment concept in an in vivo xenograft setting is under current investigation

Effects of ionizing radiation in combination with Erufosine on T98G glioblastoma xenograft tumours: a study in NMRI nu/nu mice

BACKGROUND: Erufosine is a promising anticancer drug that increases the efficacy of radiotherapy in glioblastoma cell lines in vitro. Moreover, treatment of nude mice with repeated intraperitoneal or subcutaneous injections of Erufosine is well tolerated and yields drug concentrations in the brain tissue that are higher than the concentrations required for cytotoxic drug effects on glioblastoma cell lines in vitro. METHODS: In the present study we aimed to evaluate the effects of a combined treatment with radiotherapy and Erufosine on growth and local control of T98G subcutaneous glioblastoma xenograft-tumours in NMRI nu/nu mice. RESULTS: We show that repeated intraperitoneal injections of Erufosine resulted in a significant drug accumulation in T98G xenograft tumours on NMRI nu/nu mice. Moreover, short-term treatment with 5 intraperitoneal Erufosine injections caused a transient decrease in the growth of T98G tumours without radiotherapy. Furthermore, an increased radiation-induced growth delay of T98G xenograft tumours was observed when fractionated irradiation was combined with short-term Erufosine-treatment. However, no beneficial drug effects on fractionated radiotherapy in terms of local tumour control were observed. CONCLUSIONS: We conclude that short-term treatment with Erufosine is not sufficient to significantly improve local control in combination with radiotherapy in T98G glioblastoma xenograft tumours. Further studies are needed to evaluate efficacy of extended drug treatment schedules

Survival and prognostic factors in conventional G1 chondrosarcoma

Background Chondrosarcoma is the second most frequent malignant bone tumor. Grade I chondrosarcoma (syn.: atypical cartilaginous tumor) is classified as an intermediately and locally aggressive neoplasm and typically is treated less aggressively (i.e., by intralesional curettage). Does the data regarding local recurrence (LR) and metastatic disease justify this? Methods From 1982 to 2014, 37 consecutive patients with G1 chondrosarcoma had been resected or curetted. The margin was defined as R0 (wide resection) or R1 (marginal resection). All patients were followed for evidence of local recurrence or metastatic disease. Overall and recurrence-free survival were calculated, and various potentially prognostic factors were evaluated. Results In 23 patients (62%), the tumor was widely (R0) resected, whereas in 14 patients, (38%) the resection was marginal (R1). Overall survival was 97% after 5 years, 92% after 10 years, and 67% after 20 years. Five-year local recurrence-free survival was 96%. Ten-year local recurrence-free survival was 83%. Local recurrence-free survival showed a significant correlation to margin status but no correlation to location or age. None of the patients with local recurrence died during the follow-up. One patient had metastatic disease at initial presentation, and a further five patients developed metastatic disease during follow-up. Metastatic disease proofed to be a highly significant factor for survival but was not correlated to local recurrence. Conclusions There was no significant correlation between the outcome and the primary tumor location. Marginal resection was a risk factor for LR, but there was no significant difference in the overall survival in patients with or without LR. Metastatic disease (16%) was more common than expected from the literature and a significant predictor for poor overall survival

Neoadjuvant or adjuvant sirolimus for malignant metastatic or locally advanced perivascular epithelioid cell tumors: two case reports

Perivascular epithelioid cell tumors (PEComas) are very rare mesenchymal tumors, characterized by the presence of perivascular epithelioid cells. Despite their often benign nature, malignant variants with a locally aggressive growth pattern and even distant metastases are known. We describe two cases of malignant PEComas. The first patient had an extensive peritoneal spread and a history of multiple resections, and received the mechanistic target of rapamycin inhibitor sirolimus in a postoperative setting as maintenance therapy. The second patient presented with locally advanced disease in the iliac fossa and was treated with sirolimus in a neoadjuvant setting and achieved complete remission. Both patients have been under treatment for 18 and 52 months, respectively, and are currently in complete remission. These two cases indicate that mechanistic target of rapamycin inhibition for malignant PEComas could be a safe and successful treatment strategy in a neoadjuvant setting with an acceptable toxicity profile

Thermosensitive liposomal drug delivery systems: state of the art review

Thermosensitive liposomes are a promising tool for external targeting of drugs to solid tumors when used in combination with local hyperthermia or high intensity focused ultrasound. In vivo results have demonstrated strong evidence that external targeting is superior over passive targeting achieved by highly stable long-circulating drug formulations like PEGylated liposomal doxorubicin. Up to March 2014, the Web of Science listed 371 original papers in this field, with 45 in 2013 alone. Several formulations have been developed since 1978, with lysolipid-containing, low temperature-sensitive liposomes currently under clinical investigation. This review summarizes the historical development and effects of particular phospholipids and surfactants on the biophysical properties and in vivo efficacy of thermosensitive liposome formulations. Further, treatment strategies for solid tumors are discussed. Here we focus on temperature-triggered intravascular and interstitial drug release. Drug delivery guided by magnetic resonance imaging further adds the possibility of performing online monitoring of a heating focus to calculate locally released drug concentrations and to externally control drug release by steering the heating volume and power. The combination of external targeting with thermosensitive liposomes and magnetic resonance-guided drug delivery will be the unique characteristic of this nanotechnology approach in medicine

Loss of p16(INK4a) is associated with reduced patient survival in soft tissue tumours, and indicates a senescence barrier

Aims: p16(INK4a) is an important factor in carcinogenesis, and its expression is linked to oncogene-induced senescence. Very recently it was shown that upregulation and downregulation of p16 indicates a senescence barrier in the serrated route of colorectal cancer. However, in soft tissue sarcoma (STS), the senescence mechanism is still not understood. In this study, we analysed a well characterised cohort of STS for p16(INK4a) expression and correlated the results with clinicopathological parameters including survival. Methods: Tissue microarrays (TMA) of 183 soft tissue and bone tumours were analysed immunohistochemically. Furthermore, mRNA expression of p16(INK4a) was evaluated in four sarcoma cell lines, and a demethylation test was performed by treatment with 5-aza-2 \grq-deoxycytide. Results: On protein level, expression of p16(INK4a) was observed in undifferentiated pleomorphic sarcoma (UPS) in 69.1%, leiomyosarcoma in 85.7%, synovial sarcoma in 77.8%, liposarcoma in 88.9%, angiosarcoma in 60.9% and MPNST in 22.2%. Loss of p16(INK4a) was observed in high grade sarcomas and showed a significant correlation with reduced patient survival (p=0.032). On DNA level, one out of four sarcoma cell lines exhibited a methylated p16(INK4a) promoter analysed by methylation-specific PCR. p16(INK4a) mRNA and protein expression was restored after demethylation using 5-aza-2′-deoxycytide. Conclusions: Upregulation of p16(INK4a) might be associated with the induction of senescence and indicates a senescence barrier. Downregulation of p16(INK4a) is found in malignant progression, and is significantly correlated with reduced patient survival. Downregulation of p16(INK4a) may be explained by DNA-hypermethylation in sarcoma cells

Loss of p16(INK4a) is associated with reduced patient survival in soft tissue tumours, and indicates a senescence barrier

Aims: p16(INK4a) is an important factor in carcinogenesis, and its expression is linked to oncogene-induced senescence. Very recently it was shown that upregulation and downregulation of p16 indicates a senescence barrier in the serrated route of colorectal cancer. However, in soft tissue sarcoma (STS), the senescence mechanism is still not understood. In this study, we analysed a well characterised cohort of STS for p16(INK4a) expression and correlated the results with clinicopathological parameters including survival. Methods: Tissue microarrays (TMA) of 183 soft tissue and bone tumours were analysed immunohistochemically. Furthermore, mRNA expression of p16(INK4a) was evaluated in four sarcoma cell lines, and a demethylation test was performed by treatment with 5-aza-2 \grq-deoxycytide. Results: On protein level, expression of p16(INK4a) was observed in undifferentiated pleomorphic sarcoma (UPS) in 69.1%, leiomyosarcoma in 85.7%, synovial sarcoma in 77.8%, liposarcoma in 88.9%, angiosarcoma in 60.9% and MPNST in 22.2%. Loss of p16(INK4a) was observed in high grade sarcomas and showed a significant correlation with reduced patient survival (p=0.032). On DNA level, one out of four sarcoma cell lines exhibited a methylated p16(INK4a) promoter analysed by methylation-specific PCR. p16(INK4a) mRNA and protein expression was restored after demethylation using 5-aza-2′-deoxycytide. Conclusions: Upregulation of p16(INK4a) might be associated with the induction of senescence and indicates a senescence barrier. Downregulation of p16(INK4a) is found in malignant progression, and is significantly correlated with reduced patient survival. Downregulation of p16(INK4a) may be explained by DNA-hypermethylation in sarcoma cells

Pharmacokinetics and biodistribution of Erufosine in nude mice - implications for combination with radiotherapy

<p>Abstract</p> <p>Background</p> <p>Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable alkylphosphocholine, <it>in vitro </it>leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy <it>in vivo </it>we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice.</p> <p>Methods</p> <p>NMRI (nu/nu) nude mice were treated by intraperitoneal or subcutaneous injections of 5 to 40 mg/kg body weight Erufosine every 48 h for one to three weeks. Erufosine-concentrations were measured in brain, lungs, liver, small intestine, colon, spleen, kidney, stomach, adipoid tissue, and muscle by tandem-mass spectroscopy. Weight course, blood cell count and clinical chemistry were analyzed to evaluate general toxicity.</p> <p>Results</p> <p>Intraperitoneal injections were generally well tolerated in all dose groups but led to a transient loss of the bodyweight (<10%) in a dose dependent manner. Subcutaneous injections of high-dose Erufosine caused local reactions at the injection site. Therefore, this regimen at 40 mg/kg body weight Erufosine was stopped after 14 days. No gross changes were observed in organ weight, clinical chemistry and white blood cell count in treated compared to untreated controls except for a moderate increase in lactate dehydrogenase and aspartate-aminotransferase after intensive treatment. Repeated Erufosine injections resulted in drug-accumulation in different organs with maximum concentrations of about 1000 nmol/g in spleen, kidney and lungs.</p> <p>Conclusion</p> <p>Erufosine was well tolerated and organ-concentrations surpassed the cytotoxic drug concentrations <it>in vitro</it>. Our investigations establish the basis for a future efficacy testing of Erufosine in xenograft tumor models in nude mice alone and in combination with chemo- or radiotherapy.</p