Novel biodegradable lipid nano complex for siRNA delivery significantly improving the chemosensitivity of human colon cancer stem cells to paclitaxel.
BACKGROUND
Targeting of a specific subset of cells is mandatory for the successful application of siRNA mediated silencing in anticancer therapy. A recent theory suggests that colon cancer is sustained by a small subpopulation of cells, termed cancer stem cells (CSCs). These cells are characterized by their innate drug resistance properties, which is one of the key factors of chemotherapy failure. The goal of this study was to assess whether a novel siRNA delivery carrier, with an appropriate siRNA, targeted to CD133+ cells has the potential to improve the efficacy of conventional chemotherapy.


METHODS
In this study, a novel synthetic siRNA carrier platform was designed and synthesized. This carrier was composed of a cationic oligomer (PEI(1200)), a hydrophilic polymer (polyethylene glycol) and a biodegradable lipid-based crosslinking moiety. Libraries of polymers were synthesized by varying their lipid composition. Their transfection efficacy was evaluated in vitro using CHOK1 cells. The polymer was characterized using molecular weight, particle encapsulation assay, particle size and surface charge analysis.


RESULTS
It was demonstrated that the lipid composition in the polymer plays a critical role in transfection. Optimizing the physicochemical properties of the polymers is crucial in achieving favorable knockdown. Lipid nano complex with composition PEI-Lipid(1:16) was the optimum ratio for gene silencing. Additionally, silencing of multidrug resistance gene (MDR1) and treatment with paclitaxel play a synergistic role in increasing the efficacy as compared to the drug alone.


CONCLUSIONS
In the present study a novel siRNA delivery carrier system with an MDR1-targeting siRNA (siMDR1) effectively reduced the expression of MDR1 in human colon CSCs (CD133+ enriched cell population), resulting in significantly increasing the chemosensitivity to paclitaxel.
Liu
Changxing
C
Department of General Surgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Zhao
Gang
G
Liu
Jian
J
Ma
Nianchun
N
Chivukula
Padmanabh
P
Perelman
Loren
L
Okada
Keisaku
K
Chen
Zongyou
Z
Gough
David
D
Yu
Lei
L
D000071916:AC133 Antigen; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D002412:Cations; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003432:Cross-Linking Reagents; D004339:Drug Compounding; D016503:Drug Delivery Systems; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008156:Luciferases / Q000235:genetics; D008970:Molecular Weight; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D010316:Particle Size; D010455:Peptides / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use*; D012995:Solubility; D014162:Transfection; D014867:Water
D000071916:AC133 Antigen; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000277:Adjuvants, Pharmaceutic; D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; D002412:Cations; D003432:Cross-Linking Reagents; D006023:Glycoproteins; D008055:Lipids; C000606023:PROM1 protein, human; D010455:Peptides; D011108:Polymers; D034741:RNA, Small Interfering; D014867:Water; D011092:Polyethylene Glycols; D008156:Luciferases; D017239:Paclitaxel