Mono-guanidine heterolipid based SMEDDS: A promising tool for cytosolic delivery of antineoplastics.
In the present work, we designed and synthesized a novel mono-guanidine heterolipid (MGH) and confirmed its structure by NMR and ESI-MS. The MGH was used as cationic lipid in developing etoposide loaded cationic self-microemulsifying drug delivery system (ECS) intended to be delivered by intratumoral route. The ECS exhibited size <50 nm and zeta potential +32.6 mV on dilution with various isotonic vehicles with no phase separation or drug precipitation. The ECS could be easily sterilized by membrane filtration method and showed excellent stability for 6 months. The ECS demonstrated excellent in vitro antiproliferative activity against B16F10 cells which is attributed to its high transfection efficiency and capability to cause prolonged drug release in cytosolic space. In vivo antitumor activity of ECS was conducted in B16F10 induced melanoma tumor model. ECS at 12 mg/kg dose showed superior tumor suppression ability and exhibited 100% survival compared to other formulations. Mice treated with ECS by intratumoral route, showed neither systemic side effect nor any evidences of hepatotoxicity and nephrotoxicity. In contrast, etoposide administered by intravenous route showed remarkable systemic toxicity, hepatotoxicity and nephrotoxicity.
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, Maharashtra, India.
Harshad
H
Shete
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, Maharashtra, India.
Sandip
S
Sable
Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India.
Pritish
P
Tidke
National Centre for Preclinical Reproductive and Genetic Toxicology, National Institute for Research in Reproductive Health, J. M. Street, Parel, Mumbai 400012, Maharashtra, India.
Nilakash
N
Selkar
Radiation Medicine Centre (BARC), C/o Tata Memorial Centre Annex, J. W. Road, Parel, Mumbai 400012, Maharashtra, India.
Yogita
Y
Pawar
Radiation Medicine Centre (BARC), C/o Tata Memorial Centre Annex, J. W. Road, Parel, Mumbai 400012, Maharashtra, India.
Avik
A
Chakraborty
Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India. Electronic address: ade@actrec.gov.in.
Abhijit
A
De
National Centre for Preclinical Reproductive and Genetic Toxicology, National Institute for Research in Reproductive Health, J. M. Street, Parel, Mumbai 400012, Maharashtra, India. Electronic address: vanageg@nirrh.res.in.
Geeta
G
Vanage
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, N.P. Marg, Matunga, Mumbai 400019, Maharashtra, India. Electronic address: vbp_muict@yahoo.co.in.
Vandana
V
Patravale
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004655:Emulsions / Q000737:chemistry; D005047:Etoposide / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D019791:Guanidine / Q000031:analogs & derivatives*; D008055:Lipids / Q000737:chemistry*; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008810:Mice, Inbred C57BL; D012995:Solubility
D000970:Antineoplastic Agents; D004337:Drug Carriers; D004655:Emulsions; D008055:Lipids; D005047:Etoposide; D019791:Guanidine
Cationic SMEDDS; Etoposide; Intratumoral; Melanoma; Mono-guanidine heterolipid