Synthesis, characterization, and in vitro anticancer evaluation of 1,3-bistetrahydrofuran- 2yl-5-FU as a potential agent for pancreatic cancer

Ndemazie, Nkafu Bechem; Inkoom, Andriana; Ebesoh, Dexter; Bulusu, Raviteja; Frimpong, Esther; Trevino, Jose; Han, Bo; Xiao-lin, Zhu; Agyare, Edward

doi:10.21203/rs.3.rs-1863111/v1

Cited by 1 publication

(2 citation statements)

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“…To resolve some of the issues mentioned above, we synthesized and characterized MFU from our previous studies 25 , loaded it to LnP (together called zhubech) with the surface modified with/ DSPE-PEG_2000 to enhance stability in systemic circulation and improve the therapeutic efficacy of MFU. One of the unique features of zhubech is that it is very stable at room temperatures; hence does not need any particular temperatures for storage 36 .…”

Section: Discussionmentioning

confidence: 99%

“…The conjugation confers properties such as increased membrane permeability, bioavailability, and extended duration of action, ultimately leading to higher cytotoxic effects 16 . The present study details the design of a liposomal formulation (LnP), cell viability studies with 5-FU analog previously synthesized (1,3 bistetrahydrifuran-2yl-5-FU (MFU)) 25 against Panc-1 and MiaPaCa-2 cancer cells using 2D and 3D models (spheroids and organoids) respectively, tumor efficacy studies using patient-derived xenograft (PDX) mouse model with ectopic tumors and evaluating the tissue biodistribution of Gd-Hex-LnP in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of Anticancer Activity of Zhubech, a New 5-FU Analog Liposomal Formulation, against Pancreatic Cancer

Ndemazie¹,

Xiao-lin²,

Bulusu³

et al. 2023

Preprint

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Pancreatic cancer is projected to be the second leading cause of cancer-related death by 2030 in the US. The benefits of the most common systemic therapy for various pancreatic cancer have been masked by high drug toxicities, adverse reactions, and resistance. Using nanocarriers like liposomes to overcome these unwanted effects has become very popular. This study aimed to formulate 1,3-bis tetrahydrofuran-2yl-5FU (MFU)-loaded liposomal nanoparticles (Zhubech) and evaluate the stability, MFU release kinetics, in vitro and in vivo anticancer activities, and biodistribution. Particle size and zeta potential were determined using a particle size analyzer, while cellular uptake of rhodamine-entrapped liposomal nanoparticle (Rh0-LnP) was determined by confocal microscopy. Gadolinium hexanoate (Gd-Hex) was synthesized and entrapped into the liposomal nanoparticle (LnP) (Gd-Hex-LnP) as a model contrast agent, to evaluate gadolinium biodistribution and accumulation by LnP in vivo using inductively coupled plasma mass spec-trometry (ICP-MS). The mean hydrodynamic diameters of the blank LnP and Zhubech were 90.0 ± 0.65 nm and 124.9 ± 3.2 nm, respectively. The hydrodynamic diameter of Zhubech was found to be highly stable at 4o C and 25oC for 30 days in solution. In vitro drug release of MFU from Zhubech formulation exhibited the Higuchi model (R2 value = 0.95). Both Miapaca-2 and Panc-1 treated with Zhubech showed reduced viability, two- or four-fold lower than that of MFU-treated cells in 3D spheroids (IC50Zhubech = 3.4 ± 1.0μM vs IC50MFU = 6.8 ± 1.1μM) and organoids (IC50Zhubech = 9.8 ± 1.4μM vs IC50MFU = 42.3 ± 1.0μM) culture models. Confocal imaging confirmed high uptake of rhodamine-entrapped LnP by Panc-1 cells in a time-dependent manner. Tumor efficacy studies in PDX bearing mouse model revealed more than 9-fold decrease in mean tumor volumes in Zhu-bech treated (108 ± 13.5 mm3) compared to 5-FU treated (1,107 ± 116.2 mm3) animals respectively. This study demonstrates that Zhubech may be a potential candidate for delivering drugs for pancreatic cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%