Mmp-9 responsive PEG cleavable nanovesicles for efficient delivery of chemotherapeutics to pancreatic cancer.
Significant differences in biochemical parameters between normal and tumor tissues offer an opportunity to chemically design drug carriers which respond to these changes and deliver the drugs at the desired site. For example, overexpression of the matrix metalloproteinase-9 (MMP-9) enzyme in the extracellular matrix of tumor tissues can act as a trigger to chemically modulate the drug delivery from the carriers. In this study, we have synthesized an MMP-9-cleavable, collagen mimetic lipopeptide which forms nanosized vesicles with the POPC, POPE-SS-PEG, and cholesteryl-hemisuccinate lipids. The lipopeptide retains the triple-helical conformation when incorporated into these nanovesicles. The PEG groups shield the substrate lipopeptides from hydrolysis by MMP-9. However, in the presence of elevated glutathione levels, the PEG groups are reductively removed, exposing the lipopeptides to MMP-9. The resultant peptide-bond cleavage disturbs the vesicles' lipid bilayer, leading to the release of encapsulated contents. These PEGylated nanovesicles are capable of encapsulating the anticancer drug gemcitabine with 50% efficiency. They were stable in physiological conditions and in human serum. Effective drug release was demonstrated using the pancreatic ductal carcinoma cells (PANC-1 and MIAPaCa-2) in two-dimensional and three-dimensional "tumor-like" spheroid cultures. A reduction in tumor growth was observed after intravenous administration of the gemcitabine-encapsulated nanovesicles in the xenograft model of athymic, female nude mice.
Department of Pharmaceutical Sciences, North Dakota State University , Fargo, North Dakota 58102, United States.
Prajakta S
PS
Kulkarni
Manas K
MK
Haldar
Rahul R
RR
Nahire
Preeya
P
Katti
Avinash H
AH
Ambre
Wallace W
WW
Muhonen
John B
JB
Shabb
Sathish K R
SK
Padi
Raushan K
RK
Singh
Pawel P
PP
Borowicz
D K
DK
Shrivastava
Kalpana S
KS
Katti
Katie
K
Reindl
Bin
B
Guo
Sanku
S
Mallik
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008051:Lipid Bilayers / Q000378:metabolism; D055666:Lipopeptides / Q000008:administration & dosage / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D022161:Transport Vesicles / Q000737:chemistry*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008051:Lipid Bilayers; D055666:Lipopeptides; D010713:Phosphatidylcholines; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D020780:Matrix Metalloproteinase 9; D005978:Glutathione; C028694:1-palmitoyl-2-oleoylphosphatidylcholine; D000093542:Gemcitabine