Stealth recombinant human serum albumin nanoparticles conjugating 5-fluorouracil augmented drug delivery and cytotoxicity in human colon cancer, HT-29 cells

Background and objective: 5-Fluorouracil (5-FU) is a first-line chemotherapeutic drug in colorectal cancer. However, intravenous administration of 5-FU at the dose of 7-12 mg/kg exhibits curbs like short half-life (20 min) and toxic side-effects on bone marrow cells. Therefore, in present investigation, 5-FU was conjugated to poly (ethylene glycol) anchored recombinant human serum albumin nanoparticles (5-FU-rHSA-PEG-NPs) to improve the pharmacokinetic and therapeutic profiles. Methods and results: The mean particle size of 5-FU-rHSA-NPs was measured to be 44.3 +/- 5.8-nm, significantly (P < 0.05) lesser than 65.7 +/- 7.2-nm of 5-FU-rHSA-PEG-NPs. In addition, zeta-potential of 5-FU-rHSA-NPs was estimated to be -10.2 +/- 2.6-mV significantly (P < 0.05) lower than -25.8 +/- 3.5-mV of 5-FU-rHSA-PEG-NPs. Moreover, both 5-FU-rHSA-NPs and 5-FU-rHSA-PEG-NPs were smooth, spherical and regular in shape. In-vitro drug release analysis indicated that 5-FU-rHSA-NPs and 5-FU-rHSA-PEG-NPs separately released 10.9% and 9.23% of 5-FU in PBS (pH similar to 7.4) with no significant difference (P > 0.05) up to 48 h. However, addition of 20% v/v serum to PBS (pH similar to 7.4) boosted the drug release. 5-FU-rHSA-NPs and 5-FU-rHSA-PEG-NPs released 78.26% and 48.9% of the 5-FU up to 48 h in presence of PBS (pH similar to 7.4 and 20% serum) with significant difference (P < 0.05). Furthermore, 5-FU-rHSA-PEG-NPs displayed the IC50 of 3.7-mu M significantly (P < 0.05) lower than 6.8-mu M and 11.2-mu M of 5-FU-rHSA-NPs and 5-FU solution, respectively. One compartmental pharmacokinetic elements indicated that 5-FU-rHSA-PEG-NPs demonstrated the half-life (t(1/2)) of 5.33 +/- 0.15-h significantly (P < 0.001) higher than 1.50 +/- 0.08-h and 0.30 +/- 0.09-h of 5-FU-rHSA-NPs and 5-FU solution, respectively. Conclusion: 5-FU-rHSA-PEG-NPs tendered improved cytotoxicity and pharmacokinetic profile. Hence, 5-FU-rHSA-PEG-NPs must be further tested under stringent milieu for translating in to a clinical product. (C) 2017 Elsevier B.V. All rights reserved.