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1.
J Drug Deliv ; 2011: 349206, 2011.
Article in English | MEDLINE | ID: mdl-21773044

ABSTRACT

Diblock copolymer nanoparticles encapsulating a paclitaxel prodrug, Propac 7, have been used to demonstrate the usefulness of a nonmetabolizable radioactive marker, cholesteryl hexadecyl ether (CHE), to evaluate nanoparticle formulation variables. Since CHE did not exchange out of the nanoparticles, the rate of clearance of the CHE could be used as an indicator of nanoparticle stability in vivo. We simultaneously monitored prodrug circulation and carrier circulation in the plasma and the retention of CHE relative to the retention of prodrug in the plasma was used to distinguish prodrug release from nanoparticle plasma clearance. Nanoparticles labelled with CHE were also used to evaluate accumulation of nanoparticles in the tumour. This marker has provided relevant data which we have applied to optimise our nanoparticle formulations.

2.
Chemother Res Pract ; 2011: 213848, 2011.
Article in English | MEDLINE | ID: mdl-22312548

ABSTRACT

The first liposomal formulation of cisplatin to be evaluated clinically was SPI-077. Although the formulation demonstrated enhanced cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited cisplatin release from the formulation localized within the tumor. We have examined a series of liposomal formulations to address the in vivo relationship between cisplatin release rate and formulation efficacy in the P388 murine leukemia model. The base formulation of phosphatidylcholine: phosphatidylglycerol: cholesterol was altered in the C18 and C16 phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (T(m)) ranged from 42-55°C. The high T(m) formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest T(m) formulations released the drug too rapidly in the plasma, limiting drug delivery to the tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle.

3.
Mol Cancer Ther ; 8(8): 2266-75, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19671743

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.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Camptothecin/analogs & derivatives , Cisplatin/administration & dosage , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Camptothecin/administration & dosage , Camptothecin/pharmacokinetics , Cell Line, Tumor , Cell Proliferation , Cisplatin/pharmacokinetics , Drug Synergism , Humans , Irinotecan , Mice , Mice, Nude
4.
Leuk Res ; 33(1): 129-39, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18676016

ABSTRACT

We demonstrate here that cytarabine and daunorubicin, a standard drug combination used in the treatment of leukaemia, exhibits drug ratio-dependent synergistic antitumor activity in vitro and in vivo. A cytarabine:daunorubicin molar ratio of 5:1 displayed the greatest degree of synergy and minimum antagonism in a panel of 15 tumor cell lines in vitro. Co-encapsulating cytarabine and daunorubicin inside liposomes maintained the synergistic drug ratio in plasma for 24h post-injection. Liposome-encapsulated cytarabine:daunorubicin combinations exhibited drug ratio-dependent in vivo efficacy with the 5:1 molar drug ratio (designated CPX-351) having the greatest therapeutic index, despite using sub-MTD daunorubicin doses. CPX-351 exhibited superior therapeutic activity compared to free-drug cocktails, with high proportions of long-term survivors, consistent with in vivo synergy. The therapeutic advantage of CPX-351 was associated with prolonged maintenance of synergistic drug ratios in bone marrow. These results indicate that in vitro informatics on cytarabine:daunorubicin cytotoxicity can be translated in vivo to optimize the efficacy of anticancer drug combinations by controlling the exposure of drug ratios with drug delivery vehicles.


Subject(s)
Antineoplastic Agents/pharmacology , Cytarabine/pharmacology , Daunorubicin/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cell Proliferation , Cytarabine/administration & dosage , Cytarabine/pharmacokinetics , Daunorubicin/administration & dosage , Daunorubicin/pharmacokinetics , Flow Cytometry , Humans , Liposomes , Mice
5.
J Med Chem ; 51(11): 3288-96, 2008 Jun 12.
Article in English | MEDLINE | ID: mdl-18465845

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.


Subject(s)
Paclitaxel/administration & dosage , Prodrugs/administration & dosage , Animals , Cell Line, Tumor , Drug Stability , Humans , Hydrophobic and Hydrophilic Interactions , Lipids/chemistry , Mice , Mice, Nude , Micelles , Nanoparticles , Neoplasm Transplantation , Paclitaxel/chemistry , Paclitaxel/pharmacology , Polyethylene Glycols , Polystyrenes , Prodrugs/chemistry , Prodrugs/pharmacology , Transplantation, Heterologous
6.
Oncol Res ; 16(8): 361-74, 2007.
Article in English | MEDLINE | ID: mdl-17913044

ABSTRACT

Whether anticancer drug combinations act synergistically or antagonistically often depends on the ratio of the agents being combined. We show here that combinations of irinotecan and floxuridine exhibit drug ratio-dependent cytotoxicity in a broad panel of tumor cell lines in vitro where a 1:1 molar ratio consistently provided synergy and avoided antagonism. In vivo delivery of irinotecan and floxuridine coencapsulated inside liposomes at the synergistic 1:1 molar ratio (referred to as CPX-1) lead to greatly enhanced efficacy compared to the two drugs administered as a saline-based cocktail in a number of human xenograft and murine tumor models. When compared to liposomal irinotecan or liposomal floxuridine, the therapeutic activity of CPX-1 in vivo was not only superior to the individual liposomal agents, but the extent of tumor growth inhibition was greater than that predicted for combining the activities of the individual agents. In contrast, liposome delivery of irinotecan:floxuridine ratios shown to be antagonistic in vitro provided antitumor activity that was actually less than that achieved with liposomal irinotecan alone, indicative of in vivo antagonism. Synergistic antitumor activity observed for CPX-1 was associated with maintenance of the 1:1 irinotecan:floxuridine molar ratio in plasma and tumor tissue over 16-24 h. In contrast, injection of the drugs combined in saline resulted in irinotecan:floxuridine ratios that changed 10-fold within 1 h in plasma and sevenfold within 4 h in tumor tissue. These results indicate that substantial improvements in the efficacy of drug combinations may be achieved by maintaining in vitro-identified synergistic drug ratios after systemic administration using drug delivery vehicles.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Floxuridine/administration & dosage , Neoplasms/drug therapy , Animals , Camptothecin/administration & dosage , Camptothecin/blood , Camptothecin/pharmacokinetics , Cell Survival , Dose-Response Relationship, Drug , Drug Antagonism , Drug Combinations , Drug Compounding , Drug Evaluation, Preclinical , Drug Synergism , Female , Floxuridine/blood , Floxuridine/pharmacokinetics , Humans , Injections, Intravenous , Irinotecan , Liposomes , Mice , Neoplasms/metabolism , Pharmaceutical Vehicles , Survival Rate , Tissue Distribution , Tumor Burden , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
7.
Biochim Biophys Acta ; 1768(3): 678-87, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17208196

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.


Subject(s)
Antimetabolites, Antineoplastic/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Camptothecin/analogs & derivatives , Floxuridine/chemistry , Liposomes , Animals , Antimetabolites, Antineoplastic/blood , Antimetabolites, Antineoplastic/pharmacokinetics , Antineoplastic Agents, Phytogenic/blood , Antineoplastic Agents, Phytogenic/pharmacokinetics , Camptothecin/blood , Camptothecin/chemistry , Camptothecin/pharmacokinetics , Cholesterol/chemistry , Drug Combinations , Drug Compounding , Drug Delivery Systems , Female , Floxuridine/blood , Floxuridine/pharmacokinetics , Hydrogen-Ion Concentration , Irinotecan , Mice , Mice, Inbred BALB C
8.
Eur J Pharm Biopharm ; 65(3): 289-99, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17123800

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.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lung Neoplasms/drug therapy , Phosphatidylserines/administration & dosage , Vinblastine/analogs & derivatives , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Cell Line, Tumor , Cell Survival/drug effects , Chemistry, Pharmaceutical , Dose-Response Relationship, Drug , Drug Compounding , Drug Design , Drug Synergism , Female , Humans , Injections, Intravenous , Liposomes , Lung Neoplasms/pathology , Mice , Phosphatidylserines/chemistry , Phosphatidylserines/pharmacokinetics , Technology, Pharmaceutical , Vinblastine/administration & dosage , Vinblastine/chemistry , Vinblastine/pharmacokinetics , Vinorelbine , Xenograft Model Antitumor Assays
9.
Mol Cancer Ther ; 5(7): 1854-63, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16891472

ABSTRACT

Anticancer drug combinations can act synergistically or antagonistically against tumor cells in vitro depending on the ratios of the individual agents comprising the combination. The importance of drug ratios in vivo, however, has heretofore not been investigated, and combination chemotherapy treatment regimens continue to be developed based on the maximum tolerated dose of the individual agents. We systematically examined three different drug combinations representing a range of anticancer drug classes with distinct molecular mechanisms (irinotecan/floxuridine, cytarabine/daunorubicin, and cisplatin/daunorubicin) for drug ratio-dependent synergy. In each case, synergistic interactions were observed in vitro at certain drug/drug molar ratio ranges (1:1, 5:1, and 10:1, respectively), whereas other ratios were additive or antagonistic. We were able to maintain fixed drug ratios in plasma of mice for 24 hours after i.v. injection for all three combinations by controlling and overcoming the inherent dissimilar pharmacokinetics of individual drugs through encapsulation in liposomal carrier systems. The liposomes not only maintained drug ratios in the plasma after injection, but also delivered the formulated drug ratio directly to tumor tissue. In vivo maintenance of drug ratios shown to be synergistic in vitro provided increased efficacy in preclinical tumor models, whereas attenuated antitumor activity was observed when antagonistic drug ratios were maintained. Fixing synergistic drug ratios in pharmaceutical carriers provides an avenue by which anticancer drug combinations can be optimized prospectively for maximum therapeutic activity during preclinical development and differs from current practice in which dosing regimens are developed empirically in late-stage clinical trials based on tolerability.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasms/drug therapy , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Camptothecin/blood , Cell Line, Tumor , Cisplatin/administration & dosage , Cisplatin/blood , Cytarabine/administration & dosage , Cytarabine/blood , Daunorubicin/administration & dosage , Daunorubicin/blood , Dose-Response Relationship, Drug , Drug Synergism , Floxuridine/administration & dosage , Floxuridine/blood , Humans , Irinotecan , Liposomes , Mice , Xenograft Model Antitumor Assays
10.
Am J Med Genet A ; 120A(2): 169-73, 2003 Jul 15.
Article in English | MEDLINE | ID: mdl-12833395

ABSTRACT

We report a new disorder with diverse neurological problems resulting from abnormal brainstem function. Consistent features of this disorder, which we propose should be called the Atabascan brainstem dysgenesis syndrome, include horizontal gaze palsy, sensorineural deafness, central hypoventilation, and developmental delay. Other features seen in some patients include swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, and cardiac outflow tract anomalies. All affected children described are of Athabascan Indian heritage, with eight children from the Navajo tribe and two patients who are of Apache background. The disorder can be distinguished from the Moebius syndrome by the pattern of central nervous system findings, especially the sensorineural deafness, horizontal gaze palsy, and central hypoventilation. Recognition of children with some features of Athabascan brainstem dysgenesis syndrome should prompt investigation for other related abnormalities. Published 2003 Wiley-Liss, Inc.


Subject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Brain Stem/abnormalities , Child , Deafness/complications , Deafness/genetics , Developmental Disabilities/complications , Developmental Disabilities/genetics , Disease Progression , Fatal Outcome , Female , Hearing Loss, Sensorineural/complications , Hearing Loss, Sensorineural/genetics , Humans , Hypoventilation/complications , Hypoventilation/genetics , Indians, North American , Male , Mobius Syndrome/complications , Mobius Syndrome/genetics , Ocular Motility Disorders/complications , Ocular Motility Disorders/genetics , Syndrome
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