Systems Pharmacological Analysis of Paclitaxel-Mediated Tumor Priming That Enhances Nanocarrier Deposition and Efficacy

Paclitaxel (PAC)-mediated apoptosis decompresses and primes tumors for enhanced deposition of nanoparticulate agents such as pegylated liposomal doxorubicin (DXR). A quantitative pharmacokinetic/pharmacodynamic (PK/PD) approach was developed to analyze efficacy and identify optima for PAC combined with sterically stabilized liposome (SSL)-DXR. Using data extracted from diverse literature sources, Cremophor-paclitaxel (Taxol®) PK was described by a carrier-mediated dispositional model and SSL-DXR PK was described by a two-compartment model with first-order drug release. A hybrid-physiologic, well-stirred model with partition coefficients (Kp) captured intratumor concentrations. Apoptotic responses driving tumor priming were modeled using nonlinear, time-dependent transduction functions. The tumor growth model used net first-order growth and death rate constants, and two transit compartments that captured the temporal displacement of tumor exposure versus effect, and apoptotic signals from each agent were used to drive cytotoxic effects of the combination. The final model captured plasma and intratumor PK data, apoptosis induction profiles, and tumor growth for all treatments/sequences. A feedback loop representing PAC-induced apoptosis effects on Kp_DXR enabled the model to capture tumor-priming effects. Simulations to explore time- and sequence-dependent effects of priming indicated that PAC priming increased Kp_DXR 3-fold. The intratumor concentrations producing maximal and half-maximal effects were 18 and 7.2 μg/ml for PAC, and 17.6 and 14.3 μg/ml for SSL-DXR. The duration of drug-induced apoptosis was 27.4 h for PAC and 15.8 h for SSL-DXR. Simulations suggested that PAC administered 24 h before peak priming could increase efficacy 2.5-fold over experimentally reported results. The quantitative approach developed in this article is applicable for evaluating tumor-priming strategies using diverse agents.

[1]  N. Millenbaugh,et al.  Cytostatic and Apoptotic Effects of Paclitaxel in Human Ovarian Tumors , 2004, Pharmaceutical Research.

[2]  G. Kwon,et al.  Polymeric micelles for neoadjuvant cancer therapy and tumor-primed optical imaging. , 2011, ACS nano.

[3]  R. Danesi,et al.  Pharmacokinetic-Pharmacodynamic Relationships of the Anthracycline Anticancer Drugs , 2002, Clinical pharmacokinetics.

[4]  Neil F. Johnson,et al.  Model for in vivo progression of tumors based on co-evolving cell population and vasculature , 2011, Scientific reports.

[5]  L. Peters,et al.  Kinetics of mitotic arrest and apoptosis in murine mammary and ovarian tumors treated with taxol , 1995, Cancer Chemotherapy and Pharmacology.

[6]  J. Beijnen,et al.  Determination of polyoxyethyleneglycerol triricinoleate 35 (Cremophor EL) in plasma by pre-column derivatization and reversed-phase high-performance liquid chromatography. , 1996, Journal of chromatography. B, Biomedical applications.

[7]  Anurag K. Singh,et al.  Mild elevation of body temperature reduces tumor interstitial fluid pressure and hypoxia and enhances efficacy of radiotherapy in murine tumor models. , 2011, Cancer research.

[8]  M. Wientjes,et al.  Kinetics of hallmark biochemical changes in paclitaxel-induced apoptosis , 1999, AAPS PharmSci.

[9]  R K Jain,et al.  Delivery of novel therapeutic agents in tumors: physiological barriers and strategies. , 1990, Journal of the National Cancer Institute.

[10]  Y. Barenholz,et al.  Gelation of liposome interior A novel method for drug encapsulation , 1992, FEBS letters.

[11]  Paolo Magni,et al.  Predictive Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Kinetics in Xenograft Models after Administration of Anticancer Agents , 2004, Cancer Research.

[12]  Rakesh K. Jain,et al.  Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors , 2004, Cancer Research.

[13]  W. Jusko,et al.  Mechanistic population pharmacokinetics of total and unbound paclitaxel for a new nanodroplet formulation versus Taxol in cancer patients , 2009, Cancer Chemotherapy and Pharmacology.

[14]  M. Bally,et al.  Techniques for encapsulating bioactive agents into liposomes. , 1986, Chemistry and physics of lipids.

[15]  J. Gallo,et al.  Demonstration of the equivalent pharmacokinetic/pharmacodynamic dosing strategy in a multiple-dose study of gefitinib , 2009, Molecular Cancer Therapeutics.

[16]  Donald E. Mager,et al.  General Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition , 2001, Journal of Pharmacokinetics and Pharmacodynamics.

[17]  A. Gabizon,et al.  Pharmacokinetics and tissue distribution of doxorubicin encapsulated in stable liposomes with long circulation times. , 1989, Journal of the National Cancer Institute.

[18]  Joy Joseph,et al.  Doxorubicin Induces Apoptosis in Normal and Tumor Cells via Distinctly Different Mechanisms , 2004, Journal of Biological Chemistry.

[19]  C. Davies,et al.  Collagenase Increases the Transcapillary Pressure Gradient and Improves the Uptake and Distribution of Monoclonal Antibodies in Human Osteosarcoma Xenografts , 2004, Cancer Research.

[20]  C. de Lange Davies,et al.  Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx™) in human osteosarcoma xenografts , 2005, British Journal of Cancer.

[21]  References , 1971 .

[22]  M. Bally,et al.  Irinophore C, a Novel Nanoformulation of Irinotecan, Alters Tumor Vascular Function and Enhances the Distribution of 5-Fluorouracil and Doxorubicin , 2008, Clinical Cancer Research.

[23]  R K Jain,et al.  Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications. , 1999, Cancer research.

[24]  Jessie L.-S. Au,et al.  Drug Delivery and Transport to Solid Tumors , 2003, Pharmaceutical Research.

[25]  R K Jain,et al.  Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice. , 1994, Cancer research.

[26]  J. Au,et al.  Tumor Priming Enhances Delivery and Efficacy of Nanomedicines , 2007, Journal of Pharmacology and Experimental Therapeutics.

[27]  M. Dewhirst,et al.  Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size. , 2000, Cancer research.

[28]  M. Wientjes,et al.  Enhancement of paclitaxel delivery to solid tumors by apoptosis-inducing pretreatment: effect of treatment schedule. , 2001, The Journal of pharmacology and experimental therapeutics.

[29]  David Allard,et al.  Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer , 2009, Science.

[30]  R. Zhou,et al.  Antivasculature effects of doxorubicin-containing liposomes in an intracranial rat brain tumor model. , 2002, Cancer research.

[31]  Patrick Soon-Shiong,et al.  Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[32]  J. Beijnen,et al.  Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. , 1996, Cancer research.

[33]  M Rocchetti,et al.  A mathematical model to study the effects of drugs administration on tumor growth dynamics. , 2006, Mathematical biosciences.

[34]  Theresa M Allen,et al.  Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. , 2004, Biochimica et biophysica acta.

[35]  Evelyn D. Lobo,et al.  Pharmacodynamic modeling of chemotherapeutic effects: Application of a transit compartment model to characterize methotrexate effects in vitro , 2008, AAPS PharmSci.

[36]  D. Mager,et al.  Meta-analysis of Nanoparticulate Paclitaxel Delivery System Pharmacokinetics and Model Prediction of Associated Neutropenia , 2012, Pharmaceutical Research.

[37]  Carlos Cuevas,et al.  Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. , 2012, Cancer cell.

[38]  D. Mager,et al.  Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation , 2012, Pharmaceutical Research.

[39]  R K Jain,et al.  Transport of molecules in the tumor interstitium: a review. , 1987, Cancer research.

[40]  D. Mager,et al.  Effect of Repetitive Administration of Doxorubicin-Containing Liposomes on Plasma Pharmacokinetics and Drug Biodistribution in a Rat Brain Tumor Model , 2005, Clinical Cancer Research.

[41]  Qiang Zhang,et al.  Enhanced Intracellular Uptake of Sterically Stabilized Liposomal Doxorubicin in Vitro Resulting in Improved Antitumor Activity in Vivo , 2005, Pharmaceutical Research.

[42]  M. De Waard,et al.  Efficient induction of apoptosis by doxorubicin coupled to cell-penetrating peptides compared to unconjugated doxorubicin in the human breast cancer cell line MDA-MB 231. , 2009, Cancer letters.

[43]  B. Hylander,et al.  Fever-range whole body hyperthermia increases the number of perfused tumor blood vessels and therapeutic efficacy of liposomally encapsulated doxorubicin , 2007, International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group.