Oral delivery of anticancer drugs: challenges and opportunities.

The present report focuses on the various aspects of oral delivery of anticancer drugs. The significance of oral delivery in cancer therapeutics has been highlighted which principally includes improvement in quality of life of patients and reduced health care costs. Subsequently, the challenges incurred in the oral delivery of anticancer agents have been especially emphasized. Sincere efforts have been made to compile the various physicochemical properties of anticancer drugs from either literature or predicted in silico via GastroPlus™. The later section of the paper reviews various emerging trends to tackle the challenges associated with oral delivery of anticancer drugs. These invariably include efflux transporter based-, functional excipient- and nanocarrier based-approaches. The role of drug nanocrystals and various others such as polymer based- and lipid based-nanocarriers in the bioavailability enhancement along with their clinical outcomes has also been discussed exhaustively. Furthermore, an insight on the various absorption mechanisms of these nanocarriers across the gastrointestinal tract has also been highlighted.

[1]  F. Kratz,et al.  Anticancer carrier-linked prodrugs in clinical trials , 2007, Expert opinion on investigational drugs.

[2]  V. Knick,et al.  P-Glycoprotein mediated resistance to 5′-nor-anhydro-vinblastine (Navelbine®) , 2007, Investigational New Drugs.

[3]  Takashi Okada,et al.  The Reactive Polymeric Micelle Based on An Aldehyde-Ended Poly(ethylene glycol)/Poly(lactide) Block Copolymer , 1998 .

[4]  C. Chen,et al.  Quercetin: a potential drug to reverse multidrug resistance. , 2010, Life sciences.

[5]  K. Frei,et al.  Gefitinib accumulation in glioblastoma tissue , 2006, Cancer biology & therapy.

[6]  M. Jamal-Hanjani,et al.  Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Epidermal Growth Factor Receptor–Mutant Non–Small Cell Lung Cancer Metastatic to the Brain , 2011, Clinical Cancer Research.

[7]  A. Basit,et al.  The effect of polyoxyethylene polymers on the transport of ranitidine in Caco-2 cell monolayers. , 2011, International journal of pharmaceutics.

[8]  M. Ihnat,et al.  Effects of mitomycin C and carboplatin pretreatment on multidrug resistance-associated P-glycoprotein expression and on subsequent suppression of tumor growth by doxorubicin and paclitaxel in human metastatic breast cancer xenografted nude mice. , 1999, Oncology Research.

[9]  S. Ganta,et al.  A review of multifunctional nanoemulsion systems to overcome oral and CNS drug delivery barriers , 2010, Molecular membrane biology.

[10]  M. Gordon,et al.  Tumor angiogenesis and novel antiangiogenic strategies , 2010, International journal of cancer.

[11]  P. Lønning,et al.  Survival and safety of exemestane versus tamoxifen after 2–3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial , 2007, The Lancet.

[12]  M. Wempe,et al.  Influence of vitamin E TPGS poly(ethylene glycol) chain length on apical efflux transporters in Caco-2 cell monolayers. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[13]  Deborah A. Smith,et al.  Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects. , 2009, British journal of clinical pharmacology.

[14]  G Houin,et al.  Gastrointestinal absorption of drugs: methods and studies , 1999, Fundamental & Clinical Pharmacology.

[15]  Patrick J. Sinko,et al.  Characterization of the Regional Intestinal Kinetics of Drug Efflux in Rat and Human Intestine and in Caco-2 Cells , 1998, Pharmaceutical Research.

[16]  Matthew D. Troutman,et al.  Novel Experimental Parameters to Quantify the Modulation of Absorptive and Secretory Transport of Compounds by P-Glycoprotein in Cell Culture Models of Intestinal Epithelium , 2003, Pharmaceutical Research.

[17]  M. Deli,et al.  Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery. , 2009, Biochimica et biophysica acta.

[18]  Der,et al.  Enhanced oral absorption and decreased elimination of paclitaxel in mice cotreated with cyclosporin A. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[19]  J M Irache,et al.  Increased oral bioavailability of paclitaxel by its encapsulation through complex formation with cyclodextrins in poly(anhydride) nanoparticles. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[20]  Edouard C. Nice,et al.  Bypassing Multidrug Resistance in Cancer Cells with Biodegradable Polymer Capsules , 2010, Advanced materials.

[21]  Kinam Park,et al.  Bioadhesive interaction and hypoglycemic effect of insulin-loaded lectin-microparticle conjugates in oral insulin delivery system. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[22]  Ruth Duncan,et al.  Polymer conjugates as anticancer nanomedicines , 2006, Nature Reviews Cancer.

[23]  M. Jones,et al.  Polymeric micelles - a new generation of colloidal drug carriers. , 1999, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[24]  J. Nah,et al.  Influence of molecular weight on oral absorption of water soluble chitosans. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[25]  P. Gao,et al.  Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. , 2003, Journal of pharmaceutical sciences.

[26]  C. Lipinski.  Drug-like properties and the causes of poor solubility and poor permeability. , 2000, Journal of pharmacological and toxicological methods.

[27]  Sanyog Jain,et al.  Polyelectrolyte coated multilayered liposomes (nanocapsules) for the treatment of Helicobacter pylori infection. , 2009, Molecular pharmaceutics.

[28]  S. Ostad,et al.  Thiolated chitosan nanoparticles for enhancing oral absorption of docetaxel: preparation, in vitro and ex vivo evaluation , 2011, International journal of nanomedicine.

[29]  A. Bernkop‐Schnürch,et al.  Chitosan-N-Acetyl Cysteine Conjugates: In Vitro Evaluation of Permeation Enhancing and P-Glycoprotein Inhibiting Properties , 2008, Drug delivery.

[30]  M. Paine,et al.  P-Glycoprotein Increases from Proximal to Distal Regions of Human Small Intestine , 2003, Pharmaceutical Research.

[31]  M Rowland,et al.  Differentiation of absorption and first‐pass gut and hepatic metabolism in humans: Studies with cyclosporine , 1995, Clinical pharmacology and therapeutics.

[32]  Sarsvatkumar Patel,et al.  Novel lipid based oral formulation of curcumin: development and optimization by design of experiments approach. , 2012, International journal of pharmaceutics.

[33]  H. Rosing,et al.  P-Glycoprotein (ABCB1) Transports the Primary Active Tamoxifen Metabolites Endoxifen and 4-Hydroxytamoxifen and Restricts Their Brain Penetration , 2011, Journal of Pharmacology and Experimental Therapeutics.

[34]  H. Westerhoff,et al.  The relative importance of passive and P-glycoprotein mediated anthracycline efflux from multidrug-resistant cells. , 2000, European journal of biochemistry.

[35]  Zheng-Rong Lu,et al.  Colon-specific 9-aminocamptothecin-HPMA copolymer conjugates containing a 1,6-elimination spacer. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[36]  Y. Schneider,et al.  PEGylated PLGA-based nanoparticles targeting M cells for oral vaccination. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[37]  H. Ghandehari,et al.  Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery. , 2012, Advanced drug delivery reviews.

[38]  Christopher J. H. Porter,et al.  An in vitro examination of the impact of polyethylene glycol 400, pluronic P85, and vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine , 2002, AAPS PharmSci.

[39]  James A. Platts,et al.  Estimation of Molecular Linear Free Energy Relationship Descriptors by a Group Contribution Approach. 2. Prediction of Partition Coefficients , 2000, J. Chem. Inf. Comput. Sci..

[40]  T. Dutta,et al.  Characterization and in vitro assessment of paclitaxel loaded lipid nanoparticles formulated using modified solvent injection technique. , 2009, Die Pharmazie.

[41]  F. Hirayama,et al.  Contribution of P-glycoprotein to the enhancing effects of dimethyl-beta-cyclodextrin on oral bioavailability of tacrolimus. , 2001, The Journal of pharmacology and experimental therapeutics.

[42]  Lei Qin,et al.  Pegylated phosphotidylethanolamine inhibiting P-glycoprotein expression and enhancing retention of doxorubicin in MCF7/ADR cells. , 2011, Journal of pharmaceutical sciences.

[43]  S. Srivastava,et al.  Nanoemulsions of cancer chemopreventive agent benzyl isothiocyanate display enhanced solubility, dissolution, and permeability. , 2011, Journal of agricultural and food chemistry.

[44]  A. Domb,et al.  Chitosan chemistry and pharmaceutical perspectives. , 2004, Chemical reviews.

[45]  Quanyin Hu,et al.  Lipid-based liquid crystalline nanoparticles as oral drug delivery vehicles for poorly water-soluble drugs: cellular interaction and in vivo absorption , 2012, International journal of nanomedicine.

[46]  Q. Ping,et al.  The mechanism of enhancement on oral absorption of paclitaxel by N-octyl-O-sulfate chitosan micelles. , 2011, Biomaterials.

[47]  Qi Shen,et al.  Characterization and evaluation of nanostructured lipid carrier as a vehicle for oral delivery of etoposide. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[48]  S. Lundin,et al.  Bidirectional small-intestinal permeability in the rat to some common marker molecules in vitro. , 1994, Scandinavian journal of gastroenterology.

[49]  A. Gabizon.  Liposomes as a drug delivery system in cancer chemotherapy. , 1989, Horizons in biochemistry and biophysics.

[50]  Gautam Mishra,et al.  Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[51]  Miguel X. Fernandes,et al.  Pharmacophore-Based Screening as a Clue for the Discovery of New P-Glycoprotein Inhibitors , 2010, IWPACBB.

[52]  Kinam Park,et al.  Hydrotropic polymeric micelles for enhanced paclitaxel solubility: in vitro and in vivo characterization. , 2007, Biomacromolecules.

[53]  W. Couet,et al.  Enhanced Oral Paclitaxel Bioavailability After Administration of Paclitaxel-Loaded Lipid Nanocapsules , 2006, Pharmaceutical Research.

[54]  M. V. Vijayakumar,et al.  Methyl-β-cyclodextrin enhances the susceptibility of human breast cancer cells to carboplatin and 5-fluorouracil : Involvement of akt, NF-κB and bcl- 2 , 2006 .

[55]  Kinam Park,et al.  Hydrotropic polymer micelles containing acrylic acid moieties for oral delivery of paclitaxel. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[56]  M. Garnett,et al.  Targeted drug conjugates: principles and progress. , 2001, Advanced drug delivery reviews.

[57]  H. Reiss.  Entropy-induced dispersion of bulk liquids , 1975 .

[58]  S. Zeng,et al.  Cellular uptake of solid lipid nanoparticles and cytotoxicity of encapsulated paclitaxel in A549 cancer cells. , 2008, International journal of pharmaceutics.

[59]  K. Pathak,et al.  Anticancer efficacy, tissue distribution and blood pharmacokinetics of surface modified nanocarrier containing melphalan. , 2012, International journal of pharmaceutics.

[60]  C. Dass.  Drug delivery in cancer using liposomes. , 2008, Methods in molecular biology.

[61]  Martin Werle,et al.  Natural and Synthetic Polymers as Inhibitors of Drug Efflux Pumps , 2007, Pharmaceutical Research.

[62]  Paulo Paixão,et al.  Prediction of the human oral bioavailability by using in vitro and in silico drug related parameters in a physiologically based absorption model. , 2012, International journal of pharmaceutics.

[63]  Yan Zhang,et al.  The antitumor efficacy of functional paclitaxel nanomicelles in treating resistant breast cancers by oral delivery. , 2011, Biomaterials.

[64]  A. Kabanov,et al.  Effect of Pluronic P85 on ATPase Activity of Drug Efflux Transporters , 2004, Pharmaceutical Research.

[65]  K. Abu-Salah,et al.  Solid dispersions of α-mangostin improve its aqueous solubility through self-assembly of nanomicelles. , 2012, Journal of pharmaceutical sciences.

[66]  M. Morris,et al.  ABC Transporters in Intestinal and Liver Efflux , 2011 .

[67]  Ajay Kumar,et al.  Permeability of surface-modified polyamidoamine (PAMAM) dendrimers across Caco-2 cell monolayers. , 2008, International journal of pharmaceutics.

[68]  C. Twelves,et al.  Oral cancer treatment: developments in chemotherapy and beyond , 2002, British Journal of Cancer.

[69]  Chartchalerm Isarankura-Na-Ayudhya,et al.  Molecular Docking of Aromatase Inhibitors , 2011, Molecules.

[70]  A. G. Bosanquet,et al.  Pharmacokinetics of oral and intravenous melphalan during routine treatment of multiple myeloma. , 1982, European journal of cancer & clinical oncology.

[71]  M. Wirth,et al.  Lectin-mediated Drug Delivery: Discrimination Between Cytoadhesion and Cytoinvasion and Evidence for Lysosomal Accumulation of Wheat Germ Agglutinin in the Caco-2 Model , 2002, Journal of drug targeting.

[72]  M. Varma,et al.  Prediction of in vivo intestinal absorption enhancement on P-glycoprotein inhibition, from rat in situ permeability. , 2005, Journal of pharmaceutical sciences.

[73]  E. Winer,et al.  Adherence to therapy with oral antineoplastic agents. , 2002, Journal of the National Cancer Institute.

[74]  M. Mullendore,et al.  In vivo characterization of a polymeric nanoparticle platform with potential oral drug delivery capabilities , 2008, Molecular Cancer Therapeutics.

[75]  S. B. Tiwari,et al.  Improved oral delivery of paclitaxel following administration in nanoemulsion formulations. , 2006, Journal of nanoscience and nanotechnology.

[76]  T. Wagner.  Ifosfamide Clinical Pharmacokinetics , 1994, Clinical pharmacokinetics.

[77]  Shiyin Yee,et al.  In Vitro Permeability Across Caco-2 Cells (Colonic) Can Predict In Vivo (Small Intestinal) Absorption in Man—Fact or Myth , 1997, Pharmaceutical Research.

[78]  Cui Tang,et al.  Folate-mediated solid–liquid lipid nanoparticles for paclitaxel-coated poly(ethylene glycol) , 2010, Drug development and industrial pharmacy.

[79]  Ann Partridge,et al.  Patient adherence and persistence with oral anticancer treatment , 2009, CA: a cancer journal for clinicians.

[80]  K. Sugano.  Fraction of a dose absorbed estimation for structurally diverse low solubility compounds. , 2011, International journal of pharmaceutics.

[81]  Per Artursson,et al.  Chitosans as Absorption Enhancers for Poorly Absorbable Drugs. 1: Influence of Molecular Weight and Degree of Acetylation on Drug Transport Across Human Intestinal Epithelial (Caco-2) Cells , 1996, Pharmaceutical Research.

[82]  G. Chabot.  Clinical Pharmacokinetics of Irinotecan , 1997, Clinical pharmacokinetics.

[83]  Marilena Loizidou,et al.  Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. , 2009, Trends in pharmacological sciences.

[84]  H. Lee,et al.  A novel micelle-encapsulated platinum(II) anticancer agent. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[85]  F. Liu,et al.  Targeted cancer therapy with novel high drug-loading nanocrystals. , 2010, Journal of pharmaceutical sciences.

[86]  D. Bigner,et al.  Experimental chemotherapy of human medulloblastoma with classical alkylators. , 1986, Cancer research.

[87]  S. Ganta,et al.  Coadministration of Paclitaxel and curcumin in nanoemulsion formulations to overcome multidrug resistance in tumor cells. , 2009, Molecular pharmaceutics.

[88]  K. Kataoka,et al.  A Novel Reactive Polymeric Micelle with Aldehyde Groups on Its Surface , 1995 .

[89]  T. Baykara,et al.  Preparation and characterization of polymeric micelles for solubilization of poorly soluble anticancer drugs. , 2006, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[90]  Ick Chan Kwon,et al.  Targeted delivery of low molecular drugs using chitosan and its derivatives. , 2010, Advanced drug delivery reviews.

[91]  S. Benita,et al.  Excipient effects on in vitro cytotoxicity of a novel paclitaxel self-emulsifying drug delivery system. , 2003, Journal of pharmaceutical sciences.

[92]  Abdul W. Basit,et al.  Concentration-Dependent Effects of Polyethylene Glycol 400 on Gastrointestinal Transit and Drug Absorption , 2003, Pharmaceutical Research.

[93]  T. A. Hatton,et al.  Effect of Block Size and Sequence on the Micellization of ABC Triblock Methacrylic Polyampholytes , 1995 .

[94]  O. Bugnon,et al.  [Therapeutic adherence to oral cancer therapy and interdisciplinary management]. , 2011, Revue medicale suisse.

[95]  F. Pinguet,et al.  Methyl-β-cyclodextrin in HL-60 parental and multidrug-resistant cancer cell lines: effect on the cytotoxic activity and intracellular accumulation of doxorubicin , 1997, Cancer Chemotherapy and Pharmacology.

[96]  Chunxiao Wang,et al.  Wheat germ agglutinin-conjugated PLGA nanoparticles for enhanced intracellular delivery of paclitaxel to colon cancer cells. , 2010, International journal of pharmaceutics.

[97]  Yves-Jacques Schneider,et al.  Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[98]  P. Swaan,et al.  Surface acetylation of polyamidoamine (PAMAM) dendrimers decreases cytotoxicity while maintaining membrane permeability. , 2007, Bioconjugate chemistry.

[99]  J. Beijnen,et al.  Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[100]  J. Benoit,et al.  A Novel Phase Inversion-Based Process for the Preparation of Lipid Nanocarriers , 2002, Pharmaceutical Research.

[101]  Ranjita Shegokar,et al.  Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. , 2010, International journal of pharmaceutics.

[102]  V. Préat,et al.  Fate of polymeric nanocarriers for oral drug delivery , 2011 .

[103]  H. Junginger,et al.  Oral drug absorption enhancement by chitosan and its derivatives. , 2001, Advanced drug delivery reviews.

[104]  A. Bernkop‐Schnürch,et al.  Evidence for the interpenetration of mucoadhesive polymers into the mucous gel layer , 2003 .

[105]  V. Shenoy,et al.  Paclitaxel-loaded glyceryl palmitostearate nanoparticles: in vitro release and cytotoxic activity , 2009, Journal of drug targeting.

[106]  J. Wojtacki,et al.  Breast cancer patients preferences for oral versus intravenous second-line anticancer therapy , 2006 .

[107]  Xiaojuan Gong,et al.  Lyotropic liquid crystalline self-assembly material behavior and nanoparticulate dispersions of a phytanyl pro-drug analogue of capecitabine-a chemotherapy agent. , 2011, ACS applied materials & interfaces.

[108]  Sanyog Jain,et al.  Oral delivery of doxorubicin using novel polyelectrolyte-stabilized liposomes (layersomes). , 2012, Molecular pharmaceutics.

[109]  P. S. Hiremath,et al.  Proliposomes of exemestane for improved oral delivery: formulation and in vitro evaluation using PAMPA, Caco-2 and rat intestine. , 2009, International journal of pharmaceutics.

[110]  Eszter Hazai,et al.  Predicting P-Glycoprotein-Mediated Drug Transport Based On Support Vector Machine and Three-Dimensional Crystal Structure of P-glycoprotein , 2011, PloS one.

[111]  S. Benita,et al.  Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors , 2004, Pharmaceutical Research.

[112]  Sanyog Jain,et al.  Solid lipid nanoparticles: an oral bioavailability enhancer vehicle , 2011, Expert opinion on drug delivery.

[113]  S. Yamashita,et al.  Oral delivery of insulin by using surface coating liposomes improvement of stability of insulin in GI tract , 1997 .

[114]  James A. Platts,et al.  Hydrogen bonding, solvation, and hydrolysis of cisplatin: A theoretical study , 2004, J. Comput. Chem..

[115]  J. Benoit,et al.  Lipid nanocarriers improve paclitaxel transport throughout human intestinal epithelial cells by using vesicle-mediated transcytosis. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[116]  R. Panchagnula,et al.  Nanoemulsions as versatile formulations for paclitaxel delivery: peroral and dermal delivery studies in rats. , 2007, The Journal of investigative dermatology.

[117]  Y. Shibayama,et al.  Effect of methotrexate treatment on expression levels of organic anion transporter polypeptide 2, P-glycoprotein and bile salt export pump in rats. , 2009, Biological & pharmaceutical bulletin.

[118]  B. Hirst,et al.  M cell targeting by lectins: a strategy for mucosal vaccination and drug delivery. , 2004, Advanced drug delivery reviews.

[119]  M. Qiao,et al.  Preparation and evaluation of lectin-conjugated PLGA nanoparticles for oral delivery of thymopentin. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[120]  M. Bergström,et al.  PET-evaluated transport of [11C]hydroxyurea across the rat blood-brain barrier--lack of influence of cyclosporin and probenecid. , 2007, Drug metabolism letters.

[121]  K. Audus,et al.  Effects of poly(ethylene glycol) on efflux transporter activity in Caco-2 cell monolayers. , 2002, Journal of pharmaceutical sciences.

[122]  Si-Shen Feng,et al.  Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. , 2005, Biomaterials.

[123]  Frederic Lagarce,et al.  Biopharmaceutical parameters to consider in order to alter the fate of nanocarriers after oral delivery. , 2010, Nanomedicine.

[124]  S. Svenson,et al.  Dendrimers for enhanced drug solubilization. , 2008, Nanomedicine.

[125]  F. Liu,et al.  Paclitaxel nanocrystals for overcoming multidrug resistance in cancer. , 2010, Molecular pharmaceutics.

[126]  P. Sylvester,et al.  Preparation and in vitro antiproliferative effect of tocotrienol loaded lipid nanoparticles , 2010 .

[127]  N. Mishra,et al.  Lectin anchored PLGA nanoparticles for oral mucosal immunization against hepatitis B , 2011, Journal of drug targeting.

[128]  T. A. Hatton,et al.  Pluronic block copolymers and Pluronic poly(acrylic acid) microgels in oral delivery of megestrol acetate , 2004, The Journal of pharmacy and pharmacology.

[129]  Amit Jain,et al.  The effect of the oral administration of polymeric nanoparticles on the efficacy and toxicity of tamoxifen. , 2011, Biomaterials.

[130]  I. Vural,et al.  Alternative oral exemestane formulation: improved dissolution and permeation. , 2010, International journal of pharmaceutics.

[131]  M. Harrison,et al.  A phase II study of 2-methoxyestradiol (2ME2) NanoCrystal® dispersion (NCD) in patients with taxane-refractory, metastatic castrate-resistant prostate cancer (CRPC) , 2011, Investigational New Drugs.

[132]  Li Deng,et al.  Preparation and evaluation of a self-emulsifying drug delivery system of etoposide–phospholipid complex , 2011, Drug development and industrial pharmacy.

[133]  D. Clarke,et al.  Membrane Topology of a Cysteine-less Mutant of Human P-glycoprotein (*) , 1995, The Journal of Biological Chemistry.

[134]  X. Wu,et al.  A Mechanistic Study of Enhanced Doxorubicin Uptake and Retention in Multidrug Resistant Breast Cancer Cells Using a Polymer-Lipid Hybrid Nanoparticle System , 2006, Journal of Pharmacology and Experimental Therapeutics.

[135]  A. Bernkop‐Schnürch,et al.  The Role of Glutathione in the Permeation Enhancing Effect of Thiolated Polymers , 2002, Pharmaceutical Research.

[136]  Rongqin Huang,et al.  Enhanced oral bioavailability of doxorubicin in a dendrimer drug delivery system. , 2008, Journal of pharmaceutical sciences.

[137]  B. Demoré,et al.  Development of microemulsion of mitotane for improvement of oral bioavailability , 2009, Drug development and industrial pharmacy.

[138]  J. Beijnen,et al.  Clinical Pharmacokinetics of Topotecan , 1996, Clinical pharmacokinetics.

[139]  Si-Shen Feng,et al.  Poly(d,l-lactide-co-glycolide)/montmorillonite nanoparticles for oral delivery of anticancer drugs. , 2005, Biomaterials.

[140]  H. Kong,et al.  Lack of Association Between Excretion of Sorafenib in Sweat and Hand‐Foot Skin Reaction , 2010, Pharmacotherapy.

[141]  D. Alberts,et al.  Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial. , 1987, Cancer research.

[142]  R. Müller,et al.  Lipid Nanoparticles with a Solid Matrix (SLN®, NLC®, LDC®) for Oral Drug Delivery , 2008, Drug development and industrial pharmacy.

[143]  Jianping Zhou,et al.  Enhanced oral absorption of paclitaxel in N-deoxycholic acid-N, O-hydroxyethyl chitosan micellar system. , 2010, Journal of pharmaceutical sciences.

[144]  R. Murthy,et al.  Tamoxifen Citrate Loaded Solid Lipid Nanoparticles (SLN™): Preparation, Characterization, In Vitro Drug Release, and Pharmacokinetic Evaluation , 2006, Pharmaceutical development and technology.

[145]  A. Decensi,et al.  Stimulation of erythropoiesis by the non-steroidal anti-androgen nilutamide in men with prostate cancer: evidence for an agonistic effect? , 1994, British Journal of Cancer.

[146]  Yahya E Choonara,et al.  Diverse approaches for the enhancement of oral drug bioavailability , 2011, Biopharmaceutics & drug disposition.

[147]  J. Cassidy,et al.  Evaluating the potential of polymer nanoparticles for oral delivery of paclitaxel in drug-resistant cancer , 2010, Cancer nanotechnology.

[148]  S. Urien,et al.  Pharmacokinetics of platinum after oral or intravenous cisplatin: a phase 1 study in 32 adult patients , 2004, Cancer Chemotherapy and Pharmacology.

[149]  J. Schellens,et al.  Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. , 2006, Trends in pharmacological sciences.

[150]  M. Fromm,et al.  Importance of P-glycoprotein at blood-tissue barriers. , 2004, Trends in pharmacological sciences.

[151]  Yitao Wang,et al.  Emodin loaded solid lipid nanoparticles: preparation, characterization and antitumor activity studies. , 2012, International journal of pharmaceutics.

[152]  R. Mumper,et al.  Development of idarubicin and doxorubicin solid lipid nanoparticles to overcome Pgp-mediated multiple drug resistance in leukemia. , 2009, Journal of biomedical nanotechnology.

[153]  R. Mathijssen,et al.  Prevalence of potential drug–drug interactions in cancer patients treated with oral anticancer drugs , 2013, British Journal of Cancer.

[154]  Z. Sauna,et al.  The Mechanism of Action of Multidrug-Resistance-Linked P-Glycoprotein , 2001, Journal of bioenergetics and biomembranes.

[155]  P. Fong,et al.  PEGylated PLGA nanoparticles for the improved delivery of doxorubicin. , 2009, Nanomedicine : nanotechnology, biology, and medicine.

[156]  M. Anwer,et al.  Optimization of 5-flurouracil solid-lipid nanoparticles: a preliminary study to treat colon cancer , 2010, International journal of medical sciences.

[157]  Wen-Jen Yang,et al.  In vitro suppression of oral squamous cell carcinoma growth by ultrasound-mediated delivery of curcumin microemulsions , 2012, International journal of nanomedicine.

[158]  B B Michniak,et al.  The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities. , 2001, International journal of pharmaceutics.

[159]  G. Giammona,et al.  Tamoxifen-loaded polymeric micelles: preparation, physico-chemical characterization and in vitro evaluation studies. , 2004, Macromolecular bioscience.

[160]  Xiaoming Wang,et al.  The antitumor immune responses induced by nanoemulsion-encapsulated MAGE1-HSP70/SEA complex protein vaccine following peroral administration route , 2009, Cancer Immunology, Immunotherapy.

[161]  J. Schellens,et al.  Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093) , 2004, Cancer Chemotherapy and Pharmacology.

[162]  P. B. Chock,et al.  Regulation of PTP1B via glutathionylation of the active site cysteine 215. , 1999, Biochemistry.

[163]  S. W. Kim,et al.  Soluble Flt-1 gene delivery using PEI-g-PEG-RGD conjugate for anti-angiogenesis. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[164]  B. Jo,et al.  Enhanced paclitaxel bioavailability after oral administration of pegylated paclitaxel prodrug for oral delivery in rats. , 2004, International journal of pharmaceutics.

[165]  M. Dubinsky.  Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[166]  James E Polli,et al.  Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. , 2002, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[167]  J. Iqbal,et al.  Design and in vitro evaluation of a novel polymeric P-glycoprotein (P-gp) inhibitor. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[168]  Jun-shik Choi,et al.  Effects of quercetin on the pharmacokinetics of Etoposide after oral or intravenous administration of etoposide in rats. , 2009, Anticancer research.

[169]  Amit Jain,et al.  Augmented anticancer efficacy of doxorubicin-loaded polymeric nanoparticles after oral administration in a breast cancer induced animal model. , 2011, Molecular pharmaceutics.

[170]  Mansoor M. Amiji,et al.  Poly(ethylene glycol)-modified Nanocarriers for Tumor-targeted and Intracellular Delivery , 2007, Pharmaceutical Research.

[171]  C. Porter,et al.  Uptake of drugs into the intestinal lymphatics after oral administration , 1997 .

[172]  C. Dey,et al.  P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. , 2003, Pharmacological research.

[173]  A. Wolff,et al.  Tumor targeting by conjugation of DHA to paclitaxel. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[174]  Xiaoling Fang,et al.  Effect of self-microemulsifying drug delivery systems containing Labrasol on tight junctions in Caco-2 cells. , 2005, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[175]  N. K. Jain,et al.  Enhanced Oromucosal Delivery of Progesterone Via Hexosomes , 2007, Pharmaceutical Research.

[176]  E. Magosso,et al.  Enhanced Oral Bioavailability and Intestinal Lymphatic Transport of a Hydrophilic Drug Using Liposomes , 2006, Drug development and industrial pharmacy.

[177]  Yoav D Livney,et al.  β-Casein nanoparticle-based oral drug delivery system for potential treatment of gastric carcinoma: stability, target-activated release and cytotoxicity. , 2012, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[178]  R. Samstein,et al.  The use of deoxycholic acid to enhance the oral bioavailability of biodegradable nanoparticles. , 2008, Biomaterials.

[179]  Dae-Duk Kim,et al.  Docetaxel microemulsion for enhanced oral bioavailability: preparation and in vitro and in vivo evaluation. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[180]  U. Schubert,et al.  Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. , 2010, Angewandte Chemie.

[181]  Minjie Sun,et al.  Chitosan surface-modified hydroxycamptothecin loaded nanoparticles with enhanced transport across Caco-2 cell monolayer. , 2006, Journal of nanoscience and nanotechnology.

[182]  V. Torchilin,et al.  Polyethylene glycol-phosphatidylethanolamine conjugate (PEG-PE)-based mixed micelles: some properties, loading with paclitaxel, and modulation of P-glycoprotein-mediated efflux. , 2006, International journal of pharmaceutics.

[183]  C. Chen,et al.  Development of a solid supersaturatable self-emulsifying drug delivery system of docetaxel with improved dissolution and bioavailability. , 2011, Biological & pharmaceutical bulletin.

[184]  T. Xu,et al.  Dendrimers as drug carriers: applications in different routes of drug administration. , 2008, Journal of pharmaceutical sciences.

[185]  Thierry F. Vandamme,et al.  Nano-emulsions and Micro-emulsions: Clarifications of the Critical Differences , 2011, Pharmaceutical Research.

[186]  K. Kannan,et al.  Oral microemulsions of paclitaxel: in situ and pharmacokinetic studies. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[187]  A. Bernkop‐Schnürch,et al.  Thiolated Chitosans: Design and In Vivo Evaluation of a Mucoadhesive Buccal Peptide Drug Delivery System , 2006, Pharmaceutical Research.

[188]  T. Okano,et al.  Reversibly thermo-responsive alkyl-terminated poly(N-isopropylacrylamide) core-shell micellar structures , 1997 .

[189]  S. Kohno,et al.  Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. , 2005, Lung cancer.

[190]  Lisa Brannon-Peppas,et al.  Recent advances on the use of biodegradable microparticles and nanoparticles in controlled drug delivery , 1995 .

[191]  I. Pastan,et al.  Biochemical, cellular, and pharmacological aspects of the multidrug transporter. , 1999, Annual review of pharmacology and toxicology.

[192]  A. Zarghi,et al.  Synthesis and characterization of methotrexate polyethylene glycol esters as a drug delivery system. , 2010, Chemical & pharmaceutical bulletin.

[193]  S. Chae,et al.  Conjugated chitosan as a novel platform for oral delivery of paclitaxel. , 2008, Journal of medicinal chemistry.

[194]  Robert Langer,et al.  Lectin-bearing Polymerized Liposomes as Potential Oral Vaccine Carriers , 1996, Pharmaceutical Research.

[195]  J M Irache,et al.  Combined hydroxypropyl-beta-cyclodextrin and poly(anhydride) nanoparticles improve the oral permeability of paclitaxel. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[196]  Hamidreza Ghandehari,et al.  Transepithelial transport of poly(amidoamine) dendrimers across Caco-2 cell monolayers. , 2002, Journal of controlled release : official journal of the Controlled Release Society.

[197]  J. Schellens,et al.  Development of farnesyl transferase inhibitors: a review. , 2005, The oncologist.

[198]  R. G. Crounse,et al.  Human pharmacology of griseofulvin: the effect of fat intake on gastrointestinal absorption. , 1961, The Journal of investigative dermatology.

[199]  J. Benoit,et al.  Lipid nanocapsules: a new platform for nanomedicine. , 2009, International journal of pharmaceutics.

[200]  C. Choi,et al.  Epigenetic mechanisms involved in differential MDR1 mRNA expression between gastric and colon cancer cell lines and rationales for clinical chemotherapy , 2008, BMC gastroenterology.

[201]  Y. Pore,et al.  EFFECT OF L-ARGININE ON BICALUTAMIDE COMPLEXATION WITH HYDROXYPROPYL-β-CYCLODEXTRIN , 2008 .

[202]  C. Lehr,et al.  PLGA Nanoparticles Stabilized with Cationic Surfactant: Safety Studies and Application in Oral Delivery of Paclitaxel to Treat Chemical-Induced Breast Cancer in Rat , 2009, Pharmaceutical Research.

[203]  C. Waters,et al.  Compartment-specific roles of ATP-binding cassette transporters define differential topotecan distribution in brain parenchyma and cerebrospinal fluid. , 2009, Cancer research.

[204]  H. Sakagami,et al.  Re-evaluation of tumor-specific cytotoxicity of mitomycin C, bleomycin and peplomycin. , 2006, Anticancer research.

[205]  J. Benoit,et al.  The gastrointestinal stability of lipid nanocapsules. , 2009, International journal of pharmaceutics.

[206]  C. Marianecci,et al.  Solid lipid nanoparticles incorporated in dextran hydrogels: a new drug delivery system for oral formulations. , 2006, International journal of pharmaceutics.

[207]  J. Radich,et al.  Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. , 2007, Blood.

[208]  Narendra Kumar Jain,et al.  Dendrimers in oncology: an expanding horizon. , 2009, Chemical reviews.

[209]  R. Müller,et al.  Production and characterisation of mucoadhesive nanosuspensions for the formulation of bupravaquone. , 2001, International journal of pharmaceutics.

[210]  Patrick Augustijns,et al.  Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? , 2009, Journal of pharmaceutical sciences.

[211]  J. Iqbal,et al.  Development and in vivo evaluation of an oral drug delivery system for paclitaxel. , 2011, Biomaterials.

[212]  Jong Hwa Song,et al.  Polyethylene glycol-coated liposomes for oral delivery of recombinant human epidermal growth factor. , 2003, International journal of pharmaceutics.

[213]  Amit Jain,et al.  Oral bioavailability, therapeutic efficacy and reactive oxygen species scavenging properties of coenzyme Q10-loaded polymeric nanoparticles. , 2011, Biomaterials.

[214]  Y. Kawashima,et al.  Effectiveness of submicron-sized, chitosan-coated liposomes in oral administration of peptide drugs. , 2005, International journal of pharmaceutics.

[215]  Brahma N. Singh.  Drug Delivery: Oral Route , 2015 .

[216]  E. Wang,et al.  The Farnesyl Protein Transferase Inhibitor Lonafarnib (SCH66336) Is an Inhibitor of Multidrug Resistance Proteins 1 and 2 , 2003, Chemotherapy.

[217]  Hidetoshi Arima,et al.  Involvement of cholesterol in the inhibitory effect of dimethyl‐β‐cyclodextrin on P‐glycoprotein and MRP2 function in Caco‐2 cells , 2003, FEBS letters.

[218]  Jesse V Jokerst,et al.  Nanoparticle PEGylation for imaging and therapy. , 2011, Nanomedicine.

[219]  R. Kappl,et al.  Mechanism of inhibition of P-glycoprotein mediated efflux by vitamin E TPGS: influence on ATPase activity and membrane fluidity. , 2007, Molecular pharmaceutics.

[220]  J. Benoit,et al.  Aqueous-core lipid nanocapsules for encapsulating fragile hydrophilic and/or lipophilic molecules. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[221]  L. Bromberg,et al.  Effects of polyether-modified poly(acrylic acid) microgels on doxorubicin transport in human intestinal epithelial Caco-2 cell layers. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[222]  B. Hirst,et al.  Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption , 1997 .

[223]  Ping Gao,et al.  Enhanced Oral Bioavailability of a Poorly Water Soluble Drug PNU‐91325 by Supersaturatable Formulations , 2004, Drug development and industrial pharmacy.

[224]  S. Linder,et al.  Identification of Agents that Induce Apoptosis of Multicellular Tumour Spheroids: Enrichment for Mitotic Inhibitors with Hydrophobic Properties , 2011, Chemical biology & drug design.

[225]  Peng Zhang,et al.  Development of novel self-assembled DS-PLGA hybrid nanoparticles for improving oral bioavailability of vincristine sulfate by P-gp inhibition. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[226]  M. Ranson,et al.  Phase ii comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[227]  J. Gynther,et al.  Retention Behaviour of Triphenylethylene Derivatives in Reverse Phase Liquid Chromatography , 1996 .

[228]  J. Schellens,et al.  Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[229]  K. Kang,et al.  Effects of quercetin on the bioavailability of doxorubicin in rats: Role of CYP3A4 and P-gp inhibition by quercetin , 2011, Archives of pharmacal research.

[230]  T. Buclin,et al.  Cardiovascular drug interactions with tyrosine kinase inhibitors , 2010 .

[231]  I. Larson,et al.  Chitosan nanoparticles enhance the plasma exposure of (-)-epigallocatechin gallate in mice through an enhancement in intestinal stability. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[232]  E. Göker,et al.  Controlled Release of Methotrexate from W/O Microemulsion and Its In Vitro Antitumor Activity , 2007, Drug delivery.

[233]  A. Oza,et al.  A randomised trial of oral versus intravenous topotecan in patients with relapsed epithelial ovarian cancer. , 2002, European journal of cancer.

[234]  Sang-Chul Shin,et al.  Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. , 2006, International journal of pharmaceutics.

[235]  P. Swaan,et al.  Potential Oral Delivery of 7-Ethyl-10-Hydroxy-Camptothecin (SN-38) using Poly(amidoamine) Dendrimers , 2008, Pharmaceutical Research.

[236]  Sushama Talegaonkar,et al.  Novel formulation approaches for optimising delivery of anticancer drugs based on P-glycoprotein modulation. , 2009, Drug discovery today.

[237]  M. Piciotti,et al.  Role of P-glycoprotein in colchicine and vinblastine cellular kinetics in an immortalized rat brain microvessel endothelial cell line. , 1997, Biochemical pharmacology.

[238]  Peter Lloyd,et al.  Clinical Pharmacokinetics of Imatinib , 2005, Clinical pharmacokinetics.

[239]  G. Zhai,et al.  A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting , 2012, International journal of nanomedicine.

[240]  Gautam Mishra,et al.  Oral Bioavailability Enhancement of Exemestane from Self-Microemulsifying Drug Delivery System (SMEDDS) , 2009, AAPS PharmSciTech.

[241]  Chee Wee Gan,et al.  Poly(lactide)-vitamin E derivative/montmorillonite nanoparticle formulations for the oral delivery of Docetaxel. , 2009, Biomaterials.

[242]  Lie-Chwen Lin,et al.  Optimised nano-formulation on the bioavailability of hydrophobic polyphenol, curcumin, in freely-moving rats. , 2011, Food chemistry.

[243]  Y. Jeong,et al.  Doxorubicin-incorporated polymeric micelles composed of dextran-b-poly(DL-lactide-co-glycolide) copolymer , 2011, International journal of nanomedicine.

[244]  Hong Yuan,et al.  Studies on PEG-modified SLNs loading vinorelbine bitartrate (I): preparation and evaluation in vitro. , 2008, International journal of pharmaceutics.

[245]  M. Heinrich,et al.  In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets. , 2005, Blood.

[246]  Y. Lo,et al.  Comparison of effects of surfactants with other MDR reversing agents on intracellular uptake of epirubicin in Caco-2 cell line. , 1998, Anticancer research.

[247]  E. Kantharaj,et al.  Histone Deacetylase Inhibitors as Therapeutic Agents for Cancer Therapy: Drug Metabolism and Pharmacokinetic Properties , 2011 .

[248]  H. Katsumi,et al.  Polyamidoamine dendrimers as novel potential absorption enhancers for improving the small intestinal absorption of poorly absorbable drugs in rats. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[249]  A. Narang,et al.  Anticancer Drug Development , 2009 .

[250]  A. Ray,et al.  Transepithelial transport of PEGylated anionic poly(amidoamine) dendrimers: implications for oral drug delivery. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[251]  J. Leroux,et al.  Polymeric micelles for oral drug delivery. , 2010, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[252]  P. Gros,et al.  Residues in P-glycoprotein catalytic sites that react with the inhibitor 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole. , 1998, Archives of biochemistry and biophysics.

[253]  C. Pouton,et al.  Enhancing intestinal drug solubilisation using lipid-based delivery systems. , 2008, Advanced drug delivery reviews.

[254]  A. Bernkop‐Schnürch,et al.  In vivo evaluation of thiolated poly(acrylic acid) as a drug absorption modulator for MRP2 efflux pump substrates. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[255]  Dinesh Kumar,et al.  Polyelectrolyte stabilized multilayered liposomes for oral delivery of paclitaxel. , 2012, Biomaterials.

[256]  W. Lamph,et al.  The selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced breast carcinoma , 2005, Molecular Cancer Therapeutics.

[257]  S. Tokudome,et al.  IDENTIFICATION OF THE CYTOSOLIC CARBOXYLESTERASE CATALYZING THE 5′-DEOXY-5-FLUOROCYTIDINE FORMATION FROM CAPECITABINE IN HUMAN LIVER , 2004, Drug Metabolism and Disposition.

[258]  P. Artursson,et al.  Chitosans as Absorption Enhancers for Poorly Absorbable Drugs 2: Mechanism of Absorption Enhancement , 1997, Pharmaceutical Research.

[259]  Youn-Chul Kim,et al.  Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin. , 2004, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[260]  A. Bernkop‐Schnürch,et al.  In vivo comparison of various polymeric and low molecular mass inhibitors of intestinal P-glycoprotein. , 2006, Biomaterials.

[261]  L. Lim,et al.  Preparation and in vitro anticancer activity of wheat germ agglutinin (WGA)-conjugated PLGA nanoparticles loaded with paclitaxel and isopropyl myristate. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[262]  N. K. Jain,et al.  Application of dendrimer–drug complexation in the enhancement of drug solubility and bioavailability , 2008, Expert opinion on drug metabolism & toxicology.

[263]  M. Gottesman,et al.  Multidrug resistance in cancer: role of ATP–dependent transporters , 2002, Nature Reviews Cancer.

[264]  Jos H. Beijnen,et al.  Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation , 2010, Molecular Cancer Therapeutics.

[265]  Jianhua Xu,et al.  Self-microemulsifying drug delivery system improves curcumin dissolution and bioavailability , 2011, Drug development and industrial pharmacy.

[266]  Yan-Yan Zhang,et al.  Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib , 2011, Acta Pharmacologica Sinica.

[267]  James S. Scott,et al.  Neutral 5-substituted 4-anilinoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase. , 2007, Bioorganic & Medicinal Chemistry Letters.

[268]  M. Sivakumar,et al.  Methotrexate loaded solid lipid nanoparticles (SLN) for effective treatment of carcinoma. , 2006, Journal of nanoscience and nanotechnology.

[269]  Hong Yuan,et al.  Stearic acid-g-chitosan polymeric micelle for oral drug delivery: in vitro transport and in vivo absorption. , 2011, Molecular pharmaceutics.

[270]  F. Sharom,et al.  Site-directed fluorescence labeling of P-glycoprotein on cysteine residues in the nucleotide binding domains. , 1996, Biochemistry.

[271]  J. Beisler,et al.  Potential antitumor agents: procarbazine analogs and other methylhydrazine derivatives. , 1977, Journal of pharmaceutical sciences.

[272]  F. Pinguet,et al.  Antiproliferative effect of methyl-beta-cyclodextrin in vitro and in human tumour xenografted athymic nude mice. , 1998, British Journal of Cancer.

[273]  R. D'Amato,et al.  An orally delivered small-molecule formulation with antiangiogenic and anticancer activity , 2008, Nature Biotechnology.

[274]  D. Shenoy,et al.  Micellar Nanoparticles: Applications for Topical and Passive Transdermal Drug Delivery , 2010 .

[275]  Shufeng Zhou,et al.  Self-microemulsifying drug delivery system (SMEDDS) improves anticancer effect of oral 9-nitrocamptothecin on human cancer xenografts in nude mice. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[276]  Magang Shou,et al.  The Role of P-glycoprotein in the Bioactivation of Raloxifene , 2006, Drug Metabolism and Disposition.

[277]  Gerrit Borchard,et al.  The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. III: Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro , 1996 .

[278]  C. Huck,et al.  Effect of a thiolated polymer on oral paclitaxel absorption and tumor growth in rats , 2008 .

[279]  A. Bernkop‐Schnürch,et al.  Permeation enhancing polymers in oral delivery of hydrophilic macromolecules: thiomer/GSH systems. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[280]  C. Di Giacomo,et al.  Lipophilic methotrexate conjugates with antitumor activity. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[281]  M Nakajima,et al.  [Matrix metalloproteinase inhibitors]. , 2000, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[282]  Sudesh Kumar Yadav,et al.  Biodegradable polymeric nanoparticles based drug delivery systems. , 2010, Colloids and surfaces. B, Biointerfaces.

[283]  Hua Yue,et al.  Porous quaternized chitosan nanoparticles containing paclitaxel nanocrystals improved therapeutic efficacy in non-small-cell lung cancer after oral administration. , 2011, Biomacromolecules.

[284]  A T Florence,et al.  Oral uptake and translocation of a polylysine dendrimer with a lipid surface. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[285]  J. Wijnholds,et al.  Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance. , 2000, Cancer research.

[286]  R. Salem,et al.  Dequalinium, a topical antimicrobial agent, displays anticarcinoma activity based on selective mitochondrial accumulation. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[287]  S. Benita,et al.  Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. , 2004, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[288]  M. Varma,et al.  Enhanced oral paclitaxel absorption with vitamin E-TPGS: effect on solubility and permeability in vitro, in situ and in vivo. , 2005, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[289]  K. Thanki,et al.  Gelatin coated hybrid lipid nanoparticles for oral delivery of amphotericin B. , 2012, Molecular pharmaceutics.

[290]  Hetal Thakkar,et al.  Formulation and characterization of lipid-based drug delivery system of raloxifene-microemulsion and self-microemulsifying drug delivery system , 2011, Journal of pharmacy & bioallied sciences.

[291]  Amit Jain,et al.  Folate-decorated PLGA nanoparticles as a rationally designed vehicle for the oral delivery of insulin. , 2012, Nanomedicine.

[292]  Samuel A Wickline,et al.  Nanotechnology for molecular imaging and targeted therapy. , 2003, Circulation.

[293]  J. Hanes,et al.  Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues. , 2009, Advanced drug delivery reviews.

[294]  Amit K Jain,et al.  Engineered PLGA nanoparticles: an emerging delivery tool in cancer therapeutics. , 2011, Critical reviews in therapeutic drug carrier systems.

[295]  D. Shen,et al.  Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction. , 1997, Advanced drug delivery reviews.

[296]  Han‐Gon Choi,et al.  Effect of dose and dosage interval on the oral bioavailability of docetaxel in combination with a curcumin self-emulsifying drug delivery system (SEDDS) , 2012, European Journal of Drug Metabolism and Pharmacokinetics.

[297]  G. Banna,et al.  Anticancer oral therapy: emerging related issues. , 2010, Cancer treatment reviews.

[298]  Abu T. M. Serajuddin,et al.  Development of Solid Self-Emulsifying Drug Delivery System (SEDDS) I: Use of Poloxamer 188 as Both Solidifying and Emulsifying Agent for Lipids , 2012, Pharmaceutical Research.

[299]  M. Kisel,et al.  Liposomes with phosphatidylethanol as a carrier for oral delivery of insulin: studies in the rat. , 2001, International journal of pharmaceutics.

[300]  Smadar Cohen,et al.  In Vitro Evaluation of Polymerized Liposomes as an Oral Drug Delivery System , 1995, Pharmaceutical Research.

[301]  Ruth Duncan,et al.  Anionic PAMAM Dendrimers Rapidly Cross Adult Rat Intestine In Vitro: A Potential Oral Delivery System? , 2000, Pharmaceutical Research.

[302]  F. Caruso,et al.  Uptake and intracellular fate of disulfide-bonded polymer hydrogel capsules for Doxorubicin delivery to colorectal cancer cells. , 2010, ACS nano.

[303]  D. Richel,et al.  Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[304]  J. Irache,et al.  Oral administration of paclitaxel with pegylated poly(anhydride) nanoparticles: permeability and pharmacokinetic study. , 2012, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[305]  J. Liliemark,et al.  Structure-Activity Relationships of 2-Chloro-2′-arabino-fluoro-2′-deoxyadenosine and Related Analogues: Protein Binding, Lipophilicity, and Retention in Reversed-Phase LC , 1995 .

[306]  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.

[307]  Hailong Yu,et al.  Improving the oral bioavailability of curcumin using novel organogel-based nanoemulsions. , 2012, Journal of agricultural and food chemistry.

[308]  P. Creaven,et al.  Studies on the human pharmacokinetics of isophosphamide (NSC-109724). , 1976, Cancer treatment reports.

[309]  R. Cavalli,et al.  Enhanced oral paclitaxel bioavailability after administration of paclitaxel-loaded nanosponges , 2010, Drug delivery.

[310]  K. Mäder,et al.  Solid lipid nanoparticles: production, characterization and applications. , 2001, Advanced drug delivery reviews.

[311]  Gang Cheng,et al.  Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms. , 2008, Drug discovery today.

[312]  Y. Lo,et al.  Relationships between the hydrophilic-lipophilic balance values of pharmaceutical excipients and their multidrug resistance modulating effect in Caco-2 cells and rat intestines. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[313]  Yuichi Sugiyama,et al.  Effect of excipients on breast cancer resistance protein substrate uptake activity. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[314]  Jianjun Cheng,et al.  Controlled synthesis of camptothecin-polylactide conjugates and nanoconjugates. , 2010, Bioconjugate chemistry.

[315]  M. Sehested,et al.  The solvents cremophor EL and Tween 80 modulate daunorubicin resistance in the multidrug resistant Ehrlich ascites tumor. , 1990, Cancer communications.

[316]  X. Wu,et al.  In vivo evaluation of a new polymer-lipid hybrid nanoparticle (PLN) formulation of doxorubicin in a murine solid tumor model. , 2007, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[317]  G. Pasut,et al.  Polymer-drug conjugation, recent achievements and general strategies , 2007 .

[318]  J. Iqbal,et al.  Thiomers: Inhibition of cytochrome P450 activity. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[319]  Han‐Gon Choi,et al.  Enhanced oral bioavailability of curcumin via a solid lipid-based self-emulsifying drug delivery system using a spray-drying technique. , 2011, Biological & pharmaceutical bulletin.

[320]  A. Escargueil,et al.  The multidrug transporter, P-glycoprotein, actively mediates cholesterol redistribution in the cell membrane , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[321]  Si-Shen Feng,et al.  Self-assembled nanoparticles of poly(lactide)--Vitamin E TPGS copolymers for oral chemotherapy. , 2006, International journal of pharmaceutics.

[322]  Mark E. Davis,et al.  Cyclodextrin-based pharmaceutics: past, present and future , 2004, Nature Reviews Drug Discovery.

[323]  A. Nokhodchi,et al.  Enhancement of percutaneous absorption of Finasteride by cosolvents, cosurfactant and surfactants , 2010, Pharmaceutical development and technology.

[324]  L. Cattel,et al.  Preparation, characterization, molecular modeling and in vitro activity of paclitaxel-cyclodextrin complexes. , 2002, Bioorganic & medicinal chemistry letters.

[325]  Jia-bi Zhu,et al.  Body Distribution of Camptothecin Solid Lipid Nanoparticles After Oral Administration , 1999, Pharmaceutical Research.

[326]  Brahmeshwar Mishra,et al.  Lipid--an emerging platform for oral delivery of drugs with poor bioavailability. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[327]  W. J. Johnson,et al.  Cellular Cholesterol Efflux Mediated by Cyclodextrins (*) , 1995, The Journal of Biological Chemistry.

[328]  A. E. Senior,et al.  Covalent inhibitors of P-glycoprotein ATPase activity. , 1994, The Journal of biological chemistry.

[329]  D. Bigner,et al.  Chemotherapy of subcutaneous and intracranial human medulloblastoma xenografts in athymic nude mice. , 1986, Cancer research.

[330]  Xiaoqin Yang,et al.  Nanochemoprevention by encapsulation of (-)-epigallocatechin-3-gallate with bioactive peptides/chitosan nanoparticles for enhancement of its bioavailability. , 2012, Chemical Communications.

[331]  S. Kinsky,et al.  Circumvention of the methotrexate transport system by methotrexate-phosphatidylethanolamine derivatives: effect of fatty acid chain length. , 1987, Biochimica et biophysica acta.

[332]  Feng Liu,et al.  Understanding the structure and stability of paclitaxel nanocrystals. , 2010, International journal of pharmaceutics.

[333]  G. Sharma,et al.  Design of Biodegradable Nanoparticles for Oral Delivery of Doxorubicin: In vivo Pharmacokinetics and Toxicity Studies in Rats , 2009, Pharmaceutical Research.

[334]  Martin Werle,et al.  Glutathione and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity in excised small intestine. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[335]  S. Vyas,et al.  Lipid drug conjugate (LDC) nanoparticles as autolymphotrophs for oral delivery of methotrexate. , 2011, Journal of biomedical nanotechnology.

[336]  Q. Ping,et al.  PLGA Nanoparticles for the Oral Delivery of 5-Fluorouracil Using High Pressure Homogenization-Emulsification as the Preparation Method and In Vitro/In Vivo Studies , 2008 .

[337]  Neil B. McKeown,et al.  Engineering of Dendrimer Surfaces to Enhance Transepithelial Transport and Reduce Cytotoxicity , 2003, Pharmaceutical Research.

[338]  R. Müller,et al.  Preservation of nanostructured lipid carriers (NLC). , 2010, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[339]  A. Bernkop‐Schnürch,et al.  Chemically modified chitosans as enzyme inhibitors. , 2001, Advanced drug delivery reviews.

[340]  Yan Tian,et al.  Oral Delivery of DMAB-Modified Docetaxel-Loaded PLGA-TPGS Nanoparticles for Cancer Chemotherapy , 2010, Nanoscale research letters.

[341]  Akira Yamamoto,et al.  Modulation of intestinal P-glycoprotein function by polyethylene glycols and their derivatives by in vitro transport and in situ absorption studies. , 2006, International journal of pharmaceutics.

[342]  L. Rubin,et al.  Evidence that tyrosine phosphorylation may increase tight junction permeability. , 1995, Journal of cell science.

[343]  Chin-Fu Chen,et al.  Long-Chain Polyunsaturated Fatty Acids Promote Paclitaxel Cytotoxicity via Inhibition of the MDR1 Gene in the Human Colon Cancer Caco-2 Cell Line , 2011, Journal of the American College of Nutrition.

[344]  A. Saxena,et al.  Design, Synthesis, and Biological Testing of 4β‐[(4‐Substituted)‐1,2,3‐triazol‐1‐yl]podophyllotoxin Analogues as Antitumor Agents , 2008, Archiv der Pharmazie.

[345]  S. Boppart,et al.  Lymphatic Biodistribution of Polylactide Nanoparticles , 2010, Molecular imaging.

[346]  J. Benoit,et al.  Development and characterization of a novel lipid nanocapsule formulation of Sn38 for oral administration. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[347]  Yuanjie Liu,et al.  Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer , 2012, International journal of nanomedicine.