Dawn Waterhouse | Vancouver Island Health Authority (original) (raw)
Papers by Dawn Waterhouse
BMC Cancer, Apr 8, 2011
Background: Chemotherapy for glioblastoma (GBM) patients is compromised in part by poor perfusion... more Background: Chemotherapy for glioblastoma (GBM) patients is compromised in part by poor perfusion in the tumor. The present study evaluates how treatment with liposomal formulation of irinotecan (Irinophore C™), and other liposomal anticancer drugs, influence the tumor vasculature of GBM models grown either orthotopically or subcutaneously. Methods: Liposomal vincristine (2 mg/kg), doxorubicin (Caelyx ® ; 15 mg/kg) and irinotecan (Irinophore C™; 25 mg/ kg) were injected intravenously (i.v.; once weekly for 3 weeks) in Rag2M mice bearing U251MG tumors. Tumor blood vessel function was assessed using the marker Hoechst 33342 and by magnetic resonance imagingmeasured changes in vascular permeability/flow (K trans). Changes in CD31 staining density, basement membrane integrity, pericyte coverage, blood vessel diameter were also assessed. Results: The three liposomal drugs inhibited tumor growth significantly compared to untreated control (p < 0.05-0.001). The effects on the tumor vasculature were determined 7 days following the last drug dose. There was a 2-3 fold increase in the delivery of Hoechst 33342 observed in subcutaneous tumors (p < 0.001). In contrast there was a 5-10 fold lower level of Hoechst 33342 delivery in the orthotopic model (p < 0.01), with the greatest effect observed following treatment with Irinophore C. Following treatment with Irinophore C, there was a significant reduction in K trans in the orthotopic tumors (p < 0.05). Conclusion: The results are consistent with a partial restoration of the blood-brain barrier following treatment. Further, treatment with the selected liposomal drugs gave rise to blood vessels that were morphologically more mature and a vascular network that was more evenly distributed. Taken together the results suggest that treatment can lead to normalization of GBM blood vessel the structure and function. An in vitro assay designed to assess the effects of extended drug exposure on endothelial cells showed that selective cytotoxic activity against proliferating endothelial cells could explain the effects of liposomal formulations on the angiogenic tumor vasculature.
Molecular Cancer Therapeutics, Mar 1, 2007
Various methods have been explored to enhance antibodybased cancer therapy. The use of multivalen... more Various methods have been explored to enhance antibodybased cancer therapy. The use of multivalent antibodies or fragments against tumor antigens has generated a great deal of interest, as various cellular signals, including induction of apoptosis, inhibition of cell growth/survival, or internalization of the surface molecules, can be triggered or enhanced on extensive cross-linking of the target/antibody complex by the multivalent form of the antibody. The goal of the studies reported here was to develop multivalent antibody constructs via grafting of antibody molecules onto liposome membranes to enhance antibody activity. Using trastuzumab and rituximab as examples, up to a 25-fold increase in the antibody potency in cell viability assay was observed when the antibodies were presented in the multivalent liposome formulation. Key cell survival signaling molecules, such as phosphorylated Akt and phosphorylated p65 nuclear factor-KB, were down-regulated on treatment with multivalent liposomal trastuzumab and liposomal rituximab, respectively. Potent in vivo antitumor activity was shown for liposomal trastuzumab. The data presented here showed the potential of liposome technology to enhance the therapeutic effect of antibodies via a mechanism that modulates cell survival through clustering of the target/ antibody complex.
Nanomedicine, Oct 1, 2006
Evaluation of: Sengupta S, Eavarone D, Capila I et al.: Temporal targeting of tumor cells and neo... more Evaluation of: Sengupta S, Eavarone D, Capila I et al.: Temporal targeting of tumor cells and neovasculature with a nanoscale delivery system. Nature 436(7050), 468–469 (2005) [1]. Cancer treatment has mainly evolved in small increments over the years, with a few key exceptions, where innovations in the type of therapy or delivery have resulted in large steps forward in the reduction of patient morbidity. In the work presented by Sengupta and colleagues, one such exception is presented in the form of a combination drug carrier based on nanotechnology that enables precise temporal control over the release of agents with diverse and complimentary antitumor activity.
Clinical Cancer Research, Feb 15, 2008
To assess the pharmacokinetics, tumor drug accumulation, and therapeutic activity of Irinophore C... more To assess the pharmacokinetics, tumor drug accumulation, and therapeutic activity of Irinophore C, a novel liposomal formulation of irinotecan (CPT-11). Experimental Design: The plasma lactone/carboxy levels of CPT-11 and SN-38 were determined in mice after a single i.v. dose of irinotecan (Camptosar), or Irinophore C, and the plasma t 1/2 , plasma area under the curve, plasma C max , and plasma clearance were calculated. Further, plasma and tumor drug levels were also measured in tumor-bearing mice following Irinophore C treatment. The efficacy of Irinophore C was compared with that of Camptosar in five s.c. human tumor xenografts using single-dose treatment (LS 180), a total of three doses administered at 4-day intervals (H460), or a total of three doses administered at 7-day intervals (Capan-1, PC-3, and HT-29). Results: Compared with Camptosar, Irinophore C mediated an 8-fold increase in t 1/2 , a 100-fold increase in C max , a 1,000-fold increase in area under the curve, and a 1,000-fold decrease in clearance for the active lactone form of CPT-11. Further, the plasma and tumor SN-38 lactone levels were consistent for at least 48 h post-Irinophore C injection. Camptosar treatment (40 mg/kg) mediated a delay in the time required for tumors to increase to four times their pretreatment size compared with controls (T-C). T-Cs ranged from 2 days (LS 180 model) to 18 days (PC-3 model). Irinophore C (40 mg/kg) engendered T-Cs ranging from 14 days (LS 180 model) to 87 days (Capan-1model). Conclusion: Irinophore C improved CPT-11/SN-38 pharmacokinetics, promoted tumor drug accumulation, and increased therapeutic efficacy in a panel of five distinct human tumor xenografts. Camptothecins mediate their anticancer activity by stabilizing the cleavable complex formed between topoisomerase I and DNA during the S phase of the cell cycle (1); however, this mechanism is dependent on the a-hydroxy-y-lactone ring of camptothecins (2), which is problematic because physiologic conditions promote the reversible hydrolysis of the lactone ring to yield the inactive carboxylate form (3). Resultantly, research has focused on strategies to stabilize the lactone ring structure, including the use of drug carrier technologies
Cancer Letters, Jul 1, 2013
Letters in Drug Design & Discovery, Dec 1, 2006
Humanized monoclonal antibodies specific for two ErbB family members, an anti-EGFR (HER1) antibod... more Humanized monoclonal antibodies specific for two ErbB family members, an anti-EGFR (HER1) antibody (cetuximab) and an anti-HER2 antibody (trastuzumab), are proved to be therapeutically important. In this report, we have attempted to design long circulating liposome carriers that have covalently attached, therapeutically active monoclonal antibodies (mAb) specific for EGFR or HER2. Two issues that were resolved here concerned: 1) the use of whole mAb in preparing liposomal conjugates exhibiting extended circulation lifetime and improved mAb delivery to tumors, and 2) the selection of a coupling strategy that did not influence the anti-cancer activity of the conjugated therapeutic antibody. Unlike previous studies contemplating the use of antibodies to target liposomes, the rationale for the studies described in this report was based on the potential that such liposomes could be developed as a versatile approach to deliver the associated antibody/drug combinations to sites of tumor growth. We have demonstrated that strategies which minimized the accessibility of Fc region of the conjugated mAb were useful in reducing plasma elimination of the mAb-liposome conjugates. In particular, Fc exposure could be reduced by conjugating mAb via carbohydrate moieties, which resulted in improved circulation longevity and a five-fold increase in tumor liposomal lipid levels compared to those observed for liposomes prepared with mAb conjugated through amine thiolation. Alternatively, amine conjugation of mAb to the poly(ethylene glycol) terminus resulted in circulation kinetics comparable to those of non-targeted liposomes. Using the later approach, conjugation of the therapeutically active mAb, trastuzumab, did not substantially compromise the anti-tumor activity of the mAb as measured in a human MDA-MB-435/LCC6 HER2 (LCC6 HER2) breast cancer xenograft model. These results indicate the potential of such liposomal formulations for use in combination with encapsulated anticancer drugs that would act synergistically with mAb against ErbB family members.
Cancer Research, Jun 30, 2011
Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbo... more Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction-induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein. We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets. Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu-induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression. Cancer Res; 71(13); 4484-93. Ó2011 AACR.
Chinese Medicine, Nov 27, 2009
BioMed Central have removed this article from the public domain as the article was published in e... more BioMed Central have removed this article from the public domain as the article was published in error.
Cancer Letters, Jul 1, 2013
International journal of healthcare, Feb 27, 2020
The elderly are the fastest growing portion of the world population. The majority of elderly want... more The elderly are the fastest growing portion of the world population. The majority of elderly want to remain independent as long as possible, with responsibility for their care often falling to family or caregivers. Assistive robots could help maintain independence in the elderly while relieving the burden of care on families and healthcare professionals. This scoping review seeks to examine the type and scope of global policies on the use of robotic technology for care of the elderly in international jurisdictions and to assess how they align with current Canadian policies. This review also seeks to determine current perceptions on the use of robotics in care of the elderly and potential barriers to their use that policy makers could encounter. A comprehensive literature search was conducted for articles related to robotic care of the elderly, perceptions of robotic care of the elderly and related policies, using a global lens. A three-step strategy was used to review and identify articles. The search identified 10 primary and secondary studies and 13 grey literature sources. Studies reported that response to robotic care for the elderly had both positive and negative aspects, and that concerns around privacy and cost were prevalent. Japan and the EU had the most comprehensive policy strategies and proposals. Robotic policy in healthcare is relatively new but will become increasingly important in the coming years. Canada needs to strengthen and anticipate its national policy strategy to ensure it can stay aligned with the fast pace of technological change. Further robust research should continue to explore potential for, and concerns over robotic care.
Breast Cancer Research, May 1, 2009
Introduction Substantial preclinical evidence has indicated that inhibition of integrin linked-ki... more Introduction Substantial preclinical evidence has indicated that inhibition of integrin linked-kinase (ILK) correlates with cytotoxic/ cytostatic cellular effects, delayed tumor growth in animal models of cancer, and inhibition of angiogenesis. Widely anticipated to represent a very promising therapeutic target in several cancer indications, it is increasingly evident that optimal therapeutic benefits obtained using ILK targeting strategies will only be achieved in combination settings. The purpose of this study was to investigate the therapeutic potential of the ILK small molecule inhibitor, QLT0267 (267), alone or in combination with chemotherapies commonly used to treat breast cancer patients. used in combination with Dt. In vivo studies focusing on low Her2-expressing breast cancer cells (LCC6) implanted orthotopically demonstrated that treatment with 267/Dt engendered improved therapeutic effects when compared with mice treated with either agent alone. Conclusions The findings indicate that the 267/Dt drug combination confers increased (synergistic) therapeutic efficacy towards human breast cancer cells that express low levels of Her2.
Nanomedicine, Nov 1, 2011
A number of studies have outlined the antiangiogenic effects of cytotoxic agents when administere... more A number of studies have outlined the antiangiogenic effects of cytotoxic agents when administered frequently at low doses. These studies suggest that the effect of the cytotoxic agent is on the vasculature within the tumor and it is assumed that there is little or negligible cytotoxicity. Liposomal drug delivery systems have the ability to provide a dual mechanism of activity where tumor accumulation can deliver high local concentrations of the drug at the site of action with concomitant slow release of the drug from carriers in the blood compartment that results in antivascular effects, similar to that achieved when dosing frequently at low levels. Although this dual mechanism of activity may be linked to other lipid nanoparticle formulations of anticancer drugs, this article summarizes the evidence supporting direct (cytotoxic) and indirect (antivascular) actions of a liposomal formulation of irinotecan.
Pharmaceutical Research, Dec 23, 2010
Purpose A liposomal irinotecan formulation referred to as Irinophore C relies on the ability of c... more Purpose A liposomal irinotecan formulation referred to as Irinophore C relies on the ability of copper to complex irinotecan within the liposome. It is currently being evaluated for critical drug-loading parameters. Studies presented here were designed to determine the optimum copper concentration required for the effective encapsulation and retention of irinotecan into liposomes. Methods Distearoylphosphatidylcholine/cholesterol liposomes were formulated using buffers containing various copper or manganese concentrations, and irinotecan loading was determined in the presence and absence of divalent metal ionophore A23187. The rate and extent of irinotecan encapsulation and the rate of irinotecan release from the liposomes were assessed. The amount of copper retained inside liposomes following irinotecan loading and the effect of copper on membrane permeability were determined. Results Efficient (>98%) irinotecan loading was achieved using encapsulated copper concentrations of 50 mM. However, irinotecan release was copper concentration dependent, with a minimum 300 mM concentration required for optimal drug retention. The presence of copper increased liposomal membrane permeability. Conclusion Results explain why irinotecan loading rates are enhanced in the presence of formulations prepared with copper, and we speculate that the Irinophore C formulation exhibits improved drug retention, due to generation of a complex between copper and irinotecan.
Journal of Controlled Release, Feb 1, 2015
A liposomal formulation of irinotecan, Irinophore C™ (IrC™) is efficacious in a panel of tumor mo... more A liposomal formulation of irinotecan, Irinophore C™ (IrC™) is efficacious in a panel of tumor models, normalizes tumor vasculature, and increases the accumulation of a second drug in the same tumor. We now show that Irinophore C™ is also effective against patient derived xenografts (PDX) of colon cancer, and examine the kinetics of vascular normalization in the HT-29 tumor model and assess how these changes might be used with 5-FU sequentially. Rag2M mice bearing HT-29 tumors were treated with IrC™ (25mg/kg; Q7D×3) for up to three weeks. Groups of tumors were harvested for analysis at 7, 14 and 21days after the start of treatment. Drug and lipid levels in the tumor were evaluated using HPLC and scintillation counts, respectively. Changes in tumor morphology (H&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;E), vasculature (CD31), perfusion (Hoechst 33342) and apoptosis (TUNEL) were quantified using microscopy. The accumulation of a second drug ([(14)C]-5-FU, 40mg/kg) given 3h before sacrifice was determined using liquid scintillation. The efficacy of IrC™ (Q7D×3) followed by 5-FU treatment (Q7D×3) was assessed in mice bearing established HT-29 tumors. The efficacy of IrC™ was also evaluated in primary human colorectal tumors grown orthotopically in NOD-SCID mice. Following a single dose of IrC™ the active lactone forms of irinotecan and its metabolite SN-38 were measurable in HT-29 tumors after 7days. The treatment reduced tumor cell density and increased apoptosis. Hoechst 33342 perfusion and accumulation of [(14)C]-5-FU in the treated tumors increased significantly on days 7 and 14. This was accompanied by an increase in the number of endothelial cells relative to total nuclei in the tumor sections. Pre-treatment with IrC™ (Q7D×3) followed by 5-FU (Q7D×3) delayed the time taken for tumors to reach 1cm(3) by 9days (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). IrC™ was just as effective as free irinotecan when used on patient derived xenografts of colorectal cancer. Treatment with IrC™ reduces tumor cell viability and appears to normalize the vascular function of the tumor after a single treatment cycle. A concomitant increase in the accumulation of a second drug (5-FU) in the tumor was observed in tumors from IrC™ treated animals and this was correlated with changes in vascular structure consistent with normalization. The treatment effects of sequential 5-FU dosing following IrC™ are additive with no additional toxicity in contrast to previous studies where concurrent 5-FU and IrC™ treatment exacerbated 5-FU toxicity. The studies with PDX tumors also indicate that IrC™ is just as effective as free irinotecan on PDX tumors even though the delivered dose is halved.
Investigational New Drugs, May 22, 2012
We have recently developed a liposomal nanoparticle (LNP) formulation of irinotecan based on load... more We have recently developed a liposomal nanoparticle (LNP) formulation of irinotecan based on loading method that involves formation of a complex between copper and the water soluble camptothecin. The loading methodology developed for irinotecan was evaluated to develop a LNP topotecan formulation (referred to herein as Topophore C) and test its activity in pre-clinical model of ovarian carcinoma. Topotecan was encapsulated into preformed liposomes containing 300 mM copper sulfate and the divalent metal ionophore A23187. Formulation optimization studies included assessments of loading efficiency, influence of temperature on drug loading and in vitro stability of the resulting formulation. In vivo assessments included drug and liposome pharmacokinetics, drug levels within plasma and the peritoneal cavity following intravenous (i.v.) administration in mice and efficacy studies on ES2 ovarian cancer model. Topotecan loading into liposomes was optimized with encapsulation efficiency of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;98 % at a final drug-to-lipid (D/L) mole ratio of 0.1. Higher D/L ratios could be achieved, but the resulting formulations were less stable as judged by in vitro drug release studies. Following Topophore C administration in mice the topotecan plasma half-life and AUC were increased compared to free topotecan by 10-and 22-fold, respectively. Topophore C was 2-to 3-fold more toxic than free topotecan, however showed significantly better anti-tumor activity than free topotecan administered at doses with no observable toxic effects. Topophore C is a therapeutically interesting drug candidate and we are particularly interested in developing its use in combination with liposomal doxorubicin for treatment of platinum refractory ovarian cancer.
Drug Safety, 2001
The anthracycline antibiotic doxorubicin has wide activity against a number of human neoplasms an... more The anthracycline antibiotic doxorubicin has wide activity against a number of human neoplasms and is used extensively both as a single agent and in combination regimens. In addition to the use of free, unencapsulated doxorubicin, there are two US Food and Drug Administration approved liposomal formulations of doxorubicin currently available, with several additional liposomal formulations being researched either in the laboratory or in clinical trials. The two approved liposomal formulations of doxorubicin have significantly different lipid compositions and loading techniques, which lead to both unique pharmacokinetic and toxicity profiles, distinct from those of the unencapsulated form. This article discusses the toxicities associated with the free form of doxorubicin, as well as those associated with the two most common liposomal formulations, namely Doxil and Myocet. One of the key toxicity issues linked to the use of free doxorubicin is that of both an acute and a chronic form of cardiomyopathy. This is circumvented by the use of liposomal formulations, as these systems tend to sequester the drug away from organs such as the heart, with greater accumulation in liver, spleen and tumours. However, as will be discussed, the liposomal formulations of doxorubicin are not without their own related toxicities, and, in the case of Doxil, may be associated with the unique toxicity of palmar-plantar erythrodysaesthesia. Overall, the use of liposomal doxorubicin allows for a greater lifetime cumulative dose of doxorubicin to be administered, however acute maximal tolerated doses differ significantly, with that of Myocet being essentially equivalent to free doxorubicin, while higher doses of Doxil may be safely administered. This review highlights the differences in both toxicity and pharmacokinetic properties between free doxorubicin and the different liposomal formulations, as have been determined in pre-clinical and clinical testing against a number of different human neoplasms. The need for further testing of the liposomal formulations prior to the replacement of free doxorubicin with liposomal doxorubicin in any established combination therapy regimens, as well as in combination with the newer therapeutics such as monoclonal antibodies is also discussed.
International Journal of Pharmaceutics, Jul 1, 2002
The objectives of this study were to determine the protein binding and lipoprotein distribution o... more The objectives of this study were to determine the protein binding and lipoprotein distribution of G3139 and G3139 lipoplexes following incubation in human plasma, assess complement activation of, and the effect of pre-incubation of G3139 and G3139 lipoplexes in human plasma on in vitro cellular uptake of G3139. Effect of concentration and time on incorporation of free and lipid associated (lipoplexes) [3H]Bcl-2 AO (25-600 ng/ml) into normolipidemic human plasma lipoproteins was determined by density gradient ultracentrifugation after incubation at 37°C for 5, 30, 60 and 120 min. Protein binding in the lipoprotein deficient fractions (LPDP) was determined by equilibrium dialysis. Complement interaction was determined by ELISA after exposure of human plasma to AO +/− liposomes prepared in serial dilution. In vitro uptake of G3139 and G3139 lipoplexes into human melanoma cells was assessed qualitatively by fluorescence microscopy after 4-h exposure to G3139 (free or as lipoplexes) with or without pre-incubation of G3139 in normal human plasma. Analysis of Bcl-2 AO-lipoprotein interaction over time and concentration indicated no significant movement of the compound within the different lipoprotein and LPDP fractions. Majority of drug was recovered within LPDP fraction, and more than 85% of drug recovered within LPDP fraction was protein bound. No significant activation of complement was noted for either free AO or lipoplexes. Pre-incubation of free AO or AO-lipoplexes in human plasma resulted in a greater cellular uptake of AO-lipoplexes compared with plasma free controls. These findings suggest that the majority of [3H]Bcl-2 AO is plasma protein bound with little lipoprotein association and no significant movement between different lipoprotein and LPDP fractions. Plasma protein binding other than lipoprotein binding may be responsible for the difference in cellular uptake of free AO vs. cationic lipoplexes.
BMC Cancer, Apr 8, 2011
Background: Chemotherapy for glioblastoma (GBM) patients is compromised in part by poor perfusion... more Background: Chemotherapy for glioblastoma (GBM) patients is compromised in part by poor perfusion in the tumor. The present study evaluates how treatment with liposomal formulation of irinotecan (Irinophore C™), and other liposomal anticancer drugs, influence the tumor vasculature of GBM models grown either orthotopically or subcutaneously. Methods: Liposomal vincristine (2 mg/kg), doxorubicin (Caelyx ® ; 15 mg/kg) and irinotecan (Irinophore C™; 25 mg/ kg) were injected intravenously (i.v.; once weekly for 3 weeks) in Rag2M mice bearing U251MG tumors. Tumor blood vessel function was assessed using the marker Hoechst 33342 and by magnetic resonance imagingmeasured changes in vascular permeability/flow (K trans). Changes in CD31 staining density, basement membrane integrity, pericyte coverage, blood vessel diameter were also assessed. Results: The three liposomal drugs inhibited tumor growth significantly compared to untreated control (p < 0.05-0.001). The effects on the tumor vasculature were determined 7 days following the last drug dose. There was a 2-3 fold increase in the delivery of Hoechst 33342 observed in subcutaneous tumors (p < 0.001). In contrast there was a 5-10 fold lower level of Hoechst 33342 delivery in the orthotopic model (p < 0.01), with the greatest effect observed following treatment with Irinophore C. Following treatment with Irinophore C, there was a significant reduction in K trans in the orthotopic tumors (p < 0.05). Conclusion: The results are consistent with a partial restoration of the blood-brain barrier following treatment. Further, treatment with the selected liposomal drugs gave rise to blood vessels that were morphologically more mature and a vascular network that was more evenly distributed. Taken together the results suggest that treatment can lead to normalization of GBM blood vessel the structure and function. An in vitro assay designed to assess the effects of extended drug exposure on endothelial cells showed that selective cytotoxic activity against proliferating endothelial cells could explain the effects of liposomal formulations on the angiogenic tumor vasculature.
Molecular Cancer Therapeutics, Mar 1, 2007
Various methods have been explored to enhance antibodybased cancer therapy. The use of multivalen... more Various methods have been explored to enhance antibodybased cancer therapy. The use of multivalent antibodies or fragments against tumor antigens has generated a great deal of interest, as various cellular signals, including induction of apoptosis, inhibition of cell growth/survival, or internalization of the surface molecules, can be triggered or enhanced on extensive cross-linking of the target/antibody complex by the multivalent form of the antibody. The goal of the studies reported here was to develop multivalent antibody constructs via grafting of antibody molecules onto liposome membranes to enhance antibody activity. Using trastuzumab and rituximab as examples, up to a 25-fold increase in the antibody potency in cell viability assay was observed when the antibodies were presented in the multivalent liposome formulation. Key cell survival signaling molecules, such as phosphorylated Akt and phosphorylated p65 nuclear factor-KB, were down-regulated on treatment with multivalent liposomal trastuzumab and liposomal rituximab, respectively. Potent in vivo antitumor activity was shown for liposomal trastuzumab. The data presented here showed the potential of liposome technology to enhance the therapeutic effect of antibodies via a mechanism that modulates cell survival through clustering of the target/ antibody complex.
Nanomedicine, Oct 1, 2006
Evaluation of: Sengupta S, Eavarone D, Capila I et al.: Temporal targeting of tumor cells and neo... more Evaluation of: Sengupta S, Eavarone D, Capila I et al.: Temporal targeting of tumor cells and neovasculature with a nanoscale delivery system. Nature 436(7050), 468–469 (2005) [1]. Cancer treatment has mainly evolved in small increments over the years, with a few key exceptions, where innovations in the type of therapy or delivery have resulted in large steps forward in the reduction of patient morbidity. In the work presented by Sengupta and colleagues, one such exception is presented in the form of a combination drug carrier based on nanotechnology that enables precise temporal control over the release of agents with diverse and complimentary antitumor activity.
Clinical Cancer Research, Feb 15, 2008
To assess the pharmacokinetics, tumor drug accumulation, and therapeutic activity of Irinophore C... more To assess the pharmacokinetics, tumor drug accumulation, and therapeutic activity of Irinophore C, a novel liposomal formulation of irinotecan (CPT-11). Experimental Design: The plasma lactone/carboxy levels of CPT-11 and SN-38 were determined in mice after a single i.v. dose of irinotecan (Camptosar), or Irinophore C, and the plasma t 1/2 , plasma area under the curve, plasma C max , and plasma clearance were calculated. Further, plasma and tumor drug levels were also measured in tumor-bearing mice following Irinophore C treatment. The efficacy of Irinophore C was compared with that of Camptosar in five s.c. human tumor xenografts using single-dose treatment (LS 180), a total of three doses administered at 4-day intervals (H460), or a total of three doses administered at 7-day intervals (Capan-1, PC-3, and HT-29). Results: Compared with Camptosar, Irinophore C mediated an 8-fold increase in t 1/2 , a 100-fold increase in C max , a 1,000-fold increase in area under the curve, and a 1,000-fold decrease in clearance for the active lactone form of CPT-11. Further, the plasma and tumor SN-38 lactone levels were consistent for at least 48 h post-Irinophore C injection. Camptosar treatment (40 mg/kg) mediated a delay in the time required for tumors to increase to four times their pretreatment size compared with controls (T-C). T-Cs ranged from 2 days (LS 180 model) to 18 days (PC-3 model). Irinophore C (40 mg/kg) engendered T-Cs ranging from 14 days (LS 180 model) to 87 days (Capan-1model). Conclusion: Irinophore C improved CPT-11/SN-38 pharmacokinetics, promoted tumor drug accumulation, and increased therapeutic efficacy in a panel of five distinct human tumor xenografts. Camptothecins mediate their anticancer activity by stabilizing the cleavable complex formed between topoisomerase I and DNA during the S phase of the cell cycle (1); however, this mechanism is dependent on the a-hydroxy-y-lactone ring of camptothecins (2), which is problematic because physiologic conditions promote the reversible hydrolysis of the lactone ring to yield the inactive carboxylate form (3). Resultantly, research has focused on strategies to stabilize the lactone ring structure, including the use of drug carrier technologies
Cancer Letters, Jul 1, 2013
Letters in Drug Design & Discovery, Dec 1, 2006
Humanized monoclonal antibodies specific for two ErbB family members, an anti-EGFR (HER1) antibod... more Humanized monoclonal antibodies specific for two ErbB family members, an anti-EGFR (HER1) antibody (cetuximab) and an anti-HER2 antibody (trastuzumab), are proved to be therapeutically important. In this report, we have attempted to design long circulating liposome carriers that have covalently attached, therapeutically active monoclonal antibodies (mAb) specific for EGFR or HER2. Two issues that were resolved here concerned: 1) the use of whole mAb in preparing liposomal conjugates exhibiting extended circulation lifetime and improved mAb delivery to tumors, and 2) the selection of a coupling strategy that did not influence the anti-cancer activity of the conjugated therapeutic antibody. Unlike previous studies contemplating the use of antibodies to target liposomes, the rationale for the studies described in this report was based on the potential that such liposomes could be developed as a versatile approach to deliver the associated antibody/drug combinations to sites of tumor growth. We have demonstrated that strategies which minimized the accessibility of Fc region of the conjugated mAb were useful in reducing plasma elimination of the mAb-liposome conjugates. In particular, Fc exposure could be reduced by conjugating mAb via carbohydrate moieties, which resulted in improved circulation longevity and a five-fold increase in tumor liposomal lipid levels compared to those observed for liposomes prepared with mAb conjugated through amine thiolation. Alternatively, amine conjugation of mAb to the poly(ethylene glycol) terminus resulted in circulation kinetics comparable to those of non-targeted liposomes. Using the later approach, conjugation of the therapeutically active mAb, trastuzumab, did not substantially compromise the anti-tumor activity of the mAb as measured in a human MDA-MB-435/LCC6 HER2 (LCC6 HER2) breast cancer xenograft model. These results indicate the potential of such liposomal formulations for use in combination with encapsulated anticancer drugs that would act synergistically with mAb against ErbB family members.
Cancer Research, Jun 30, 2011
Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbo... more Since cancer cells depend on glucose more than normal cells, we compared the effects of low carbohydrate (CHO) diets to a Western diet on the growth rate of tumors in mice. To avoid caloric restriction-induced effects, we designed the low CHO diets isocaloric with the Western diet by increasing protein rather than fat levels because of the reported tumor-promoting effects of high fat and the immune-stimulating effects of high protein. We found that both murine and human carcinomas grew slower in mice on diets containing low amylose CHO and high protein compared with a Western diet characterized by relatively high CHO and low protein. There was no weight difference between the tumor-bearing mice on the low CHO or Western diets. Additionally, the low CHO-fed mice exhibited lower blood glucose, insulin, and lactate levels. Additive antitumor effects with the low CHO diets were observed with the mTOR inhibitor CCI-779 and especially with the COX-2 inhibitor Celebrex, a potent anti-inflammatory drug. Strikingly, in a genetically engineered mouse model of HER-2/neu-induced mammary cancer, tumor penetrance in mice on a Western diet was nearly 50% by the age of 1 year whereas no tumors were detected in mice on the low CHO diet. This difference was associated with weight gains in mice on the Western diet not observed in mice on the low CHO diet. Moreover, whereas only 1 mouse on the Western diet achieved a normal life span, due to cancer-associated deaths, more than 50% of the mice on the low CHO diet reached or exceeded the normal life span. Taken together, our findings offer a compelling preclinical illustration of the ability of a low CHO diet in not only restricting weight gain but also cancer development and progression. Cancer Res; 71(13); 4484-93. Ó2011 AACR.
Chinese Medicine, Nov 27, 2009
BioMed Central have removed this article from the public domain as the article was published in e... more BioMed Central have removed this article from the public domain as the article was published in error.
Cancer Letters, Jul 1, 2013
International journal of healthcare, Feb 27, 2020
The elderly are the fastest growing portion of the world population. The majority of elderly want... more The elderly are the fastest growing portion of the world population. The majority of elderly want to remain independent as long as possible, with responsibility for their care often falling to family or caregivers. Assistive robots could help maintain independence in the elderly while relieving the burden of care on families and healthcare professionals. This scoping review seeks to examine the type and scope of global policies on the use of robotic technology for care of the elderly in international jurisdictions and to assess how they align with current Canadian policies. This review also seeks to determine current perceptions on the use of robotics in care of the elderly and potential barriers to their use that policy makers could encounter. A comprehensive literature search was conducted for articles related to robotic care of the elderly, perceptions of robotic care of the elderly and related policies, using a global lens. A three-step strategy was used to review and identify articles. The search identified 10 primary and secondary studies and 13 grey literature sources. Studies reported that response to robotic care for the elderly had both positive and negative aspects, and that concerns around privacy and cost were prevalent. Japan and the EU had the most comprehensive policy strategies and proposals. Robotic policy in healthcare is relatively new but will become increasingly important in the coming years. Canada needs to strengthen and anticipate its national policy strategy to ensure it can stay aligned with the fast pace of technological change. Further robust research should continue to explore potential for, and concerns over robotic care.
Breast Cancer Research, May 1, 2009
Introduction Substantial preclinical evidence has indicated that inhibition of integrin linked-ki... more Introduction Substantial preclinical evidence has indicated that inhibition of integrin linked-kinase (ILK) correlates with cytotoxic/ cytostatic cellular effects, delayed tumor growth in animal models of cancer, and inhibition of angiogenesis. Widely anticipated to represent a very promising therapeutic target in several cancer indications, it is increasingly evident that optimal therapeutic benefits obtained using ILK targeting strategies will only be achieved in combination settings. The purpose of this study was to investigate the therapeutic potential of the ILK small molecule inhibitor, QLT0267 (267), alone or in combination with chemotherapies commonly used to treat breast cancer patients. used in combination with Dt. In vivo studies focusing on low Her2-expressing breast cancer cells (LCC6) implanted orthotopically demonstrated that treatment with 267/Dt engendered improved therapeutic effects when compared with mice treated with either agent alone. Conclusions The findings indicate that the 267/Dt drug combination confers increased (synergistic) therapeutic efficacy towards human breast cancer cells that express low levels of Her2.
Nanomedicine, Nov 1, 2011
A number of studies have outlined the antiangiogenic effects of cytotoxic agents when administere... more A number of studies have outlined the antiangiogenic effects of cytotoxic agents when administered frequently at low doses. These studies suggest that the effect of the cytotoxic agent is on the vasculature within the tumor and it is assumed that there is little or negligible cytotoxicity. Liposomal drug delivery systems have the ability to provide a dual mechanism of activity where tumor accumulation can deliver high local concentrations of the drug at the site of action with concomitant slow release of the drug from carriers in the blood compartment that results in antivascular effects, similar to that achieved when dosing frequently at low levels. Although this dual mechanism of activity may be linked to other lipid nanoparticle formulations of anticancer drugs, this article summarizes the evidence supporting direct (cytotoxic) and indirect (antivascular) actions of a liposomal formulation of irinotecan.
Pharmaceutical Research, Dec 23, 2010
Purpose A liposomal irinotecan formulation referred to as Irinophore C relies on the ability of c... more Purpose A liposomal irinotecan formulation referred to as Irinophore C relies on the ability of copper to complex irinotecan within the liposome. It is currently being evaluated for critical drug-loading parameters. Studies presented here were designed to determine the optimum copper concentration required for the effective encapsulation and retention of irinotecan into liposomes. Methods Distearoylphosphatidylcholine/cholesterol liposomes were formulated using buffers containing various copper or manganese concentrations, and irinotecan loading was determined in the presence and absence of divalent metal ionophore A23187. The rate and extent of irinotecan encapsulation and the rate of irinotecan release from the liposomes were assessed. The amount of copper retained inside liposomes following irinotecan loading and the effect of copper on membrane permeability were determined. Results Efficient (>98%) irinotecan loading was achieved using encapsulated copper concentrations of 50 mM. However, irinotecan release was copper concentration dependent, with a minimum 300 mM concentration required for optimal drug retention. The presence of copper increased liposomal membrane permeability. Conclusion Results explain why irinotecan loading rates are enhanced in the presence of formulations prepared with copper, and we speculate that the Irinophore C formulation exhibits improved drug retention, due to generation of a complex between copper and irinotecan.
Journal of Controlled Release, Feb 1, 2015
A liposomal formulation of irinotecan, Irinophore C™ (IrC™) is efficacious in a panel of tumor mo... more A liposomal formulation of irinotecan, Irinophore C™ (IrC™) is efficacious in a panel of tumor models, normalizes tumor vasculature, and increases the accumulation of a second drug in the same tumor. We now show that Irinophore C™ is also effective against patient derived xenografts (PDX) of colon cancer, and examine the kinetics of vascular normalization in the HT-29 tumor model and assess how these changes might be used with 5-FU sequentially. Rag2M mice bearing HT-29 tumors were treated with IrC™ (25mg/kg; Q7D×3) for up to three weeks. Groups of tumors were harvested for analysis at 7, 14 and 21days after the start of treatment. Drug and lipid levels in the tumor were evaluated using HPLC and scintillation counts, respectively. Changes in tumor morphology (H&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;E), vasculature (CD31), perfusion (Hoechst 33342) and apoptosis (TUNEL) were quantified using microscopy. The accumulation of a second drug ([(14)C]-5-FU, 40mg/kg) given 3h before sacrifice was determined using liquid scintillation. The efficacy of IrC™ (Q7D×3) followed by 5-FU treatment (Q7D×3) was assessed in mice bearing established HT-29 tumors. The efficacy of IrC™ was also evaluated in primary human colorectal tumors grown orthotopically in NOD-SCID mice. Following a single dose of IrC™ the active lactone forms of irinotecan and its metabolite SN-38 were measurable in HT-29 tumors after 7days. The treatment reduced tumor cell density and increased apoptosis. Hoechst 33342 perfusion and accumulation of [(14)C]-5-FU in the treated tumors increased significantly on days 7 and 14. This was accompanied by an increase in the number of endothelial cells relative to total nuclei in the tumor sections. Pre-treatment with IrC™ (Q7D×3) followed by 5-FU (Q7D×3) delayed the time taken for tumors to reach 1cm(3) by 9days (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). IrC™ was just as effective as free irinotecan when used on patient derived xenografts of colorectal cancer. Treatment with IrC™ reduces tumor cell viability and appears to normalize the vascular function of the tumor after a single treatment cycle. A concomitant increase in the accumulation of a second drug (5-FU) in the tumor was observed in tumors from IrC™ treated animals and this was correlated with changes in vascular structure consistent with normalization. The treatment effects of sequential 5-FU dosing following IrC™ are additive with no additional toxicity in contrast to previous studies where concurrent 5-FU and IrC™ treatment exacerbated 5-FU toxicity. The studies with PDX tumors also indicate that IrC™ is just as effective as free irinotecan on PDX tumors even though the delivered dose is halved.
Investigational New Drugs, May 22, 2012
We have recently developed a liposomal nanoparticle (LNP) formulation of irinotecan based on load... more We have recently developed a liposomal nanoparticle (LNP) formulation of irinotecan based on loading method that involves formation of a complex between copper and the water soluble camptothecin. The loading methodology developed for irinotecan was evaluated to develop a LNP topotecan formulation (referred to herein as Topophore C) and test its activity in pre-clinical model of ovarian carcinoma. Topotecan was encapsulated into preformed liposomes containing 300 mM copper sulfate and the divalent metal ionophore A23187. Formulation optimization studies included assessments of loading efficiency, influence of temperature on drug loading and in vitro stability of the resulting formulation. In vivo assessments included drug and liposome pharmacokinetics, drug levels within plasma and the peritoneal cavity following intravenous (i.v.) administration in mice and efficacy studies on ES2 ovarian cancer model. Topotecan loading into liposomes was optimized with encapsulation efficiency of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;98 % at a final drug-to-lipid (D/L) mole ratio of 0.1. Higher D/L ratios could be achieved, but the resulting formulations were less stable as judged by in vitro drug release studies. Following Topophore C administration in mice the topotecan plasma half-life and AUC were increased compared to free topotecan by 10-and 22-fold, respectively. Topophore C was 2-to 3-fold more toxic than free topotecan, however showed significantly better anti-tumor activity than free topotecan administered at doses with no observable toxic effects. Topophore C is a therapeutically interesting drug candidate and we are particularly interested in developing its use in combination with liposomal doxorubicin for treatment of platinum refractory ovarian cancer.
Drug Safety, 2001
The anthracycline antibiotic doxorubicin has wide activity against a number of human neoplasms an... more The anthracycline antibiotic doxorubicin has wide activity against a number of human neoplasms and is used extensively both as a single agent and in combination regimens. In addition to the use of free, unencapsulated doxorubicin, there are two US Food and Drug Administration approved liposomal formulations of doxorubicin currently available, with several additional liposomal formulations being researched either in the laboratory or in clinical trials. The two approved liposomal formulations of doxorubicin have significantly different lipid compositions and loading techniques, which lead to both unique pharmacokinetic and toxicity profiles, distinct from those of the unencapsulated form. This article discusses the toxicities associated with the free form of doxorubicin, as well as those associated with the two most common liposomal formulations, namely Doxil and Myocet. One of the key toxicity issues linked to the use of free doxorubicin is that of both an acute and a chronic form of cardiomyopathy. This is circumvented by the use of liposomal formulations, as these systems tend to sequester the drug away from organs such as the heart, with greater accumulation in liver, spleen and tumours. However, as will be discussed, the liposomal formulations of doxorubicin are not without their own related toxicities, and, in the case of Doxil, may be associated with the unique toxicity of palmar-plantar erythrodysaesthesia. Overall, the use of liposomal doxorubicin allows for a greater lifetime cumulative dose of doxorubicin to be administered, however acute maximal tolerated doses differ significantly, with that of Myocet being essentially equivalent to free doxorubicin, while higher doses of Doxil may be safely administered. This review highlights the differences in both toxicity and pharmacokinetic properties between free doxorubicin and the different liposomal formulations, as have been determined in pre-clinical and clinical testing against a number of different human neoplasms. The need for further testing of the liposomal formulations prior to the replacement of free doxorubicin with liposomal doxorubicin in any established combination therapy regimens, as well as in combination with the newer therapeutics such as monoclonal antibodies is also discussed.
International Journal of Pharmaceutics, Jul 1, 2002
The objectives of this study were to determine the protein binding and lipoprotein distribution o... more The objectives of this study were to determine the protein binding and lipoprotein distribution of G3139 and G3139 lipoplexes following incubation in human plasma, assess complement activation of, and the effect of pre-incubation of G3139 and G3139 lipoplexes in human plasma on in vitro cellular uptake of G3139. Effect of concentration and time on incorporation of free and lipid associated (lipoplexes) [3H]Bcl-2 AO (25-600 ng/ml) into normolipidemic human plasma lipoproteins was determined by density gradient ultracentrifugation after incubation at 37°C for 5, 30, 60 and 120 min. Protein binding in the lipoprotein deficient fractions (LPDP) was determined by equilibrium dialysis. Complement interaction was determined by ELISA after exposure of human plasma to AO +/− liposomes prepared in serial dilution. In vitro uptake of G3139 and G3139 lipoplexes into human melanoma cells was assessed qualitatively by fluorescence microscopy after 4-h exposure to G3139 (free or as lipoplexes) with or without pre-incubation of G3139 in normal human plasma. Analysis of Bcl-2 AO-lipoprotein interaction over time and concentration indicated no significant movement of the compound within the different lipoprotein and LPDP fractions. Majority of drug was recovered within LPDP fraction, and more than 85% of drug recovered within LPDP fraction was protein bound. No significant activation of complement was noted for either free AO or lipoplexes. Pre-incubation of free AO or AO-lipoplexes in human plasma resulted in a greater cellular uptake of AO-lipoplexes compared with plasma free controls. These findings suggest that the majority of [3H]Bcl-2 AO is plasma protein bound with little lipoprotein association and no significant movement between different lipoprotein and LPDP fractions. Plasma protein binding other than lipoprotein binding may be responsible for the difference in cellular uptake of free AO vs. cationic lipoplexes.