Chitosan–phospholipid blend for sustained and localized delivery of docetaxel to the peritoneal cavity

Zahedi, Payam; Souza, Raquel De; Piquette-Miller, Micheline; Allen, Christine

doi:10.1016/j.ijpharm.2009.05.003

Cited by 33 publications

(46 citation statements)

References 67 publications

(74 reference statements)

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“…The main concern of continuous drug exposure is toxicity to healthy tissues. However, we have shown a lack of systemic and local toxicity in mice treated in this manner (11). We have previously shown that continuous docetaxel treatment did not cause myelosuppression in mice (48,49), which is the most significant toxicity caused by docetaxel (50), as counts of red blood cells, platelets, and leukocytes were within normal baseline values (data not shown).…”

Section: Discussionmentioning

confidence: 57%

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Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

Souza

Zahedi

Badame

et al. 2011

Molecular Cancer Therapeutics

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Drug resistance leads to chemotherapy failure and is responsible for the death of a great majority of patients with metastatic, late-stage ovarian cancer. The present study addressed whether changes in the chemotherapy dosing schedule affect the development, further worsening, or circumvention of drug resistance in chemosensitive and chemoresistant ovarian cancer. Severe combined immunodeficient mice bearing HeyA8 and HeyA8-MDR xenografts were treated with docetaxel intermittently (1Â/wk or 3Â/wk) or continuously for 21 days. Tumor mRNA expression of genes implicated in docetaxel resistance was measured by quantitative real-time-PCR. Analyzed genes included those encoding for the drug efflux transporters mdr1 and mrp7 and for molecules that interfere with or overcome the effects of docetaxel, including b-tubulinIII, actinin4, stathmin1, bcl2, rpn2, thoredoxin, and akt2. In both models, continuous docetaxel resulted in greater antitumor efficacy than 1Â/wk or 3Â/wk dosing and did not induce upregulation of any analyzed genes. Once weekly dosing caused upregulation of various drug resistance-related genes, especially in chemoresistant xenografts. More frequent, 3Â/wk dosing diminished this effect, although levels of various genes were higher than for continuous chemotherapy. Drug efflux transporter expression was further examined by Western blotting, confirming that intermittent, but not continuous, docetaxel induced significant upregulation. Overall, our results show that the presence and length of treatment-free intervals contribute to the development of drug resistance. Elimination of these intervals by continuous dosing resulted in superior antitumor efficacy and prevented drug resistance induction in chemosensitive and chemoresistant disease. These results encourage the clinical implementation of continuous chemotherapy to overcome and/or prevent drug resistance in newly diagnosed and recurrent, refractory ovarian cancer.

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Section: Discussionmentioning

confidence: 57%

“…Continuous therapy consisted of an i.p. injection of DTX-PoLi gel (32 mg/kg), prepared as previously described (11), which releases 8 mg/kg docetaxel weekly. Intermittent therapy consisted of either 1 or 3 i.p.…”

Section: Xenograft Establishment and Treatment Groupsmentioning

confidence: 99%

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

Souza

Zahedi

Badame

et al. 2011

Molecular Cancer Therapeutics

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“…The DTX-PoLi gel formulation is a blend of watersoluble chitosan, laurinaldehyde, egg phosphatidylcholine, and DTX at final material ratios of 1:4:1:0.71 (w/w/w/w), which was prepared as previously described (15,16 16,24, and 32 mg/kg, released at a rate of 3.6% per day] (n = 6/group). Mice were monitored daily for signs of lethargy, weight loss, and abdominal distention.…”

Section: In Vitro Activity Of Dtx-poli Gelmentioning

confidence: 99%

“…Antitumor efficacy was calculated as: [(mean tumor weight nontreated) − (mean tumor weight treated)]/(mean tumor weight nontreated) × 100%. Tumor and plasma DTX content was determined by high-performance liquid chromatography using an established method (16).…”

Section: In Vitro Activity Of Dtx-poli Gelmentioning

confidence: 99%

“…We previously developed an implantable polymer-lipid film capable of continuous release of paclitaxel, which showed efficacy in an ovarian cancer xenograft model (13,14). The need for surgical implantation and slow biodegradation led to the development of an injectable paste with similar properties composed of chitosan, phospholipids, and laurinaldehyde, termed PoLi gel , which showed good biocompatibility and biodegradation (15,16). Although paclitaxel is used in first-line therapy, its analogue docetaxel (DTX) has shown advantages, including slower cellular efflux and higher solubility, allowing for higher intracellular concentrations (17).…”

Section: Introductionmentioning

confidence: 99%

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Continuous Docetaxel Chemotherapy Improves Therapeutic Efficacy in Murine Models of Ovarian Cancer

Souza

Zahedi

Moriyama

et al. 2010

Molecular Cancer Therapeutics

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Ovarian cancer is known as the silent killer for being asymptomatic until late stages. Current first-line treatment consists of debulking surgery followed by i.v. chemotherapeutics administered intermittently, which leads to insufficient drug concentrations at tumor sites, accelerated tumor proliferation rates, and drug resistance, resulting in an overall median survival of only 2 to 4 years. For these reasons, more effective treatment strategies must be developed. We have investigated a localized, continuous chemotherapy approach in tumor models of human and murine ovarian cancers using the antineoplastic agent docetaxel. We show here that continuous docetaxel therapy is considerably more efficacious than intermittent therapy, resulting in a greater decrease in tumor burden and ascites fluid accumulation. Immunohistochemical analyses show that continuous chemotherapy abrogates tumor cell proliferation and angiogenesis to the tumor microenvironment, leading to greater tumor cell death than intermittent docetaxel therapy. Overall, our results show greater therapeutic advantages of continuous over intermittent chemotherapy in the treatment of ovarian cancer.

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Thermosensitive Depot-Forming Injectable Phosphatidylcholine Blends Tailored for Localized Drug Delivery

Grant

Zahedi

Tsallas

et al. 2013

Journal of Pharmaceutical Sciences

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Chitosan–phospholipid blend for sustained and localized delivery of docetaxel to the peritoneal cavity

Cited by 33 publications

References 67 publications

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

Continuous Docetaxel Chemotherapy Improves Therapeutic Efficacy in Murine Models of Ovarian Cancer

Thermosensitive Depot-Forming Injectable Phosphatidylcholine Blends Tailored for Localized Drug Delivery

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