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Folic Acid–Chitosan Oligosaccharide Conjugates Decorated Nanodiamond as Potential Carriers for the Oral Delivery of Doxorubicin

  • Research Article
  • Advancements in Modified-release Oral Drug Delivery - Delivery throughout the Gastro-intestinal Tract
  • Published:
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Abstract

Oral administration of doxorubicin (DOX) is preferred but challenged owing to poor permeability in the gastrointestinal tract (GIT), efflux of P-glycoprotein, short residence time in the intestine, and rapid hydrolysis. Herein, folic acid–chitosan oligosaccharide conjugate (FA-COS)-modified hydroxylated nanodiamond (ND-OH) was designed to enhance the oral bioavailability of DOX. The carboxyl surface of ND was modified into hydroxyl terminal group to increase the colloidal stability of the system under different pH conditions in GIT. FA-COS modification could prolong retention time, endow the drug with sustained release properties, and actively target intestinal FA receptors. In contrast to DOX/ND-OH, the particle size of DOX/ND-OH/FA-COS increased from 189.5 ± 2.8 to 224.5 ± 1.4 nm, and the zeta potential reversed from − 9.1 ± 0.2 to 14.8 ± 0.4 mV. At 48 h, DOX/ND-OH and DOX/ND-OH/FA-COS released 69.07 ± 5.70% and 35.87 ± 5.64%, respectively. FA-COS modification effectively enhanced the cytotoxicity and intracellular uptake of ND-OH/DOX by Caco-2 cells and prolonged intestinal retention in rats. The internalization of DOX/ND-OH and DOX/ND-OH/FA-COS was mainly mediated by energy-dependent clathrin- and caveolae-mediated endocytosis pathways. Pharmacokinetic study demonstrated that the AUC0−t of DOX/ND-OH and DOX/ND-OH/FA-COS was enhanced by 3.94- and 6.08-fold compared to DOX solution, respectively. These results illustrated that DOX/ND-OH/FA-COS could be an effective strategy to enhance the oral bioavailability of DOX.

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Funding

We are grateful for the financial support from the National Natural Science Foundation of China (No. 82073794) and the Natural Science Foundation of Liaoning Province (No. 2021-MS-310).

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Authors and Affiliations

  1. School of Biomedical & Chemical Engineering, Liaoning Institute of Science and Technology, Benxi, 117004, People’s Republic of China

    Dandan Liu

  2. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China

    Yupei Su, Jixuan Chen & Weisan Pan

  3. College of Pharmacy, Liaoning University, Shenyang, 110036, People’s Republic of China

    Hao Pan

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  1. Dandan Liu
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  5. Weisan Pan
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Contributions

Dandan Liu performed the experiments and analysis and drafted the work; Yupei Su participated in the experiments and the data analysis; Jixuan Chen participated in the experiments and the data analysis; Hao Pan designed the work and revised the paper; Weisan Pan designed and supervised the work.

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Correspondence to Hao Pan or Weisan Pan.

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Liu, D., Su, Y., Chen, J. et al. Folic Acid–Chitosan Oligosaccharide Conjugates Decorated Nanodiamond as Potential Carriers for the Oral Delivery of Doxorubicin. AAPS PharmSciTech 24, 86 (2023). https://doi.org/10.1208/s12249-023-02545-4

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