title: Somatostatin receptor targeted liposomes with Diacerein inhibit IL-6 for breast cancer therapy.
abstract: Selective targeting to the tumor niche remains a major challenge in successful cancer therapy. Somatostatin receptor 2 (SSTR2) is overexpressed in breast cancer cells thus making this receptor an attractive target for selective guidance of ligand-conjugated drug liposomes to the tumor site. In this study, a synthetic somatostatin analogue (SST) was used as SSTR2 targeting agent and Diacerein was employed as therapeutic molecule. Diacerein loaded liposomes (DNL) were prepared and they were further decorated with the synthetic and stable analogue of somatostatin (SST-DNL). Fabricated liposomes were nano-size in range and biocompatible. SST-DNL displayed significantly better anti-tumor efficacy as compared to free Diacerein (DN) and DNL in breast cancer models. Enhanced apoptosis in breast cancer cells was detected in SST-DNL treated groups as monitored by cell cycle analysis and changes in expression level of apoptotic/anti-apoptotic proteins Bcl-2, Bax, cleaved Caspase 3 and PARP. SST-DNL more effectively inhibited the oncogenic IL-6/IL-6R/STAT3/MAPK/Akt signalling pathways as compared to DN or DNL in cancer cells. In addition, SST-DNL effectively suppressed angiogenesis and cancer cell invasion. In vivo tumor growth in a MDA-MB-231 mouse xenograft model was significantly suppressed following SST-DNL treatment. In xenograft model, immunohistochemistry of Ki-67 and CD-31 indicated that SST-DNL improved the anti-proliferative and anti-angiogenic impacts of Diacerein. In vivo pharmacokinetic studies in rats showed enhanced circulation time in the DNL or SST-DNL treated groups as compared to free DN. Considering all of these findings, we conclude that SST-DNL provides a novel strategy with better efficacy for breast cancer therapy.
authors.affiliation: School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bharti
authors.affiliation: School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
authors.forename: Goutam
authors.initials: G
authors.lastname: Dey
authors.affiliation: Division of Nuclear Medicine, Indian Institute of Chemical Biology, Kolkata 700032, West Bengal, India.
authors.forename: Indranil
authors.initials: I
authors.lastname: Banerjee
authors.affiliation: School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
authors.forename: Kaushik Kumar
authors.initials: KK
authors.lastname: Dey
authors.affiliation: School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
authors.forename: Sheetal
authors.initials: S
authors.lastname: Parida
authors.affiliation: School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
authors.forename: B N Prashanth
authors.initials: BN
authors.lastname: Kumar
authors.affiliation: School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
authors.forename: Chandan Kanta
authors.initials: CK
authors.lastname: Das
authors.affiliation: School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
authors.forename: Ipsita
authors.initials: I
authors.lastname: Pal
authors.affiliation: Saha Institute of Nuclear Physics, Kolkata 700064, India.
authors.forename: Manabendra
authors.initials: M
authors.lastname: Mukherjee
authors.affiliation: Division of Nuclear Medicine, Indian Institute of Chemical Biology, Kolkata 700032, West Bengal, India.
authors.forename: Mridula
authors.initials: M
authors.lastname: Misra
authors.affiliation: Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Anjan K
authors.initials: AK
authors.lastname: Pradhan
authors.affiliation: Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India. Electronic address: mahitosh@smst.iitkgp.ernet.in.
authors.forename: Mahitosh
authors.initials: M
authors.lastname: Mandal
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D015850:Interleukin-6; D008081:Liposomes / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D017481:Receptors, Somatostatin / Q000378:metabolism*
chemical_list: D000880:Anthraquinones; D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008081:Liposomes; D017481:Receptors, Somatostatin; C025292:diacerein
keywords: Diacerein and breast cancer; Liposome; Somatostatin analogue (SST)