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Suzanne M D'Addio,
Walid Saad,
Steven M Ansell,
John J Squiers,
Douglas H Adamson,
Margarita Herrera-Alonso,
Adam R Wohl,
Thomas R Hoye,
Christopher W Macosko, Lawrence D Mayer,
Christine Vauthier,
Robert K Prud'homme
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ABSTRACT: Drug nanocarrier clearance by the immune system must be minimized to achieve targeted delivery to pathological tissues. There is considerable interest in finding in vitro tests that can predict in vivo clearance outcomes. In this work, we produce nanocarriers with dense PEG layers resulting from block copolymer-directed assembly during rapid precipitation. Nanocarriers are formed using block copolymers with hydrophobic blocks of polystyrene (PS), poly-ε-caprolactone (PCL), poly-D,L-lactide (PLA), or poly-lactide-co-glycolide (PLGA), and hydrophilic blocks of polyethylene glycol (PEG) with molecular weights from 1 kg/mol to 9 kg/mol. Nanocarriers with paclitaxel prodrugs are evaluated in vivo in Foxn1(nu) mice to determine relative rates of clearance. The amount of nanocarrier in circulation after 4h varies from 10% to 85% of initial dose, depending on the block copolymer. In vitro complement activation assays are conducted to correlate in vivo circulation to the protection of the nanocarrier surface from complement binding and activation. Guidelines for optimizing block copolymer structure to maximize circulation of nanocarriers formed by rapid precipitation and directed assembly are proposed, relating to the relative sizes of the hydrophilic and hydrophobic blocks, the hydrophobicity of the anchoring block, the absolute size of the PEG block, and polymer crystallinity. The in vitro results distinguish between the poorly circulating PEG(5k)-PCL(9 k) and the better circulating nanocarriers, but could not rank the better circulating nanocarriers in order of circulation time. Analysis of PEG surface packing on monodisperse 200 nm latex spheres indicates that the size of the hydrophobic PCL, PS, and PLA blocks are correlated with the PEG blob size. Suggestions for next steps for in vitro measurements are made.
Journal of Controlled Release 06/2012; 162(1):208-17. · 5.73 Impact Factor
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ABSTRACT: To evaluate the possibility of improved selective killing of acute myeloid leukemia (AML) cells with CPX-351 (a liposomal formulation of cytarabine and daunorubicin). CPX-351 and the same molar ratio of free drugs were compared for cytotoxicity against colony-forming cells (CFCs) and subpopulations of cells enriched for primitive progenitors from AML patients and normal granulocyte colony-stimulating factor-mobilized peripheral blood (PB) and bone marrow (BM) donors.
AML blasts (n = 13) and normal PB and BM cells (n = 7) were incubated for 24 hours in various concentrations of CPX-351 or free drugs before plating in CFC assay or staining with anti-CD34 and anti-CD38 antibodies, Annexin-V, and propidium iodide followed by fluorescence-activated cell sorting analysis. High performance liquid chromatography was used to measure intracellular daunorubicin accumulation.
AML blasts and progenitors from patients who achieved complete remission were more sensitive to both CPX-351 and free drugs than the same cells from patients with chemotherapy refractory leukemia. However, AML CFCs and CD34(+)CD38(-) AML blasts (enriched for candidate leukemia stem cells) from the same patient showed similar sensitivity to the liposomal or free drug formulations. In contrast, CFCs and CD34(+)CD38(-) cells from normal PB and BM were fivefold more sensitive to the free drugs than to CPX-351. Consistent with these observations, preferential intracellular accumulation of CPX-351 in AML over normal cells was observed, while there was little difference in drug uptake between AML and normal cells with the free drug cocktail.
CPX-351, as compared to free cytarabine:daunorubicin, shows enhanced selective in vitro cytotoxicity for AML rather than normal progenitors.
Experimental hematology 04/2011; 39(7):741-50. · 3.11 Impact Factor
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Eric J Feldman,
Jeffrey E Lancet,
Jonathan E Kolitz,
Ellen K Ritchie,
Gail J Roboz,
Alan F List,
Steven L Allen,
Ekatherine Asatiani, Lawrence D Mayer,
Christine Swenson,
Arthur C Louie
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ABSTRACT: This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351.
CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m(2) with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred.
The maximum-tolerated dose was 101 units/m(2). DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m(2). Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours.
The recommended dose of CPX-351 for phase II study is 101 units/m(2). Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML.
Journal of Clinical Oncology 01/2011; 29(8):979-85. · 18.37 Impact Factor
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ABSTRACT: Drug combinations have been the standard of care in the treatment of cancer for > 50 years. Typically, combination chemotherapy uses agents with non-overlapping toxicities which are escalated to their maximum tolerated dose. However, emerging evidence indicates that this approach may not be providing optimal efficacy depending on the drug ratios to which the tumor is exposed. Combined drugs can be synergistic whereas other ratios of the same agents may be antagonistic or additive.
In this review, we examine the importance of drug ratios in cancer therapy. We describe how manipulation of the lipid membrane and internal buffer composition maintains synergistic ratios of irinotecan and floxuridine (CPX-1), daunorubicin and cytarabine (CPX-351) or cisplatin and irinotecan (CPX-571). For polymer-based nanoparticles, prodrug hydrophobicity was exploited to coordinate the release of gemcitabine and the more hydrophobic paclitaxel. We present preclinical data for liposomal drug combinations which demonstrate that the most efficacious formulation is not always the highest dose of both agents.
An insight into the use of liposomes and polymer-based nanoparticles to deliver synergistic drug combinations to the tumor site and avoid antagonistic drug-drug interactions.
The ability to control and maintain drug ratios in vivo through the use of nanoscale delivery vehicles results in a significant improvement in therapeutic activity.
Expert Opinion on Drug Delivery 12/2010; 7(12):1329-41. · 4.90 Impact Factor
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ABSTRACT: CPX-351, a liposomal formulation co-encapsulating cytarabine (Cyt) and daunorubicin (Daun), has been developed, which delivers synergistic Cyt:Daun molar ratios to bone marrow. CPX-351 has demonstrated markedly superior anti-leukemic activity over free Cyt:Daun drug cocktails in preclinical models. Given the prolonged plasma lifetime of CPX-351, we examined the relationship between therapeutic efficacy and the frequency of treatment in the consolidation setting using a bone marrow-engrafting human leukemia xenograft model. Adding a day 1,3,5 consolidation treatment course for CPX-351 therapy improved the increase in lifespan (ILS) from 116% and no cures for a single induction course, to 268% plus a 33% cure rate for an induction plus consolidation course. In contrast, free Cyt:Daun cocktail treatment provided much lower ILS values with no cures. Administering CPX-351 as consolidation therapy starting on day 42 using a day 1,3, day 1,5, or day 1,7 schedule yielded ILS values of 154%, 185%, and 108%, respectively. The increased efficacy observed for the day 1,3 and day 1,5 consolidation schedules was associated with elevated bone marrow drug accumulation for the second doses. The enhanced efficacy obtained for intermediate dosing frequency in the consolidation setting suggests that the anti-leukemic activity of synergistic drug ratios is dependent on both duration of exposure and maintenance above a therapeutic threshold.
Leukemia & lymphoma 08/2010; 51(8):1536-42. · 2.40 Impact Factor
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ABSTRACT: The objective of this study was to examine the pharmacodynamic basis for the potent preclinical and clinical anti-leukemic activity of CPX-351, a nano-scale liposome formulation of cytarabine and daunorubicin co-encapsulated at a synergistic 5:1 molar ratio. A bone marrow-engrafting CCRF-CEM leukemia model in Rag2-M mice was utilized to correlate the therapeutic and myelosuppressive properties of CPX-351 with bone marrow delivery and drug uptake in leukemia cells relative to normal bone marrow cell populations. When administered to mice bearing CCRF-CEM human leukemia xenografts, CPX-351 ablated bone marrow (BM) leukemic cells to below detectable levels for multiple weeks, whereas the free-drug cocktail only transiently suppressed leukemia growth. In contrast to the activity against leukemia cells, CPX-351 and free-drug cocktail induced similar myelosuppression in non-tumor-bearing BM. In leukemia-laden BM, drug concentrations were markedly elevated for CPX-351 over free-drug cocktail and the first dose of CPX-351, but not free-drug cocktail, potentiated BM drug accumulation for subsequent doses. Confocal fluorescence microscopy revealed that CPX-351 liposomes are taken up by CCRF-CEM cells and subsequently release drugs intracellularly. The improved in vivo efficacy of CPX-351 appears related to increased and prolonged exposure of synergistic cytarabine:daunorubicin ratios in BM, and the selective killing of leukemia may arise from direct liposome-leukemia cell interactions. These features may also have broader applicability in the treatment of other haematological malignancies.
Leukemia research 02/2010; 34(9):1214-23. · 2.36 Impact Factor
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ABSTRACT: The biophysical characterization of CPX-351, a liposomal formulation of cytarabine and daunorubicin encapsulated in a synergistic 5:1 molar ratio (respectively), is presented. CPX-351 is a promising drug candidate currently in two concurrent Phase 2 trials for treatment of acute myeloid leukemia. Its therapeutic activity is dependent on maintenance of the synergistic 5:1 drug:drug ratio in vivo. CPX-351 liposomes have a mean diameter of 107 nm, a single phase transition temperature of 55.3 degrees C, entrapped volume of 1.5 microL/micromol lipid and a zeta potential of -33 mV. Characterization of these physicochemical properties led to identification of an internal structure within the liposomes, later shown to be produced during the cytarabine loading procedure. Fluorescence labeling studies are presented that definitively show that the structure is composed of lipid and represents a second lamella. Extensive spectroscopic studies of the drug-excipient interactions within the liposome and in solution reveal that interactions of both cytarabine and daunorubicin with the copper(II) gluconate/triethanolamine-based buffer system play a role in maintenance of the 5:1 cytarabine:daunorubicin ratio within the formulation. These studies demonstrate the importance of extensive biophysical study of liposomal drug products to elucidate the key physicochemical properties that may impact their in vivo performance.
International journal of pharmaceutics 02/2010; 391(1-2):248-59. · 2.96 Impact Factor
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ABSTRACT: A newly identified form of multidrug resistance (MDR) in tumor cells is presented, pertaining to the commonly encountered resistance of cancer cells to anticancer drug combinations at discrete drug:drug ratios. In vitro studies have revealed that whether anticancer drug combinations interact synergistically or antagonistically can depend on the ratio of the combined agents. Failure to control drug ratios in vivo due to uncoordinated pharmacokinetics could therefore lead to drug resistance if tumor cells are exposed to antagonistic drug ratios. Consequently, the most efficacious drug combination may not occur at the typically employed maximum tolerated doses of the combined drugs if this leads to antagonistic ratios in vivo after administration and resistance to therapeutic effects of the drug combination. Our approach to systematically screen a wide range of drug ratios and concentrations and encapsulate the drug combination in a liposomal delivery vehicle at identified synergistic ratios represents a means to mitigate this drug ratio-dependent MDR mechanism. The in vivo efficacy of the improved agents (CombiPlex formulations) is demonstrated and contrasted with the decreased efficacy when drug combinations are exposed to tumor cells in vivo at antagonistic ratios.
Methods in molecular biology (Clifton, N.J.) 01/2010; 596:291-323.
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ABSTRACT: Irinotecan and cisplatin are two established anticancer drugs, which together constitute an effective combination for treating small-cell lung cancer. We investigated whether the efficacy of this combination could be improved by controlling drug ratios following in vivo administration. Irinotecan and cisplatin combinations were evaluated systematically for drug ratio-dependent synergy in vitro using a panel of 20 tumor cell lines. In vitro screening informatics on drug ratio-dependent cytotoxicity identified a consistently antagonistic region between irinotecan/cisplatin molar ratios of 1:2 to 4:1, which was bordered by two synergistic regions. Liposomal co-formulations of these two agents were developed that exhibited plasma drug half-lives of approximately 6 hours and maintained a fixed drug ratio for more than 24 hours. Drug ratio-dependent antitumor activity was shown in vivo for these liposome formulations, and irinotecan/cisplatin ratios between 5:1 and 10:1 were identified as therapeutically optimal. The relationship between irinotecan/cisplatin ratio and in vivo efficacy was consistent with in vitro drug ratio dependency results. Superior antitumor activity was observed for the liposome-encapsulated 7:1 molar ratio of irinotecan/cisplatin (designated CPX-571) compared with the free-drug cocktail in all models tested. Further efficacy studies in a range of human tumor xenografts, including an irinotecan-resistant model, showed that both liposomal agents contributed to the overall efficacy in a manner consistent with in vivo synergy. These results show the ability of drug delivery technology to enhance the therapeutic activity of irinotecan/cisplatin combination treatment by maintaining synergistic ratios in vivo. CPX-571, a fixed-ratio formulation of irinotecan and cisplatin, is a promising candidate for clinical development.
Molecular Cancer Therapeutics 09/2009; 8(8):2266-75. · 5.23 Impact Factor
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ABSTRACT: CPX-1 is a novel, liposome-encapsulated formulation of irinotecan and floxuridine designed to prolong in vitro optimized synergistic molar ratios of both drugs postinfusion. This open-label, single-arm, dose-escalating phase I study was designed to determine the maximum tolerated dose and pharmacokinetics of CPX-1 in patients with advanced solid tumors.
Patients received CPX-1 at 30, 60, 100, 150, 210, or 270 units/m(2) (1 unit = 1 mg irinotecan + 0.36 mg floxuridine) infused over 90 minutes every 14 days in 28-day cycles. Pharmacokinetic samples were collected on days 1 and 15 of cycle 1.
Thirty-three patients were enrolled, treated, and evaluated for safety; 30 patients were evaluated for response. A 1:1 plasma irinotecan to floxuridine molar ratio was maintained for 8 to 12 hours. Grade 3/4 toxicities included diarrhea (24.2%), neutropenia (12.1%), and hypokalemia (12.1%); 1 patient (270 units/m(2)) died of persistent diarrhea, which led to dehydration and renal failure (grade 5). Partial response occurred in 3 (12%) of the 25 subjects evaluated through Response Evaluation Criteria in Solid Tumors. Progression-free survival lasting >6 months occurred in 9 patients, 6 with colorectal cancer. Among 15 colorectal cancer patients (10 with prior irinotecan), the calculated median progression-free survival was 5.4 months; 11 patients (72.7%) achieved disease control and 2 patients (13%) had partial response.
Outpatient CPX-1 was well tolerated and antitumor activity was shown in patients with advanced solid tumors. The recommended dose for future studies is 210 units/m(2). This is the first clinical evaluation of fixed drug ratio dosing designed to maintain synergistic molar ratios for enhanced therapeutic benefit.
Clinical Cancer Research 01/2009; 15(2):692-700. · 7.74 Impact Factor
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ABSTRACT: CPX-351 (cytarabine/daunorubicin liposome injection) is a liposomal formulation of a synergistic, fixed combination of the antineoplastic drugs cytarabine and daunorubicin for intravenous infusion. The two drugs are contained within the liposome in a 5:1 molar ratio, shown to be synergistic in vitro and in murine models of hematological malignancies. Mice were given a single intravenous dose of CPX-351 or conventional cytarabine and daunorubicin in saline and plasma and bone marrow were assayed for drug and lipid concentrations. A pharmacokinetic model was developed to assess the disposition of the coencapsulated drugs in mice, including the free and encapsulated fractions after measurement of the total plasma concentrations. Through the measurement of the loss of both encapsulated drug and liposomal lipid from the plasma, the routes of elimination, extravasation (uptake of encapsulated drugs into the tissues) and leak (passage of the drugs across the liposome membrane into the plasma), could be discerned. Knowing the leak rates from the liposome into the plasma and the plasma pharmacokinetics of the conventional drugs, the free drug concentrations could be predicted. The free concentrations in the bone marrow from the liposome leak in plasma could also be predicted using the bone marrow responses to the conventional drugs.
Journal of Pharmaceutical Sciences 12/2008; 98(7):2540-8. · 3.06 Impact Factor
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ABSTRACT: Abstract The toxicity and efficacy properties of doxorubicin entrapped inside liposomes are sensitive to the physical characteristics of the vesicle carrier system. Studies addressing such relationships must use preparation procedures with the ability to independently vary vesicle size, lipid composition and drug to lipid ratio while maintaining high trapping efficiencies. The transmembrane pH gradient-driven encapsulation technique allows such liposomal doxorubicin formulations to be prepared. Pharmacokinetic, toxicology and antitumour studies with these systems have revealed several important relationships between liposome physical properties and biological activity. The acute toxicity of liposomal doxorubicin is related primarily to the ability of the liposomes to retain doxorubicin after administration. Including cholesterol and increasing the degree of acyl chain saturation of the phospholipid component in the liposomes significantly decreases drug leakage in the blood, reduces cardiac tissue accumulation of doxorubicin and results in increased LD50 values. In contrast, the efficacy of liposomal doxorubicin is most influenced by liposome size. Specifically, liposomes with a diameter of approximately 100 nm or less exhibit enhanced circulation lifetimes and antitumour activity. While these relationships appear to be rather straightforward, there exist anomalies which suggest that a more thorough evaluation of liposomal doxorubicin pharmacokinetics may be required in order to fully understand its mechanism of action. A key feature in this regard is the ability to differentiate between non-encapsulated and liposome encapsulated doxorubicin pools in the circulation as well as in tumours and normal tissues. This represents a major challenge that must be addressed if significant advances in the design of more effective liposomal doxorubicin formulations are to be achieved.
09/2008; 4(1):529-553.
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ABSTRACT: Abstract Liposome encapsulation of doxorubicin can dramatically alter its biological activity, resulting in decreased toxicity and equivalent or increased antitumor potency. Since the physical characteristics of the liposome carrier system (size, lipid composition, and lipid dose) can have profound effects on the pharmacologic properties of vesicles administered intravenously, it may be expected that the therapeutic activity of liposomal doxorubicin will be sensitive to these properties. To determine the influence of these variables on the toxicity and efficacy properties of liposomal doxorubicin, transmembrane pH gradient-dependent active encapsulation techniques have been utilized to generate liposomal doxorubicin preparations in which the vesicle size, lipid composition, and drug to lipid ratio can be independently varied. these studies indicate that the toxicity of liposomal doxorubicin is related to the stability of the preparation in the circulation. This property is dictated primarily by vesicle lipid composition, although the drug to lipid ratio can also exert an influence. In contrast, the antitumor activity of liposomal doxorubicin appears most sensitive to the size of the vesicle system. Specifically, antitumor drug potency increases as the vesicle size is decreased. these studies demonstrate that manipulating the physical characteristics of liposomal anticancer pharmaceuticals can lead to preparations with optimized therapeutic activity.
09/2008; 1(4):463-480.
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ABSTRACT: Abstract Vincristine is one of the most commonly administered anticancer drugs and is active in a wide range of indications including non-Hodgkin's lymphomas, acute lymphocytic leukemias and lung cancer. Administration of vincristine in long-circulating liposomes may be expected to result in increased accumulation of drug at tumor sites due to “passive targeting” or “disease-site targeting” effects arising from the more permeable vasculature in these regions. Further, for liposomes with appropriate drug release characteristics, extended exposure of tumor cells to vincristine would result from liposomal delivery. The combination of increased drug delivery and extended duration of drug exposure may be expected to result in increased efficacy, particularly because vincristine is a cell-cycle specific drug. It is shown that vincristine can be encapsulated in large unilamellar vesicles (diameter β 100 nm) using a pH gradient (interior acidic) approach. Further, the efficacy of liposomal formulations of vincristine in animal models is highly sensitive to the drug release rate in vivo. A liposomal formulation with drug retention characteristics such that more than 50% of the vincristine is retained in the carrier 24 h following i.v. injection exhibits significantly improved antitumor efficacy in A431 xenograft and P388 murine tumor models in comparison to either free drug or leakier liposomal formulations. The clinical activity of liposomal vincristine has been investigated in relapsed or refractory non-Hodgkin's lymphoma patients at a dose level of 2 mg/m2 every two weeks. Of 83 registered patients, there were 24 responses in 68 evaluable patients. The responses according to histology are: Indolent-13%; Transformed-42%; Aggressive-45%. There were no serious cases of myelosuppression or any toxic deaths. It is concluded that liposomal vincristine can be given at high doses, is active and well tolerated and is rarely neurotoxic or myelosuppressive in these heavily pretreated patients. It appears that the benefits of low toxicity and enhanced efficacy noted in the tumor models are also observed in the clinical setting. A multicenter pivotal Phase II trial of liposomal vincristine in relapsed and refractory non-Hodgkin's lymphoma has been approved by the US FDA and is ongoing.
09/2008; 10(4):501-512.
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09/2008; 8(3):299-335.
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Awa Dicko,
April A Frazier,
Barry D Liboiron,
Anne Hinderliter,
Jeff F Ellena,
Xiaowei Xie,
Connie Cho,
Tom Weber,
Paul G Tardi,
Donna Cabral-Lilly,
David S Cafiso, Lawrence D Mayer
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ABSTRACT: The inter/intramolecular interactions between drugs (floxuridine, irinotecan) and excipients (copper gluconate, triethanolamine) in the dual-drug liposomal formulation CPX-1 were elucidated in order to identify the physicochemical properties that allow coordinated release of irinotecan and floxuridine and maintenance of the two agents at a fixed, synergistic 1:1 molar ratio.
Release of irinotecan and floxuridine from the liposomes was assessed using an in vitro-release assay. Fluorescence, Nuclear Magnetic Resonance spectroscopy (NMR) and UV-Vis were used to characterize the aggregation state of the drugs within the liposomes.
Coordinated release of the drugs from liposomes was disrupted by removing copper gluconate. Approximately 45% of the total irinotecan was detectable in the copper-containing CPX-1 formulation by NMR, which decreased to 19% without copper present in the liposomal interior. Formation of higher order, NMR-silent aggregates was associated with slower and uncoordinated irinotecan release relative to floxuridine and loss of the synergistic drug/drug ratio. Solution spectroscopy and calorimetry revealed that while all formulation components were required to achieve the highest solubility of irinotecan, direct drug-excipient binding interactions were absent.
Long-range interactions between irinotecan, floxuridine and excipients modulate the aggregation state of irinotecan, allowing for simultaneous release of both drugs from the liposomes.
Pharmaceutical Research 08/2008; 25(7):1702-13. · 4.09 Impact Factor
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Steven M Ansell,
Sharon A Johnstone,
Paul G Tardi,
Lily Lo,
Sherwin Xie,
Yu Shu,
Troy O Harasym,
Natashia L Harasym,
Laura Williams,
David Bermudes,
Barry D Liboiron,
Walid Saad,
Robert K Prud'homme, Lawrence D Mayer
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ABSTRACT: A series of paclitaxel prodrugs designed for formulation in lipophilic nanoparticles are described. The hydrophobicity of paclitaxel was increased by conjugating a succession of increasingly hydrophobic lipid anchors to the drug using succinate or diglycolate cross-linkers. The prodrugs were formulated in well defined block copolymer-stabilized nanoparticles. These nanoparticles were shown to have an elimination half-life of approximately 24 h in vivo. The rate at which the prodrug was released from the nanoparticles could be controlled by adjusting the hydrophobicity of the lipid anchor, resulting in release half-lives ranging from 1 to 24 h. The diglycolate and succinate cross-linked prodrugs were 1-2 orders of magnitude less potent than paclitaxel in vitro. Nanoparticle formulations of the succinate prodrugs showed no evidence of efficacy in HT29 human colorectal tumor xenograph models. Efficacy of diglycolate prodrug nanoparticles increased as the anchor hydrophobicity increased. Long circulating diglycolate prodrug nanoparticles provided significantly enhanced therapeutic activity over commercially formulated paclitaxel at the maximum tolerated dose.
Journal of Medicinal Chemistry 07/2008; 51(11):3288-96. · 5.25 Impact Factor
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ABSTRACT: Cancer chemotherapy treatments typically employ drug combinations in which the dose of each agent is pushed to the brink of unacceptable toxicity; however, emerging evidence indicates that this approach may not be providing optimal efficacy due to the manner in which drugs interact. Specifically, whereas certain ratios of combined drugs can be synergistic, other ratios of the same agents may be antagonistic, implying that the most efficacious combinations may be those that utilize certain agents at reduced doses. Advances in nano-scale drug delivery vehicles now enable the translation of in vitro information on synergistic drug ratios into improved anticancer combination therapies in which the desired drug ratio can be controlled and maintained following administration in vivo, so that synergistic effects can be exploited. This "ratiometric" approach to combination chemotherapy opens new opportunities to enhance the effectiveness of existing and future treatment regimens across a spectrum of human diseases.
Molecular Interventions 09/2007; 7(4):216-23. · 4.59 Impact Factor
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Murray S Webb,
Sharon Johnstone,
Tara J Morris,
Allison Kennedy,
Ryan Gallagher,
Natashia Harasym,
Troy Harasym,
Clifford R Shew,
Paul Tardi,
Wieslawa H Dragowska, Lawrence D Mayer,
Marcel B Bally
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ABSTRACT: The purpose of these studies was to design an intravenous drug formulation consisting of two active agents having synergistic in vitro activity. Specifically, we describe a novel drug combination consisting of a cytotoxic agent (vinorelbine) with an apoptosis-inducing lipid (phosphatidylserine, PS). In vitro cytotoxicity screening of PS and vinorelbine, alone and in combination, against human MDA435/LCC6 breast cancer and H460 lung cancer cells was used to identify the molar ratio of these two agents required for synergistic activity. PS and vinorelbine were co-formulated in a lipid-based system at the synergistic molar ratio and the pharmacokinetic and antitumor characteristics of the combination assessed in mice bearing H460 tumors. The cytotoxicity of the lipid, and the synergy between the lipid and vinorelbine, were specific to PS; these effects were not observed using control lipids. A novel formulation of PS, incorporated as a membrane component in liposomes, and encapsulating vinorelbine using a pH gradient based loading method was developed. The PS to vinorelbine ratio in this formulation was 1/1, a ratio that produced synergistic in vitro cytotoxicity over a broad concentration range. The vinorelbine and PS dual-agent treatment significantly delayed the growth of subcutaneous human H460 xenograft tumors in Rag2M mice compared to the same dose of free vinorelbine given alone or given as a cocktail of the free vinorelbine simultaneously with empty PS-containing liposomes. These studies demonstrate the potential to develop clinically relevant drug combinations identified using in vitro drug-drug interactions combined with lipid-based delivery systems to co-formulate drugs at their synergistic ratios.
European Journal of Pharmaceutics and Biopharmaceutics 04/2007; 65(3):289-99. · 4.27 Impact Factor
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ABSTRACT: A liposomal delivery system that coordinates the release of irinotecan and floxuridine in vivo has been developed. The encapsulation of floxuridine was achieved through passive entrapment while irinotecan was actively loaded using a novel copper gluconate/triethanolamine based procedure. Coordinating the release rates of both drugs was achieved by altering the cholesterol content of distearoylphosphatidylcholine (DSPC)/distearoylphosphatidylglycerol (DSPG) based formulations. The liposomal retention of floxuridine in plasma after intravenous injection was dramatically improved by decreasing the cholesterol content of the formulation below 20 mol%. In the case of irinotecan, the opposite trend was observed where increasing cholesterol content enhanced drug retention. Liposomes composed of DSPC/DSPG/Chol (7:2:1, mole ratio) containing co-encapsulated irinotecan and floxuridine at a 1:1 molar ratio exhibited matched leakage rates for the two agents so that the 1:1 ratio was maintained after intravenous administration to mice. The encapsulation of irinotecan was optimal when copper gluconate/triethanolamine (pH 7.4) was used as the intraliposomal buffer. The efficiency of irinotecan loading was approximately 80% with a starting drug to lipid molar ratio of 0.1/1. Leakage of floxuridine from the liposomes during irinotecan loading at 50 degrees C complicated the ability to readily achieve the target 1:1 irinotecan/floxuridine ratio inside the formulation. As a result, a procedure for the simultaneous encapsulation of irinotecan and floxuridine was developed. This co-encapsulation method has the advantage over sequential loading in that extrusion can be performed in the absence of chemotherapeutic agents and the drug/drug ratios in the final formulation can be more precisely controlled.
Biochimica et Biophysica Acta 04/2007; 1768(3):678-87. · 4.66 Impact Factor
