Liposome drugs' loading efficiency: a working model based on loading conditions and drug's physicochemical properties.

Remote loading of liposomes by transmembrane gradients is one of the best approaches for achieving the high enough drug level per liposome required for the liposomal drug to be therapeutically efficacious. This breakthrough, which enabled the approval and clinical use of nanoliposomal drugs such as Doxil, has not been paralleled by an in-depth understanding that allows predicting loading efficiency of drugs. Here we describe how applying data-mining algorithms on a data bank based on Barenholz's laboratory's 15 years of liposome research experience on remote loading of 9 different drugs enabled us to build a model that relates drug physicochemical properties and loading conditions to loading efficiency. This model enables choosing candidate molecules for remote loading and optimizing loading conditions according to logical considerations. The model should also help in designing pro-drugs suitable for remote loading. Our approach is expected to improve and accelerate development of liposomal formulations for clinical applications.

[1]  R. Biltonen,et al.  The use of differential scanning calorimetry as a tool to characterize liposome preparations , 1993 .

[2]  Y. Barenholz,et al.  Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. , 1993, Biochimica et biophysica acta.

[3]  Yechezkel Barenholz,et al.  Enzymatic assays for quality control and pharmacokinetics of liposome formulations: comparison with nonenzymatic conventional methodologies. , 2003, Methods in enzymology.

[4]  Yechezkel Barenholz,et al.  Relevancy of Drug Loading to Liposomal Formulation Therapeutic Efficacy , 2003, Journal of liposome research.

[5]  D. Deamer,et al.  Catecholamine uptake and concentration by liposomes maintaining p/ gradients. , 1976, Biochimica et biophysica acta.

[6]  D. Deamer,et al.  Permeability of lipid bilayers to water and ionic solutes. , 1986, Chemistry and physics of lipids.

[7]  Ian H. Witten,et al.  Data mining: practical machine learning tools and techniques, 3rd Edition , 1999 .

[8]  C. Hartrick,et al.  Extended‐Release Epidural Morphine (DepoDur™): An Old Drug with a New Profile , 2005, Pain practice : the official journal of World Institute of Pain.

[9]  D. Massart,et al.  Determination of vinca alkaloids in mouse tissues by high-performance liquid chromatography. , 1992, Journal of chromatography.

[10]  D. Tzemach,et al.  Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes , 1999, Cancer.

[11]  M. Simionescu,et al.  Designing of ‘intelligent’ liposomes for efficient delivery of drugs , 2002, Journal of cellular and molecular medicine.

[12]  Y. Barenholz,et al.  Ammonium Sulfate Gradients for Efficient and Stable Remote Loading of Amphipathic Weak Bases into Liposomes and Ligandoliposomes. , 1994 .

[13]  H. Turndorf,et al.  Prolonged Analgesia With Liposomal Bupivacaine in a Mouse Model , 1993, Regional Anesthesia & Pain Medicine.

[14]  B. D. Anderson,et al.  Initial rate studies of hydrolysis and acyl migration in methylprednisolone 21-hemisuccinate and 17-hemisuccinate. , 1981, Journal of pharmaceutical sciences.

[15]  Yechezkel Barenholz,et al.  A Novel Liposomal Bupivacaine Formulation to Produce Ultralong-Acting Analgesia , 2004, Anesthesiology.

[16]  M. Stuart,et al.  Transmembrane gradient driven phase transitions within vesicles: lessons for drug delivery. , 1995, Biochimica et biophysica acta.

[17]  Y. Barenholz,et al.  Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. , 1994, Cancer research.

[18]  Y. Barenholz,et al.  DRV Liposomal Bupivacaine: Preparation, Characterization, and In Vivo Evaluation in Mice , 2001, Pharmaceutical Research.

[19]  K. Edwards,et al.  Optimization and characterization of a sphingomyelin/cholesterol liposome formulation of vinorelbine with promising antitumor activity. , 2005, Journal of pharmaceutical sciences.

[20]  M. Wauben,et al.  Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes. , 2003, Arthritis and rheumatism.

[21]  X Zhang,et al.  Effect of stealthy liposomal topotecan plus amlodipine on the multidrug‐resistant leukaemia cells in vitro and xenograft in mice , 2006, European journal of clinical investigation.

[22]  Yechezkel Barenholz,et al.  Amphipathic weak acid glucocorticoid prodrugs remote-loaded into sterically stabilized nanoliposomes evaluated in arthritic rats and in a Beagle dog: a novel approach to treating autoimmune arthritis. , 2008, Arthritis and rheumatism.

[23]  P. Cullis,et al.  Liposome-encapsulated vincristine, vinblastine and vinorelbine: a comparative study of drug loading and retention. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[24]  J. Fuchs,et al.  Electron paramagnetic resonance studies on nitroxide radical 2,2,5,5-tetramethyl-4-piperidin-1-oxyl (TEMPO) redox reactions in human skin. , 1997, Free radical biology & medicine.

[25]  S. Clerc,et al.  A quantitative model for using acridine orange as a transmembrane pH gradient probe. , 1998, Analytical biochemistry.

[26]  Y. Barenholz,et al.  Liposomes: preparation, characterization, and preservation. , 2006 .

[27]  S. Strychor,et al.  Plasma, Tumor, and Tissue Disposition of STEALTH Liposomal CKD-602 (S-CKD602) and Nonliposomal CKD-602 in Mice Bearing A375 Human Melanoma Xenografts , 2007, Clinical Cancer Research.

[28]  J. Gier.  Osmotic behaviour and permeability properties of liposomes , 1993 .

[29]  Lasic Dd,et al.  Sterically stabilized liposomes in cancer therapy and gene delivery. , 1999 .

[30]  J. Ross Quinlan,et al.  C4.5: Programs for Machine Learning , 1992 .

[31]  M. Bally,et al.  Liposomal encapsulation of topotecan enhances anticancer efficacy in murine and human xenograft models. , 2000, Cancer research.

[32]  D. Tzemach,et al.  Pharmacological studies of cisplatin encapsulated in long-circulating liposomes in mouse tumor models. , 1999, Anti-cancer drugs.

[33]  T Nagai,et al.  Remote loading of diclofenac, insulin and fluorescein isothiocyanate labeled insulin into liposomes by pH and acetate gradient methods. , 1999, International journal of pharmaceutics.

[34]  Yechezkel Barenholz,et al.  The antioxidant tempamine: in vitro antitumor and neuroprotective effects and optimization of liposomal encapsulation and release. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[35]  Čeh,et al.  A Rigorous Theory of Remote Loading of Drugs into Liposomes: Transmembrane Potential and Induced pH-Gradient Loading and Leakage of Liposomes , 1997, Journal of colloid and interface science.

[36]  Wilfred D. Stein,et al.  Transport and Diffusion Across Cell Membranes , 1986 .

[37]  D. Crommelin,et al.  The interaction of cytostatic drugs with adsorbents in aqueous media. The potential implications for liposome preparation. , 1985, Biochimica et biophysica acta.

[38]  Y. Oh,et al.  Formulation and efficacy of liposome-encapsulated antibiotics for therapy of intracellular Mycobacterium avium infection , 1995, Antimicrobial agents and chemotherapy.

[39]  Y. Barenholz,et al.  Characterization of sterically stabilized cisplatin liposomes by nuclear magnetic resonance. , 2001, Biochimica et biophysica acta.

[40]  Yechezkel Barenholz,et al.  Liposome application: problems and prospects , 2001 .

[41]  S. Clerc,et al.  Loading of amphipathic weak acids into liposomes in response to transmembrane calcium acetate gradients. , 1995, Biochimica et biophysica acta.