Ovarian cancer has the highest mortality rate of all gynecological malignancies, due to inadequate treatment strategies and poor early diagnosis. Intraperitoneal (IP) chemotherapy administered on an intermittent schedule has been pursued for ovarian cancer treatment. However, local toxicities and complications associated with indwelling IP catheters required to deliver the chemotherapeutics have been documented. Furthermore, shortening or completely removing treatment-free periods between each chemotherapy cycle has shown improved efficacy compared to intermittent chemotherapy. The focus of this thesis was to develop and characterize a biocompatible and biodegradable IP injectable depot sustained drug delivery system as a new treatment strategy for ovarian cancer. A polymer-lipid injectable formulation (PoLigel) was developed and used for sustained docetaxel (DTX) delivery. The PoLigel resulted in homogeneous DTX peritoneal distribution and sustained plasma levels in healthy mice, which was in contrast to Taxotere®, the clinically used formulation of DTX. Sustained plasma, tissue, tumor and ascites DTX concentrations were observed in mice bearing IP SKOV3 tumors or ID8 ascites over a 3 week period following IP administration of the PoLigel. The intratumoral distribution and tumor penetration of DTX in subcutaneous (SC) and IP SKOV3 tumors were characterized. DTX distributed more towards the tumor core and diffused 1.5 fold further from blood vessels of the IP tumors compared to the SC tumors. The high efficacy observed in the IP SKOV3 and ID8 models and the SC SKOV3 model was attributed to favorable drug distribution at the whole-body, peritoneal and intratumoral levels in combination with local and systemic sustained drug exposure. Sustained chemotherapy with DTX alone and in combination with a drug efflux transporter inhibitor was investigated in multidrug resistant (MDR) ovarian cancer. In vitro, combination delivery via the PoLigel resulted in more apoptosis, greater intracellular accumulation of DTX, and lower DTX efflux in MDR ovarian cancer cells. Sustained combination chemotherapy was more than twice as efficacious as intermittent Taxotere® treatment in MDR ovarian cancer. Significant anti-tumor efficacy was also observed in the MDR model following sustained DTX chemotherapy compared to intermittent Taxotere®. Overall, results presented here encourage the clinical investigation of IP sustained chemotherapy for ovarian cancer treatment.

Title: “A comparative study of the impact of sustained and intermittent docetaxel chemotherapy in brain in a mouse model” Ji Zhang Master of Science Graduate Department of Pharmaceutical Sciences, University of Toronto November, 2011 Abstract A subset of patients suffers cognitive impairment during or long after chemotherapy. This may result from chemotherapeutic agents crossing the blood brain barrier (BBB). This thesis examined the effects of docetaxel (DTX) on brain toxicity, and the effects of different dosing schedules on brain DTX concentrations and neurotoxicity. Examination of DTX treated mice (total dose of 32mg/kg) revealed appreciable amounts of DTX crossed the BBB after either intermittent (four weekly doses) or sustained (one injection of DTX-PoLigel) administration despite differences in peak drug concentrations and overall exposure profiles. Measurements of autophagy and astrocytes activation not only provided evidence of DTX caused neurotoxicity in the central nervous system, but also revealed a link between dosing schedule and neurotoxicity. Furthermore, the discovery suggested connections between DTX brain exposure, diverse biological events (such as BBB permeability and reactive oxygen species activity), and the microenvironment at synapse-neuron junctions, which should be further explored.

Title: “A comparative study of the impact of sustained and intermittent docetaxel chemotherapy in brain in a mouse model” Ji Zhang Master of Science Graduate Department of Pharmaceutical Sciences, University of Toronto November, 2011 Abstract A subset of patients suffers cognitive impairment during or long after chemotherapy. This may result from chemotherapeutic agents crossing the blood brain barrier (BBB). This thesis examined the effects of docetaxel (DTX) on brain toxicity, and the effects of different dosing schedules on brain DTX concentrations and neurotoxicity. Examination of DTX treated mice (total dose of 32mg/kg) revealed appreciable amounts of DTX crossed the BBB after either intermittent (four weekly doses) or sustained (one injection of DTX-PoLigel) administration despite differences in peak drug concentrations and overall exposure profiles. Measurements of autophagy and astrocytes activation not only provided evidence of DTX caused neurotoxicity in the central nervous system, but also revealed a link between dosing schedule and neurotoxicity. Furthermore, the discovery suggested connections between DTX brain exposure, diverse biological events (such as BBB permeability and reactive oxygen species activity), and the microenvironment at synapse-neuron junctions, which should be further explored.

Ovarian cancer has the highest mortality rate of all gynecological malignancies, due to inadequate treatment strategies and poor early diagnosis. Intraperitoneal (IP) chemotherapy administered on an intermittent schedule has been pursued for ovarian cancer treatment. However, local toxicities and complications associated with indwelling IP catheters required to deliver the chemotherapeutics have been documented. Furthermore, shortening or completely removing treatment-free periods between each chemotherapy cycle has shown improved efficacy compared to intermittent chemotherapy. The focus of this thesis was to develop and characterize a biocompatible and biodegradable IP injectable depot sustained drug delivery system as a new treatment strategy for ovarian cancer. A polymer-lipid injectable formulation (PoLigel) was developed and used for sustained docetaxel (DTX) delivery. The PoLigel resulted in homogeneous DTX peritoneal distribution and sustained plasma levels in healthy mice, which was in contrast to Taxotere®, the clinically used formulation of DTX. Sustained plasma, tissue, tumor and ascites DTX concentrations were observed in mice bearing IP SKOV3 tumors or ID8 ascites over a 3 week period following IP administration of the PoLigel. The intratumoral distribution and tumor penetration of DTX in subcutaneous (SC) and IP SKOV3 tumors were characterized. DTX distributed more towards the tumor core and diffused 1.5 fold further from blood vessels of the IP tumors compared to the SC tumors. The high efficacy observed in the IP SKOV3 and ID8 models and the SC SKOV3 model was attributed to favorable drug distribution at the whole-body, peritoneal and intratumoral levels in combination with local and systemic sustained drug exposure. Sustained chemotherapy with DTX alone and in combination with a drug efflux transporter inhibitor was investigated in multidrug resistant (MDR) ovarian cancer. In vitro, combination delivery via the PoLigel resulted in more apoptosis, greater intracellular accumulation of DTX, and lower DTX efflux in MDR ovarian cancer cells. Sustained combination chemotherapy was more than twice as efficacious as intermittent Taxotere® treatment in MDR ovarian cancer. Significant anti-tumor efficacy was also observed in the MDR model following sustained DTX chemotherapy compared to intermittent Taxotere®. Overall, results presented here encourage the clinical investigation of IP sustained chemotherapy for ovarian cancer treatment.

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Orientador: Marlus Chorilli / Resumo: O câncer de próstata (CP) é a segunda neoplasia mais frequente entre homens no Brasil e é caracterizado por não apresentar sintomas em seus estágios iniciais, sendo diagnosticado em seu estágio avançado, o que muitas vezes dificulta o tratamento. Alguns fatores relacionados podem intensificar sua agressividade como, por exemplo, a superexpressão do receptor do fator de crescimento epidérmico (EGFR) em alguns subtipos de tumores de próstata. Neste contexto, a inibição do EGFR auxilia no combate da neoplasia, função essa que pode ser atribuída ao anticorpo monoclonal quimérico IgG1 (cetuximabe-CTX) que se liga à porção externa do EGFR, inibindo a proliferação celular, angiogênese e metástase, além de promover a apoptose. Dentre as formas de tratamento destacam-se a braquiterapia, a radioterapia e a quimioterapia utilizando o docetaxel (DTX), o qual apresenta vantagem de prolongar a sobrevivência em pacientes com CP metastático resistentes à terapia antiandrogênica. No entanto, a formulação comercial (Taxotere®) causa efeitos colaterais, como febre, anemia, retenção de líquidos, hipersensibilidades, mialgias, mucosite, neuropatias periféricas e toxidade a pele e unhas, tornando necessário o estudo de novas formas de veiculação para este fármaco Deste modo, o objetivo deste trabalho foi desenvolver uma nanodispersão de cristal líquido (NCL) de fase cúbica baseada em álcool cetílico etoxilado 20 e propoxilado 5 como tensoativo (T), ácido oleico, DSPE-PEG-MAL e fosfatidilcolina de ... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

Prostatacancer är idag den vanligaste cancerformen i Sverige, och drygt 10 000 män årligen blir diagnosticerade med sjukdomen. En obotlig variant med dödlig utgång är kastrationsresistent prostatacancer som behandlas primärt med Docetaxel. Tumörcellerna utvecklar dock med tiden resistens mot cytostatikan, och det föreligger därför ett stort behov av att utveckla kombinationsbehandlingar med Docetaxel som grund. Mangan har i flera studier visat sig kunna inducera apoptos hos olika celltyper, och är därför intressant som ett möjligt komplement till Docetaxelbehandling. Syftet med studien var att analysera apoptos hos prostatacancerceller från cellinjen PC3 som exponerats för Docetaxel i kombination med mangan. Cellerna odlades och behandlades med Docetaxel i kombination med mangan under 24, 48 och 72 timmar. Analys av apoptos utfördes med flödescytometer efter infärgning med Annexin V och propidiumjodid. Beroende på cellernas tillstånd färgas de in i olika kombinationer och kan därmed detekteras som tidigt respektive sent apoptotiska, eller som nekrotiska. Resultaten visade på en ökning av apoptos hos kombinationsbehandlade celler, men ingen signifikant skillnad förelåg i jämförelse med obehandlade celler. Ytterligare försök bör därför upprepas med ökad koncentration av Docetaxel i kombination med olika koncentrationer av mangan, och även med andra prostatacancer cellinjer såsom DU145 och LnCaP. Dessutom bör analyser av apoptotiska markörer genomföras, i syfte att bekräfta apoptos.

Docetaxel is a chemotherapeutic agent in the taxane group of drugs which is commonly used in the first line setting for metastatic hormone receptor negative breast cancer. We present a case of a 46 year old female who was diagnosed with de novo triple negative metastatic breast carcinoma, and has had an extended progression free survival (PFS) of almost 5 years on first line single agent treatment with Docetaxel. 46 year old female presented with a large left breast mass as well as axillary mass which revealed grade 3 invasive ductal carcinoma of breast on biopsy of both sites. Tumor was estrogen and progesterone receptor negative. Pathology showed discordance in HER2 testing between FISH and IHC, however on repeat testing, HER2 was confirmed to be negative. PET/CT scan for staging revealed large left sided pleural effusion and abnormal soft tissue in the lower anterior and posterior chest on the left concerning for pleural metastases. Patient underwent CT guided biopsy of left lower pleural space which was consistent with metastatic adenocarcinoma with breast primary. She was started on first line single agent chemotherapy with Docetaxel 100mg/m2 every 3 weeks. Tumor markers were non-contributory to assess disease response. Repeat systemic imaging in 3 months showed excellent partial response with decrease in size of breast mass, conglomerate axillary lymph nodes as well as pleural based metastatic foci. Patient had grade 1 neuropathy secondary to Docetaxel which was tolerable. Patient also had significant fatigue with warranted dose reduction by 20% after 6 months. She also demonstrated other adverse effects of Docetaxel such as nail dystrophy and mild blepharitis which were also tolerable. Patient showed good tolerance to chemotherapy, with intermittent treatment holidays. CT scans continued to demonstrate good response with stable size of breast and lung masses. After two years of stable disease and fair tolerance (after completing 34 cycles), chemo regimen was changed to every 4 weeks per patient’s wish. She was also started on Gabapentin for chemotherapy related neuropathy. At the end of 4 years, patient had completed 55 cycles of agent Docetaxel, maintaining ECOG of 1, with grade 2 neuropathy controlled with gabapentin. Patient is currently 56 months out from her initial diagnosis of metastatic triple negative breast cancer and follow-up scans continue to show stable disease. She has developed profound fatigue after several months of treatment. Patient has also faced challenges with fluid retention secondary to Docetaxel. Although her performance status remains fair, patient is contemplating changing frequency of chemotherapy to every 5 or every 6 weeks. Triple negative breast cancer is an aggressive disease with limited options of treatment with chemotherapy agents and no role for endocrine therapy or HER2 targeted treatment options. Docetaxel has shown to have median survival ranging between 10.1 to 14.7 months depending on the dose. Our patient has so far shown extended PFS of 56 months, with single agent Docetaxel in first line setting which surpasses current national averages.

Recent advancements in cancer research has led to the synthesis of a new drug known as docetaxel. Meant to replace paclitaxel, its more natural counterpart whose ingredients are difficult to obtain, the drug is known to effectively treat a wide array of cancers, including breast cancer, ovarian cancer, and prostate cancer. The establishment of a synthetic alternative to paclitaxel has increased its bioavailability, thereby lowering the cost needed to utilize the drug. Still, the limiting factor in minimizing costs is the method in which the drug is processed. Current methods in drug processing have their limitations, which include the introduction of impurities and a low effective yield due to poor powder geometry. Thus, the goal of this study looks to explore a new way to process the drug in a more efficient manner. In this study, a new method for processing docetaxel is explored on in great detail. A more direct method of using electrospray deposition is utilized for the creation of monodisperse nanoparticles, with the main intention of increasing the efficiency at which the drug is processed and prepared for drug delivery to the patient by means of injection. A key feature in electrospray deposition is its ability to produce droplets that are sized homogenously. These droplets eventually evaporate at homogenous rates. These two concepts have been exploited to consistently produce nanoparticles of the cancer drug, which is made possible by the fact that the minimal variation in droplet sizes has easily translated to minimal variation in dry particle sizes. Compared to other methods of drug processing, one other benefit that electrospray deposition conveys is that through evaporation, virtually all impurities and unwanted foreign material are eliminated.