title: Adenosine conjugated lipidic nanoparticles for enhanced tumor targeting.
abstract: Delivering chemotherapeutics by nanoparticles into tumor is impeded majorly by two factors: nonspecific targeting and inefficient penetration. Targeted delivery of anti-cancer agents solely to tumor cells introduces a smart strategy because it enhances the therapeutic index compared with untargeted drugs. The present study was performed to investigate the efficiency of adenosine (ADN) to target solid lipid nanoparticles (SLN) to over expressing adenosine receptor cell lines such as human breast cancer and prostate cancer (MCF-7 and DU-145 cells), respectively. SLN were prepared by emulsification and solvent evaporation process using docetaxel (DTX) as drug and were characterized by various techniques like dynamic light scattering, differential scanning calorimeter and transmission electron microscopy. DTX loaded SLNs were surface modified with ADN, an adenosine receptors ligand using carbodiimide coupling. Conjugation was confirmed using infrared spectroscopy and quantified using phenol-sulfuric acid method. Conjugated SLN were shown to have sustained drug release as compared to unconjugated nanoparticles and drug suspension. Compared with free DTX and unconjugated SLN, ADN conjugated SLN showed significantly higher cytotoxicity of loaded DTX, as evidenced by in vitro cell experiments. The IC50 was 0.41 μg/ml for native DTX, 0.30 μg/ml for unconjugated SLN formulation, and 0.09 μg/ml for ADN conjugated SLN formulation in MCF-7 cell lines. Whereas, in DU-145, there was 2 fold change in IC50 of ADN-SLN as compared to DTX. IC50 was found to be 0.44 μg/ml for free DTX, 0.39 μg/ml for unconjugated SLN and 0.22 μg/ml for ADN-SLN. Annexin assay and cell cycle analysis assay further substantiated the cell cytotoxicity. Fluorescent cell uptake and competitive ligand-receptor binding assay corroborated the receptor mediated endocytosis pathway indicated role of adenosine receptors in internalization of conjugated particles. Pharmacokinetic studies of lipidic formulations depicted significant improvement in pharmacokinetic parameters than marketed formulation. ADN conjugated SLN proved to be an efficient drug delivery vehicle. Hence, ADN can be used as a potential ligand to target breast and prostate cancer.
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
authors.forename: Rajan
authors.initials: R
authors.lastname: Swami
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
authors.forename: Indu
authors.initials: I
authors.lastname: Singh
authors.affiliation: Department of Pharmacology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
authors.forename: Manish Kumar
authors.initials: MK
authors.lastname: Jeengar
authors.affiliation: Department of Pharmacology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
authors.forename: V G M
authors.initials: VG
authors.lastname: Naidu
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India. Electronic address: wahid@niperhyd.ac.in.
authors.forename: Wahid
authors.initials: W
authors.lastname: Khan
authors.affiliation: Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India. Electronic address: sistla@iict.res.in.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Sistla
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids; D043823:Taxoids; D000077143:Docetaxel; D000241:Adenosine
keywords: Adenosine; Adenosine receptors; Cell cycle analysis; Conjugation; Solid lipid nanoparticles