Dual drug loaded liposome bearing apigenin and 5-Fluorouracil for synergistic therapeutic efficacy in colorectal cancer.
Multidrug-based combinatorial therapeutic regiments which target multiple pathways simultaneously are being utilized as a therapeutic strategy of choice due to reduction in toxicity profile and enhancement of therapeutic index of the individual drugs. 5-Fluorouracil is a clinically approved drug which has limited response rate in the realm of colorectal cancer amelioration, hence our study aims to improve its efficacy by aiming the simultaneous delivery of 5-Flurouracil and apigenin which is naturally occurring flavone abundantly present in fruit and vegetables through a single liposome to combat and control colorectal cancer effectively in-vitro and in-vivo. The liposomal nanocarrier bearing the anti-tumorigenic agent apigenin was designed in this study in order to improve the bioavailability of the flavone while at the same time achieve combinatorial drug regime with 5- Fluorouracil. This study reports the synthesis and production of a relatively robust dual drug-loaded liposomal formulation by modified thin film hydration method which substantially entraps both the drugs. Even though there have been reports of the combinatorial regimen involving apigenin and 5-Flurouracil our study reports the optimal molar ratio for effective synergistic therapeutic application of this drug combination to alleviate colorectal cancer. The cytotoxicity and cellular effects of individual, combinatorial free drugs and their liposomal counterparts tested against two human colon cancer cell lines revealed significantly higher cytotoxicity of the dual-drug liposomes. The dual-drug liposomes demonstrated enhanced inhibition of angiogenesis, better reduction in cell proliferation and increased apoptotic potential. Cell signaling studies indicating a significant upregulation of pAMPK and activity against downstream targets by dual drug liposomes suggested its role in the reversal of Warburg effect. The formulation was tested in a preclinical setting in nude mice tumor xenograft model and was found to have greater anti-neoplastic and anti-tumorigenic effect. The study indicated that the increased chemotherapeutic potential in vivo was due to the passive targeting achieved by the liposomal drug loaded nano-carrier and the synergistic effect of apigenin in 5-Fluorouracil treatment offers a new attractive alternative to enhance the therapeutic potency of drugs and paves way for potential clinical applications.
['Sen|Kacoli|K|', 'Banerjee|Shubhadeep|S|', 'Mandal|Mahitosh|M|']
D055372:AMP-Activated Protein Kinases D000818:Animals D000970:Antineoplastic Agents D000971:Antineoplastic Combined Chemotherapy Protocols D047310:Apigenin D002453:Cell Cycle D049109:Cell Proliferation D049033:Chorioallantoic Membrane D015179:Colorectal Neoplasms D004337:Drug Carriers D004357:Drug Synergism D005472:Fluorouracil D015972:Gene Expression Regulation, Neoplastic D019073:HT29 Cells D006801:Humans D051795:Hypoxia-Inducible Factor 1, alpha Subunit D008081:Liposomes D051379:Mice D008819:Mice, Nude D041681:NIH 3T3 Cells D058570:TOR Serine-Threonine Kinases D047368:Tumor Burden D023041:Xenograft Model Antitumor Assays
Dual drug loaded liposomes Apigenin 5-Fluorouracil Colorectal cancer Drug delivery