A comparison of changes to doxorubicin pharmacokinetics, antitumor activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems.

UNLABELLED The pharmacokinetics, biodistribution, and antitumor efficacy of three doxorubicin formulations (doxorubicin in saline, conjugated to a polylysine dendrimer, and encapsulated within a stealth liposome) were investigated in Walker 256 tumor-bearing rats. Liposomal and dendrimer-based delivery systems resulted in more prolonged plasma exposure of total doxorubicin when compared to administration of doxorubicin in saline, although concentrations of free doxorubicin remained low in both cases. Biodistribution profiles revealed enhanced accumulation of dendrimer- and liposome-associated doxorubicin in tumors when compared to doxorubicin alone, although all three doxorubicin formulations reduced tumor growth to a similar extent. Markers of systemic toxicity (spleen weight, white blood cell counts, body weight, and cardiotoxicity) were more pronounced in rats that received doxorubicin and liposomal doxorubicin when compared to dendrimer-doxorubicin. The data provide preliminary evidence that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity (resulting from reduced drug exposure to nontarget organs). FROM THE CLINICAL EDITOR In this manuscript, three different doxorubicin preparations are compared and preliminary evidence suggests that dendrimer-doxorubicin displays similar antitumor efficacy to PEGylated liposomal doxorubicin, but with lower systemic toxicity.

[1]  S. Kane,et al.  LIPOSOMAL DAUNORUBICIN OVERCOMES DRUG RESISTANCE IN HUMAN BREAST, OVARIAN AND LUNG CARCINOMA CELLS , 2002, Journal of liposome research.

[2]  A. Hauschild,et al.  Pegylated liposomal doxorubicin-associated hand-foot syndrome: recommendations of an international panel of experts. , 2008, European Journal of Cancer.

[3]  Ben J Boyd,et al.  Cationic poly-L-lysine dendrimers: pharmacokinetics, biodistribution, and evidence for metabolism and bioresorption after intravenous administration to rats. , 2006, Molecular pharmaceutics.

[4]  Y. Kawashima,et al.  Prolonged circulation time of doxorubicin-loaded liposomes coated with a modified polyvinyl alcohol after intravenous injection in rats. , 1999, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[5]  Yoshio Kobayashi,et al.  Dynamics of different-sized solid-state nanocrystals as tracers for a drug-delivery system in the interstitium of a human tumor xenograft , 2009, Breast Cancer Research.

[6]  F. Zanella,et al.  Toxicological studies of doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles in healthy rats and rats with intracranial glioblastoma. , 2002, Toxicology letters.

[7]  F M Muggia,et al.  Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  L. Kaminskas,et al.  Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties. , 2011, Nanomedicine.

[9]  F. Westwood,et al.  Liposomal encapsulation enhances the antitumour efficacy of the vascular disrupting agent ZD6126 in murine B16.F10 melanoma , 2008, British Journal of Cancer.

[10]  D. Owen,et al.  Characterisation and tumour targeting of PEGylated polylysine dendrimers bearing doxorubicin via a pH labile linker. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[11]  Ashutosh Chilkoti,et al.  Self-assembling chimeric polypeptide-doxorubicin conjugate nanoparticles that abolish tumors after a single injection , 2009, Nature materials.

[12]  Z. Duan,et al.  Biodistribution and Pharmacokinetic Analysis of Paclitaxel and Ceramide Administered in Multifunctional Polymer-Blend Nanoparticles in Drug Resistant Breast Cancer Model , 2008, Molecular pharmaceutics.

[13]  R. Duncan,et al.  Dendrimer-platinate: a novel approach to cancer chemotherapy. , 1999, Anti-cancer drugs.

[14]  F. Martin,et al.  Pegylated liposomal doxorubicin: proof of principle using preclinical animal models and pharmacokinetic studies. , 2004, Seminars in oncology.

[15]  A. Bao,et al.  Direct 99mTc Labeling of Pegylated Liposomal Doxorubicin (Doxil) for Pharmacokinetic and Non-Invasive Imaging Studies , 2004, Journal of Pharmacology and Experimental Therapeutics.

[16]  J. Drevs,et al.  Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study , 2004, Cancer Chemotherapy and Pharmacology.

[17]  K. Yokoyama,et al.  Comparison of efficacy, toxicity and pharmacokinetics of free adriamycin and adriamycin linked to oxidized dextran in rats. , 1989, Chemical & pharmaceutical bulletin.

[18]  L. Kaminskas,et al.  Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-l-lysine dendrimers. , 2009, Molecular pharmaceutics.

[19]  D. Alberts,et al.  Safety Aspects of Pegylated Liposomal Doxorubicin in Patients with Cancer , 2012, Drugs.

[20]  Theresa M. Allen,et al.  Determination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors , 2005, Clinical Cancer Research.

[21]  A. Bao,et al.  [(186)Re]Liposomal doxorubicin (Doxil): in vitro stability, pharmacokinetics, imaging and biodistribution in a head and neck squamous cell carcinoma xenograft model. , 2009, Nuclear medicine and biology.

[22]  R. Langer,et al.  Antitumor efficacy of a novel polymer–peptide–drug conjugate in human tumor xenograft models , 2006, International journal of cancer.

[23]  Yechezkel Barenholz,et al.  Pharmacokinetics of Pegylated Liposomal Doxorubicin , 2003, Clinical pharmacokinetics.

[24]  N. K. Jain,et al.  Dextran conjugated dendritic nanoconstructs as potential vectors for anti-cancer agent. , 2009, Biomaterials.

[25]  M. Thanou,et al.  Targeting nanoparticles to cancer. , 2010, Pharmacological research.

[26]  R. Duncan,et al.  Polymer-protein and polymer-drug conjugates in cancer therapy. , 2003, Current opinion in investigational drugs.

[27]  H. Maeda,et al.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. , 1986, Cancer research.

[28]  T. Okano,et al.  Selective delivery of adriamycin to a solid tumor using a polymeric micelle carrier system. , 1999, Journal of drug targeting.

[29]  R. Jain,et al.  Continuous noninvasive monitoring of pH and temperature in rat Walker 256 carcinoma during normoglycemia and hyperglycemia. , 1984, Journal of the National Cancer Institute.

[30]  A. Gabizon,et al.  Polyethylene Glycol-Coated (Pegylated) Liposomal Doxorubicin , 2012, Drugs.

[31]  L. Decosterd,et al.  A validated assay for measuring doxorubicin in biological fluids and tissues in an isolated lung perfusion model: matrix effect and heparin interference strongly influence doxorubicin measurements. , 2003, Journal of pharmaceutical and biomedical analysis.

[32]  Y. Pei,et al.  Partly PEGylated polyamidoamine dendrimer for tumor-selective targeting of doxorubicin: the effects of PEGylation degree and drug conjugation style. , 2010, Biomaterials.

[33]  Li Zhang,et al.  Direct comparison of two pegylated liposomal doxorubicin formulations: is AUC predictive for toxicity and efficacy? , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[34]  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.

[35]  F. Szoka,et al.  A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas , 2006, Proceedings of the National Academy of Sciences.

[36]  A. Santoro,et al.  Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  M. Bally,et al.  Method for rapid separation of liposome-associated doxorubicin from free doxorubicin in plasma. , 1990, Analytical biochemistry.

[38]  S. Kawakami,et al.  Designing Dendrimers for Drug Delivery and Imaging: Pharmacokinetic Considerations , 2011, Pharmaceutical Research.

[39]  L. Mayer,et al.  Liposomal doxorubicin circumvents PSC 833-free drug interactions, resulting in effective therapy of multidrug-resistant solid tumors. , 1997, Cancer research.

[40]  S. Biswas,et al.  Enhancement of the tumour inhibitory activity, in vivo, of diospyrin, a plant-derived quinonoid, through liposomal encapsulation. , 2005, Toxicology letters.