Intra and Inter-Molecular Interactions Dictate the Aggregation State of Irinotecan Co-Encapsulated with Floxuridine Inside Liposomes

Dicko, Awa; Frazier, April A.; Liboiron, Barry D.; Hinderliter, Anne; Ellena, Jeff F.; Xie, Xiaobing; Cho, Connie; Weber, Tom; Tardi, Paul; Cabral-Lilly, Donna; Cafiso, David S.; Mayer, Lawrence D.

doi:10.1007/s11095-008-9561-z

Cited by 22 publications

(11 citation statements)

References 31 publications

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“…IRN in the external buffer is then able to cross the liposome bilayer and become protonated. IRN within the liposomes that is positively charged (pKa = 8.1) interacts with FOA that is negatively charged (pKa = 2.4) and probably forms a complex [36]. …”

Section: Resultsmentioning

confidence: 99%

Anti-tumor activity of liposome encapsulated fluoroorotic acid as a single agent and in combination with liposome irinotecan

Riviere

Ferguson

Jerger

et al. 2011

Journal of Controlled Release

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To test the hypothesis that co-delivery of synergistic drug combinations in the same liposome provides a better anti-tumor effect than the drugs administered in separate liposomes, fluoroorotic acid (FOA) alone and in combination with irinotecan (IRN) were encapsulated in liposomes and evaluated for their anti-tumor activity in the C26 colon carcinoma mouse model. Fluoroorotic acid was dissolved in 7 M urea to increase its solubility so it could be passively loaded into liposomes at a high concentration. IRN was remote loaded into liposomes that contained the ammonium salt of the multi-valent 1,2,3,4-butanetetratcarboxylic acid with a greater than 90% efficiency and at a drug to lipid ratio of 0.2/1. When the two molecules were loaded into the same liposome, FOA was used to remote load IRN. Modulation of the drug/lipid ratio, temperature, and loading time allowed for consistent co-encapsulation of FOA + IRN at various molar ratios. The anti-tumor activity of L-FOA, L-IRN, L-FOA-IRN (5:1), and the L-FOA + L-IRN mixture (5:1) were examined in the C26 mouse model. The maximum tolerated dose of L-FOA was 10 mg/kg given weekly as compared to 100 mg/kg of the non-encapsulated FOA. Delivering two drugs in the same liposome provided a statistically better antitumor effect than delivering the drugs in separate liposomes at the same drug ratio. However, the synergistic activity of the 5:1 ratio of free drugs measured on C26 cells in vitro was not observed in the C26 tumor mouse model. These findings point out the challenges to the design of synergistic treatment protocols based upon results from in vitro cytotoxicity studies. L-FOA at 10 mg/kg as a single agent provided the best anti-tumor efficacy which supports previous suggestions that L-FOA has useful properties as a liposome dependent drug.

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Section: Resultsmentioning

confidence: 99%

Anti-tumor activity of liposome encapsulated fluoroorotic acid as a single agent and in combination with liposome irinotecan

Riviere

Ferguson

Jerger

et al. 2011

Journal of Controlled Release

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“…However, through thorough understanding of interactions among excipients and drugs, drug distribution inside nanoparticles, and properties of nanoparticle components in relation to their biofate and drug release mechanism, it is possible to engineer nanocarrier to meet the goals. For example, Dicko et al studied the drug-drug and drug-excipient molecular interactions that drive the co-loading process and coordinated release of irinotecan and floxuridine from the liposomal formulation CPX-1 [71]. To co-encapsulate drugs at the desired ratio, irinotecan was loaded via the neutral active antiport by exchanging its proton with triethanolamine buffer across the liposomal membrane, whereas floxuridine was passively loaded into the liposome.…”

Section: Technical Challenges and Limitationsmentioning

confidence: 99%

“…To co-encapsulate drugs at the desired ratio, irinotecan was loaded via the neutral active antiport by exchanging its proton with triethanolamine buffer across the liposomal membrane, whereas floxuridine was passively loaded into the liposome. Examinations using fluorescence, NMR and UV-V is revealed that the interplay between copper gluconate buffer and drugs limited the aggregate formation of irinotecan, allowing for slow release of irinotecan together with floxuridine from the liposomes [71]. …”

Section: Technical Challenges and Limitationsmentioning

confidence: 99%

Nanomedicine of synergistic drug combinations for cancer therapy – Strategies and perspectives

Zhang

Wong

Xue

et al. 2016

Journal of Controlled Release

285

166

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Nanomedicine of synergistic drug combinations has shown increasing significance in cancer therapy due to its promise in providing superior therapeutic benefits to the current drug combination therapy used in clinical practice. In this article, we will examine the rationale, principles, and advantages of applying nanocarriers to improve anticancer drug combination therapy, review the use of nanocarriers for delivery of a variety of combinations of different classes of anticancer agents including small molecule drugs and biologics, and discuss the challenges and future perspectives of the nanocarrier-based combination therapy. The goal of this review is to provide better understanding of this increasingly important new paradigm of cancer treatment and key considerations for rational design of nanomedicine of synergistic drug combinations for cancer therapy.

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“…Productspecific characterization focuses on drug-excipient interaction, drug loading mechanisms, drug-drug interactions, and physical disposition of the drug in the carrier. An example was presented where data from two characterization techniques were used to help determine the final drug product formulation (48). CPX-1 (irinotecan/floxuridine) liposome injection is a clinical stage liposomal nanomedicine intended for the treatment of advanced colorectal cancer.…”

Section: Liposomes: D Cabral-lillymentioning

confidence: 99%

Summary Report of PQRI Workshop on Nanomaterial in Drug Products: Current Experience and Management of Potential Risks

Bartlett

Brewster

Brown

et al. 2014

AAPS J

Self Cite

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At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations. Areas where additional regulatory guidance and material characterization standards would help in the development and approval of nanomedicines were explored. Representatives from the US Food and Drug Administration (USFDA), Health Canada, and European Medicines Agency (EMA) presented information about the diversity of nanomaterials in approved and newly developed drug products. USFDA, Health Canada, and EMA regulators discussed the applicability of current regulatory policies in presentations and open discussion. Information contained in several of the recent EMA reflection papers was discussed in detail, along with their scope and intent to enhance scientific understanding about disposition, efficacy, and safety of nanomaterials introduced in vivo and regulatory requirements for testing and market authorization. Opportunities for interaction with regulatory agencies during the lifecycle of nanomedicines were also addressed at the meeting. This is a summary of the workshop presentations and discussions, including considerations for future regulatory guidance on drug products containing nanomaterials.

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Intra and Inter-Molecular Interactions Dictate the Aggregation State of Irinotecan Co-Encapsulated with Floxuridine Inside Liposomes

Abstract: Long-range interactions between irinotecan, floxuridine and excipients modulate the aggregation state of irinotecan, allowing for simultaneous release of both drugs from the liposomes.

Cited by 22 publications

References 31 publications

Anti-tumor activity of liposome encapsulated fluoroorotic acid as a single agent and in combination with liposome irinotecan

Anti-tumor activity of liposome encapsulated fluoroorotic acid as a single agent and in combination with liposome irinotecan

Nanomedicine of synergistic drug combinations for cancer therapy – Strategies and perspectives

Summary Report of PQRI Workshop on Nanomaterial in Drug Products: Current Experience and Management of Potential Risks

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