Application of smart solid lipid nanoparticles to enhance the efficacy of 5-fluorouracil in the treatment of colorectal cancer

Taylor Smith,Sunil Krishnan,Felix Amissah,Kevin Affram,Jose Trevino,Bo Han,Edward Agyare,Ebony L Nottingham

doi:10.1038/s41598-020-73218-6

Abstract

5-Fluorouracil (5-FU) is a standard treatment option for colorectal cancer (CRC) but its rapid metabolism and systemic instability (short half-life) has hindered its therapeutic efficacy. The objective of this study was to develop a novel drug delivery system, solid lipid nanoparticle (SLN), capable of delivering high payload of 5-FU to treat CRC. The rational was to improve 5FU-nanocarrier compatibility and therapeutic efficacy. The SLN-loaded 5-FU was developed by utilizing a Strategic and unique Method to Advance and Refine the Treatment (SMART) of CRC through hot and cold homogenization approach. The SLN was made of unique PEGylated lipids and combination of the surfactants. Cytotoxicity studies, clonogenic assay, flow cytometry and confocal imaging were conducted to evaluate the effectiveness and cellular uptake of 5FU-SLN4 in HCT-116 cancer cells. Pharmacokinetic (PK) parameters and receptor expressions were determined while tumor efficacy studies were conducted on mouse bearing subcutaneous HCT-116 cancer. Among the all the formulations, 5FU-SLN4 was the most effective with particle size of was 263 ± 3 nm, zeta potential was 0.1 ± 0.02 and entrapment efficiency of 81 ± 10%. The IC50 value of 5FU-SLN4 (7.4 ± 0.02 µM) was 2.3 fold low compared with 5-FU (17.7 ± 0.03 µM). For tumor efficacy studies, 5FU-SLN4 significantly inhibited tumor growth in comparison to 5-FU while area-under plasma concentration-time curve (AUC) of 5FU-SLN4 was 3.6 fold high compared with 5-FU. HER2 receptors expression were markedly reduced in 5-FU-SLN4 treated mice compared with 5FU and liver and kidney tissues showed no toxicity at dose of 20 mg/kg. 5FU-SLN4 was highly cytotoxic against HCT-116 cells and significantly inhibited subcutaneous tumor growth in mice compared with 5-FU. This emphasizes the significance of developing a smart nano-delivery system to optimize the delivery efficiency of anticancer drugs to tumors.

Highlights

5-Fluorouracil (5-FU) is a standard treatment option for colorectal cancer (CRC) but its rapid metabolism and systemic instability has hindered its therapeutic efficacy
The present treatment of CRC largely depends on radiotherapy, surgery, targeted therapy and chemotherapy; surgery is the preferred option if CRC is at stages one through to four with or without chemotherapy and/or radiotherapy[3]
The current study aimed to develop a smart delivery system capable of delivery a high payload of 5-FU, a hydrophilic drug, into optimized solid lipid nanoparticle (SLN) (5FU-SLNs) with special emphasis on protection and prolonging systemic circulation of 5-FU and, to improve its therapeutic outcome

Summary

Introduction

5-Fluorouracil (5-FU) is a standard treatment option for colorectal cancer (CRC) but its rapid metabolism and systemic instability (short half-life) has hindered its therapeutic efficacy. Pharmacokinetic (PK) parameters and receptor expressions were determined while tumor efficacy studies were conducted on mouse bearing subcutaneous HCT-116 cancer. This emphasizes the significance of developing a smart nano-delivery system to optimize the delivery efficiency of anticancer drugs to tumors. The existing therapeutic agents for the treatment of CRC are diverse They include cytotoxic agents such as 5-FU, oxaliplatin, capecitabine and irinotecan, and targeted therapies such as bevacizumab and anti-epidermal growth factor receptor anti-bodies (examples are cetuximab and panitumumab). While 5-FU is often used alone or in combination with other anticancer agents such as irinotecan and folinic acid (FOLFIRI) or folinic acid and oxaliplatin (FOLFOX)[4], it’s antimetabolite mimics uracil and thymine which eventually incorporates into DNA and RNA synthesis leading to cytotoxicity and cell d eath5. 5-FU is a fluorinated pyrimidine that inhibits DNA and RNA activity through inhibition of the rate-limiting enzyme (thymidylate synthetase) in pyrimidine nucleotide s ynthesis[6]

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