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Current Pharmaceutical Design

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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

Functionalized PAMAM-based Nanoformulation for Targeted Delivery of 5-Fluorouracil in Hepatocellular Carcinoma

Author(s): Siwei Chen, Hu Ouyang, Dongxiu He*, Daquan Liu, Xiao Wang, Hongyuan Chen, Wei Pan, Qi Li, Weiquan Xie and Cuiyun Yu

Volume 28, Issue 25, 2022

Published on: 21 July, 2022

Page: [2113 - 2125] Pages: 13

DOI: 10.2174/1381612828666220506111918

Price: $65

Abstract

Background: The efficacy of a traditional anticancer drug is challenged by adverse effects of the drug, including its nonspecific bio-distribution, short half-life, and side effects. Dendrimer-based targeted drug delivery system has been considered a promising strategy to increase targeting ability and reduce adverse effects of anti-cancer drugs.

Objective: This study analyzed the feasibility of whether the anticancer drug 5-fluorouracil (5-FU) could be delivered by functionalized fifth-poly(amidoamine) (PAMAM) with the peptide WP05 and the acetic anhydride to the liver cancer cells, reducing the toxicity of the PAMAM and improving the targeting property of 5-FU during delivery.

Methods: The functionalized PAMAM-based nanoformulation (WP05-G5.0NHAC-FUA) was fabricated through an amide condensation reaction to improve the therapeutic efficacy of 5-Fluorouracil (5-FU) in hepatocellular carcinoma (HCC). The physicochemical structure, particle size, zeta potential, stability, and in vitro release characteristics of WP05-G5.0NHAC-FUA were evaluated. In addition, the targeting, biocompatibility, anti-proliferation, and anti-migration of WP05-G5.0NHAC-FUA were investigated. The anti-tumor effect of WP05-G5.0NHAC-FUA in vivo was evaluated by constructing xenograft tumor models of human hepatoma cells (Bel-7402) implanted in nude mice.

Results: The resultant WP05-G5.0NHAC-FUA displayed spherical-like nanoparticles with a size of 174.20 ± 3.59 nm. Zeta potential and the drug loading of WP05-G5.0NHAC-FUA were 5.62 ± 0.41mV and 28.67 ± 1.25%, respectively. Notably, the optimized 5-FU-loaded formulation showed greater cytotoxicity with an IC50 of 30.80 ± 4.04 μg/mL than free 5-FU (114.93 ± 1.43 μg/mL) in Bel-7402 cancer liver cells, but a significantly reduced side effect relative to free 5-FU in L02 normal liver cells. In vivo animal study further confirmed efficient tumor accumulation and enhanced therapeutic efficiency.

Conclusion: The developed nanoformulation is a promising platform for the targeting delivery of 5-FU and provides a promising solution for improving the efficacy of hepatocellular carcinoma chemotherapy.

Keywords: WP05, 5-Fluorouracil, drug delivery system, functionalized PAMAM, hepatocellular carcinoma, chemotherapy.

« Previous
[1]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Utsunomiya T, Shimada M, Morine Y, Tajima A, Imoto I. Specific molecular signatures of non-tumor liver tissue may predict a risk of hepatocarcinogenesis. Cancer Sci 2014; 105(7): 749-54.
[http://dx.doi.org/10.1111/cas.12431] [PMID: 24766251]
[3]
Yu CY, Li NM, Yang S, et al. Fabrication of galactosylated chitosan-5‐fluorouracil acetic acid based nanoparticles for controlled drug delivery. J Appl Polym Sci 2015; 132(40): n/a.
[http://dx.doi.org/10.1002/app.42625]
[4]
Katharotiya K, Shinde G, Katharotiya D, et al. Development, evaluation and biodistribution of stealth liposomes of 5-fluorouracil for effective treatment of breast cancer. J Liposome Res 2021; 1-13.
[http://dx.doi.org/10.1080/08982104.2021.1905661] [PMID: 33847220]
[5]
Ndreshkjana B, Çapci A, Klein V, et al. Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells. Cell Death Dis 2019; 10(6): 379.
[http://dx.doi.org/10.1038/s41419-019-1611-4] [PMID: 31097715]
[6]
Lollo G, Matha K, Bocchiardo M, et al. Drug delivery to tumours using a novel 5-FU derivative encapsulated into lipid nanocapsules. J Drug Target 2019; 27(5-6): 634-45.
[http://dx.doi.org/10.1080/1061186X.2018.1547733] [PMID: 30461322]
[7]
Vodenkova S, Buchler T, Cervena K, Veskrnova V, Vodicka P, Vymetalkova V. 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future. Pharmacol Ther 2020; 206: 107447.
[http://dx.doi.org/10.1016/j.pharmthera.2019.107447] [PMID: 31756363]
[8]
Tokarczyk K, Jachimska B. Characterization of G4 PAMAM dendrimer complexes with 5-fluorouracil and their interactions with bovine serum albumin. Colloids Surf A Physicochem Eng Asp 2019; 561: 357-63.
[http://dx.doi.org/10.1016/j.colsurfa.2018.10.080]
[9]
Liu J, Liu K, Zhang L, et al. Heat/pH-boosted release of 5-fluorouracil and albumin-bound paclitaxel from Cu-doped layered double hydroxide nanomedicine for synergistical chemo-photo-therapy of breast cancer. J Control Release 2021; 335: 49-58.
[http://dx.doi.org/10.1016/j.jconrel.2021.05.011] [PMID: 33989692]
[10]
Huang C, Li NM, Gao P, et al. In vitro and in vivo evaluation of macromolecular prodrug GC-FUA based nanoparticle for hepatocellular carcinoma chemotherapy. Drug Deliv 2017; 24(1): 459-66.
[http://dx.doi.org/10.1080/10717544.2016.1264499] [PMID: 28219253]
[11]
Shi X, He D, Tang G, et al. Fabrication and characterization of a folic acid-bound 5-fluorouracil loaded quantum dot system for hepatocellular carcinoma targeted therapy. RSC Advances 2018; 8(35): 19868-78.
[http://dx.doi.org/10.1039/C8RA01025K]
[12]
Araste F, Abnous K, Hashemi M, Taghdisi SM, Ramezani M, Alibolandi M. Peptide-based targeted therapeutics: Focus on cancer treatment. J Control Release 2018; 292: 141-62.
[http://dx.doi.org/10.1016/j.jconrel.2018.11.004] [PMID: 30408554]
[13]
Xiao L, Hou Y, He H, et al. A novel targeted delivery system for drug-resistant hepatocellular carcinoma therapy. Nanoscale 2020; 12(32): 17029-44.
[http://dx.doi.org/10.1039/D0NR01908A] [PMID: 32780053]
[14]
Du B, Qian M, Zhou Z, et al. In vitro panning of a targeting peptide to hepatocarcinoma from a phage display peptide library. Biochem Biophys Res Commun 2006; 342(3): 956-62.
[http://dx.doi.org/10.1016/j.bbrc.2006.02.050] [PMID: 16598852]
[15]
Guo XL, Kang XX, Wang YQ, et al. Co-delivery of cisplatin and doxorubicin by covalently conjugating with polyamidoamine dendrimer for enhanced synergistic cancer therapy. Acta Biomater 2019; 84: 367-77.
[http://dx.doi.org/10.1016/j.actbio.2018.12.007] [PMID: 30528609]
[16]
Li J, Liang H, Liu J, Wang Z. Poly (amidoamine) (PAMAM) dendrimer mediated delivery of drug and pDNA/siRNA for cancer therapy. Int J Pharm 2018; 546(1-2): 215-25.
[http://dx.doi.org/10.1016/j.ijpharm.2018.05.045] [PMID: 29787895]
[17]
Ambekar RS, Choudhary M, Kandasubramanian B. Recent advances in dendrimer-based nanoplatform for cancer treatment: A review. Eur Polym J 2020; 126: 109546.
[http://dx.doi.org/10.1016/j.eurpolymj.2020.109546]
[18]
Rompicharla SVK, Kumari P, Bhatt H, Ghosh B, Biswas S. Biotin functionalized PEGylated poly(amidoamine) dendrimer conjugate for active targeting of paclitaxel in cancer. Int J Pharm 2019; 557: 329-41.
[http://dx.doi.org/10.1016/j.ijpharm.2018.12.069] [PMID: 30599231]
[19]
Surekha B, Kommana NS, Dubey SK, Kumar AVP, Shukla R, Kesharwani P. PAMAM dendrimer as a talented multifunctional biomimetic nanocarrier for cancer diagnosis and therapy. Colloids Surf B Biointerfaces 2021; 204: 111837.
[http://dx.doi.org/10.1016/j.colsurfb.2021.111837] [PMID: 33992888]
[20]
Hong S, Bielinska AU, Mecke A, et al. Interaction of poly(amidoamine) dendrimers with supported lipid bilayers and cells: Hole formation and the relation to transport. Bioconjug Chem 2004; 15(4): 774-82.
[http://dx.doi.org/10.1021/bc049962b] [PMID: 15264864]
[21]
Enciso AE, Neun B, Rodriguez J, Ranjan AP, Dobrovolskaia MA, Simanek EE. Nanoparticle effects on human platelets in vitro: A comparison between PAMAM and triazine dendrimers. Molecules 2016; 21(4): 428.
[http://dx.doi.org/10.3390/molecules21040428] [PMID: 27043508]
[22]
Iacobazzi RM, Porcelli L, Lopedota AA, et al. Targeting human liver cancer cells with lactobionic acid-G(4)-PAMAM-FITC sorafenib loaded dendrimers. Int J Pharm 2017; 528(1-2): 485-97.
[http://dx.doi.org/10.1016/j.ijpharm.2017.06.049] [PMID: 28624661]
[23]
Luong D, Kesharwani P, Deshmukh R, et al. PEGylated PAMAM dendrimers: Enhancing efficacy and mitigating toxicity for effective anticancer drug and gene delivery. Acta Biomater 2016; 43: 14-29.
[http://dx.doi.org/10.1016/j.actbio.2016.07.015] [PMID: 27422195]
[24]
Chang H, Zhang J, Wang H, Lv J, Cheng Y. A combination of guanidyl and phenyl groups on a dendrimer enables efficient siRNA and DNA delivery. Biomacromolecules 2017; 18(8): 2371-8.
[http://dx.doi.org/10.1021/acs.biomac.7b00567] [PMID: 28686016]
[25]
Vu MT, Bach LG, Nguyen DC, et al. Modified carboxyl-terminated PAMAM dendrimers as great cytocompatible nano-based drug delivery system. Int J Mol Sci 2019; 20(8): 2016.
[http://dx.doi.org/10.3390/ijms20082016] [PMID: 31022905]
[26]
Ortiz N, Vásquez PA, Vidal F, et al. Polyamidoamine-based nanovector for the efficient delivery of methotrexate to U87 glioma cells. Nanomedicine (Lond) 2020; 15(28): 2771-84.
[http://dx.doi.org/10.2217/nnm-2020-0305] [PMID: 33073670]
[27]
Yan C, Gu J, Lv Y, Shi W, Jing H. Improved intestinal absorption of water-soluble drugs by acetylation of G2 PAMAM dendrimer nanocomplexes in rat. Drug Deliv Transl Res 2017; 7(3): 408-15.
[http://dx.doi.org/10.1007/s13346-017-0373-8] [PMID: 28303451]
[28]
Qiao LL, Yao WJ, Zhang ZQ, Yang X, Zhao MX. The biological activity research of the nano-drugs based on 5-fluorouracil-modified quantum dots. Int J Nanomedicine 2020; 15: 2765-76.
[http://dx.doi.org/10.2147/IJN.S244693] [PMID: 32425520]
[29]
Gan BK, Rullah K, Yong CY, et al. Targeted delivery of 5-fluorouracil-1-acetic acid (5-FA) to cancer cells overexpressing epithelial growth factor receptor (EGFR) using virus-like nanoparticles. Sci Rep 2020; 10(1): 16867.
[http://dx.doi.org/10.1038/s41598-020-73967-4] [PMID: 33033330]
[30]
Ma P, Chen J, Bi X, et al. Overcoming multidrug resistance through the GLUT1-mediated and enzyme-triggered mitochondrial targeting conjugate with redox-sensitive paclitaxel release. ACS Appl Mater Interfaces 2018; 10(15): 12351-63.
[http://dx.doi.org/10.1021/acsami.7b18437] [PMID: 29569435]
[31]
Zhang Y, Zhang S, Chen J, et al. Blood sampling from peripherally inserted central catheter is effective and safe for patients with head and neck cancers. J Vasc Access 2021; 22(3): 424-31.
[32]
Sun Y, Bai Y, Zeng M, et al. Pharmacokinetics and tissue distribution evaluation of α-asaronol and its main metabolite in rats by HPLC method. J Pharm Biomed Anal 2019; 172: 349-56.
[http://dx.doi.org/10.1016/j.jpba.2019.05.004] [PMID: 31085397]

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