title: Hyaluronic acid modified pH-sensitive liposomes for targeted intracellular delivery of doxorubicin.
abstract: BACKGROUND
  Surface-modified pH-sensitive liposomal system may be useful for intracellular delivery of chemotherapeutics.
  
  
  OBJECTIVE
  Achieving site-specific targeting with over-expressed hyaluronic acid (HA) receptors along with using pH sensitive liposome carrier for intracellular drug delivery was the aim of this study.
  
  
  METHODS
  Stealth HA-targeted pH-sensitive liposomes (SL-pH-HA) were developed and evaluated to achieve effective intracellular delivery of doxorubicin (DOX) vis-a-vis enhanced antitumor activity.
  
  
  RESULTS
  The in vitro release studies demonstrated that the release of DOX from SL-pH-HA was pH-dependent, i.e. faster at mildly acidic pH ∼5, compared to physiological pH ∼7.4. SLpH-HA was evaluated for their cytotoxicity potential on CD44 receptor expressing MCF-7 cells. The half maximal inhibitory concentration (IC50) of SL-pH-HA and SL-HA were about 1.9 and 2.5 μM, respectively, after 48 h of incubation. The quantitative uptake study revealed higher localization of targeted liposomes in the receptor positive cells, which was further confirmed by fluorescent microscopy. The antitumor efficacy of the DOX-loaded HA-targeted pH-sensitive liposomes was also verified in a tumor xenograft mouse model.
  
  
  CONCLUSIONS
  DOX was efficiently delivered to the tumor site by active targeting via HA and CD44 receptor interaction. The major side-effect of conventional DOX formulation, i.e. cardiotoxicity was also estimated by measuring serum enzyme levels of LDH and CPK and found to be minimized with developed formulation. Overall, HA targeted pH-sensitive liposomes were significantly more potent than the non-targeted liposomes in cells expressing high levels of CD44.
  
  
  CONCLUSIONS
  Results strongly implies the promise of such liposomal system as an intracellular drug delivery carrier developed for potential anticancer treatment.
authors.affiliation: a SLT Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya , Bilaspur , Chhattisgarh , India .|b Department of Pharmaceutical Sciences , Dr. H. S. Gour University , Sagar, Madhya Pradesh , India , and.
authors.forename: Shivani Rai
authors.initials: SR
authors.lastname: Paliwal
authors.affiliation: b Department of Pharmaceutical Sciences , Dr. H. S. Gour University , Sagar, Madhya Pradesh , India , and.|c Columbia Institute of Pharmacy , Raipur , Chhattisgarh , India.
authors.forename: Rishi
authors.initials: R
authors.lastname: Paliwal
authors.affiliation: b Department of Pharmaceutical Sciences , Dr. H. S. Gour University , Sagar, Madhya Pradesh , India , and.
authors.forename: Govind Prasad
authors.initials: GP
authors.lastname: Agrawal
authors.affiliation: b Department of Pharmaceutical Sciences , Dr. H. S. Gour University , Sagar, Madhya Pradesh , India , and.
authors.forename: Suresh Prasad
authors.initials: SP
authors.lastname: Vyas
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008081:Liposomes / Q000737:chemistry*; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D004317:Doxorubicin; D006820:Hyaluronic Acid; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase
keywords: Breast cancer; CD44 receptors; doxorubicin; hyaluronic acid; targeting