β-Casein nanoparticle-based oral drug delivery system for potential treatment of gastric carcinoma: stability, target-activated release and cytotoxicity.

We studied a potential drug delivery system comprising the hydrophobic anticancer drug paclitaxel entrapped within β-casein (β-CN) nanoparticles and its cytotoxicity to human gastric carcinoma cells. Paclitaxel was entrapped by stirring its dimethyl sulfoxide (DMSO) solution into PBS containing β-CN. Cryo-TEM analysis revealed drug nanocrystals, the growth of which was blocked by β-CN. Entrapment efficiency was nearly 100%, and the nanovehicles formed were colloidally stable. Following encapsulation and simulated digestion with pepsin (2 hours at pH=2, 37 °C), paclitaxel retained its cytotoxic activity to human N-87 gastric cancer cells; the IC(50) value (32.5 ± 6.2 nM) was similar to that of non-encapsulated paclitaxel (25.4 ± 2.6 nM). Without prior simulated gastric digestion, β-CN-paclitaxel nanoparticles were non-cytotoxic, suggesting the lack of untoward toxicity to bucal and esophageal epithelia. We conclude that β-CN shows promise to be useful for target-activated oral delivery of hydrophobic chemotherapeutics in the treatment of gastric carcinoma, one of the leading causes of cancer mortality worldwide.

[1]  P. Deymier,et al.  Heterogeneous and homogeneous nucleation of Taxol crystals in aqueous solutions and gels: effect of tubulin proteins. , 2010, Colloids and surfaces. B, Biointerfaces.

[2]  Na Li,et al.  Novel nanogels as drug delivery systems for poorly soluble anticancer drugs. , 2011, Colloids and surfaces. B, Biointerfaces.

[3]  Y. Kodera,et al.  Paclitaxel chemotherapy for the treatment of gastric cancer , 2009, Gastric Cancer.

[4]  L. Denis,et al.  Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[5]  C. Wischke,et al.  Increased sensitivity of chitosan determination by a dye binding method. , 2006, Carbohydrate research.

[6]  S. Gaier,et al.  In vitro digestibility of beta-casein and beta-lactoglobulin under simulated human gastric and duodenal conditions: a multi-laboratory evaluation. , 2009, Regulatory toxicology and pharmacology : RTP.

[7]  Y. Talmon.  CRYOGENIC TEMPERATURE TRANSMISSION ELECTRON MICROSCOPY IN THE STUDY OF SURFACTANT SYSTEMS , 1999 .

[8]  H. Chung,et al.  Growth inhibitory effects of trastuzumab and chemotherapeutic drugs in gastric cancer cell lines. , 2004, Cancer letters.

[9]  Optical CDMA System Using Bacteriorhodopsin for Optical Data Storage , 1999, Biotechnology progress.

[10]  Y. Assaraf,et al.  Beta-casein-based nanovehicles for oral delivery of chemotherapeutic drugs: drug-protein interactions and mitoxantrone loading capacity. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[11]  J. Beijnen,et al.  Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer , 2006, British Journal of Cancer.

[12]  J Szebeni,et al.  Formation of complement-activating particles in aqueous solutions of Taxol: possible role in hypersensitivity reactions. , 2001, International immunopharmacology.

[13]  Wim E Hennink,et al.  Thermosensitive and biodegradable polymeric micelles for paclitaxel delivery. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[14]  J. Schellens,et al.  Intravenous‐to‐Oral Switch in Anticancer Chemotherapy: A Focus on Docetaxel and Paclitaxel , 2010, Clinical pharmacology and therapeutics.

[15]  R. Neubert,et al.  Peptic digestion of beta-casein. Time course and fate of possible bioactive peptides. , 2007, Journal of chromatography. A.

[16]  U. Cogan,et al.  Micellization of bovine β-casein studied by isothermal titration microcalorimetry and cryogenic transmission electron microscopy , 2006 .

[17]  R. Zana.  Dynamics in Micellar Solutions of Amphiphilic Block Copolymers , 2005 .

[18]  L. Mikheeva,et al.  Thermodynamics of Micellization of Bovine β-Casein Studied by High-Sensitivity Differential Scanning Calorimetry , 2003 .

[19]  Yoav D Livney,et al.  Beta-casein nanovehicles for oral delivery of chemotherapeutic drugs. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[20]  F. Ciardiello,et al.  Novel investigational drugs for gastric cancer , 2009, Expert opinion on investigational drugs.

[21]  D. Horne.  Casein structure, self-assembly and gelation , 2002 .

[22]  H. Choy,et al.  Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  H. Swaisgood,et al.  Chemistry of the Caseins , 2003 .

[24]  H. Rosing,et al.  Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[25]  L E Scriven,et al.  Controlled environment vitrification system: an improved sample preparation technique. , 1988, Journal of electron microscopy technique.

[26]  L. Hegedũs,et al.  High affinity binding of paclitaxel to human serum albumin. , 2001, European journal of biochemistry.

[27]  J. Schellens,et al.  The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients , 2001, British Journal of Cancer.

[28]  B. Binks.  Modern characterization methods of surfactant systems , 1999 .

[29]  H. T. Davis,et al.  Viscoelastic micellar solutions: microscopy and rheology , 1992 .

[30]  E. Warner,et al.  Patient preferences for oral versus intravenous palliative chemotherapy. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  J Verweij,et al.  Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. , 2001, European journal of cancer.

[32]  D. Dalgleish,et al.  A study of β-casein tertiary structure by intramolecular crosslinking and mass spectrometry , 2004 .

[33]  X. Yao,et al.  Interaction of Taxol with intravenous immunoglobulin: an inhibition of Taxol from crystallizing in aqueous solution. , 2008, International immunopharmacology.