Rational design of a new cytarabine-based prodrug for highly efficient oral delivery of cytarabine

Zhang, Jing; Zhang, Di; Hu, Xu; Liu, Ruiling; Li, Zhonghao; Luan, Yuxia

doi:10.1039/c8ra01225c

Cited by 13 publications

(11 citation statements)

References 27 publications

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“…Fourier Transform Infrared Spectroscopic study was carried out on active ingredient as well as formulation excipients (polymers, monomer, and cross-linker) using Alpha Bruker-Germany, ECO-ATR [49]. Samples were crushed and loaded on crystal spot with the help of spatula and pressure was applied to form compact disc for analysis and then scanned between defined ranges of 4000-400 cm −1 [50,51].…”

Section: Ftir Analysismentioning

confidence: 99%

pH Sensitive Pluronic Acid/Agarose-Hydrogels as Controlled Drug Delivery Carriers: Design, Characterization and Toxicity Evaluation

et al. 2022

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The objective of this study was to fabricate and evaluate a pH sensitive cross-linked polymeric network through the free radical polymerization technique for the model drug, cyclophosphamide, used in the treatment of non-Hodgkin’s lymphoma. The Hydrogels were prepared using a polymeric blend of agarose, Pluronic acid, glutaraldehyde, and methacrylic acid. The prepared hydrogels were characterized for drug loading (%), swelling pattern, release behavior, the ingredient’s compatibility, structural evaluation, thermal integrity, and toxicity evaluation in rabbits. The new polymer formation was evident from FTIR findings. The percentage loaded into the hydrogels was in the range of 58.65–75.32%. The developed hydrogels showed significant differences in swelling dynamics and drug release behavior in simulated intestinal fluid (SIF) when compared with simulated gastric fluid (SGF). The drug release was persistent and performed in a controlled manner for up to 24 h. A toxicity study was conducted on white albino rabbits. The developed hydrogels did not show any signs of ocular, skin, or oral toxicity; therefore, these hydrogels can be regarded as safe and potential carriers for controlled drug delivery in biomedical applications.

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Section: Ftir Analysismentioning

confidence: 99%

pH Sensitive Pluronic Acid/Agarose-Hydrogels as Controlled Drug Delivery Carriers: Design, Characterization and Toxicity Evaluation

et al. 2022

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“…Fatty acid conjugation to cytarabine was done with various fatty acid chain lengths, even with some non-common ones like 24-carbon long double acid chain . When palmitic acid was attached, the octanol partition coefficient increased by 4 orders of magnitude …”

Section: Results and Discussionmentioning

confidence: 99%

“…40 When palmitic acid was attached, the octanol partition coefficient increased by 4 orders of magnitude. 41 As can be seen from the examples above, adding esterattached fatty acid is one of the common strategies to enhance cytarabine permeability (and bioavailability). However, a rational guideline for the choice of the fatty acid chain length and its position seems to be lacking.…”

Section: Molecule Selection and Case Study Strategymentioning

confidence: 99%

Computational Prodrug Design Methodology for Liposome Formulability Enhancement of Small-Molecule APIs

et al. 2023

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Encapsulation into liposomes is a formulation strategy that can improve efficacy and reduce side effects of active pharmaceutical ingredients (APIs) that exhibit poor biodistribution or pharmacokinetics when administered alone. However, many APIs are unsuitable for liposomal formulations intended for parenteral administration due to their inherent physicochemical properties�lipid bilayer permeability and water−lipid equilibrium partitioning coefficient. Too high permeability results in premature leakage from liposomes, while too low permeability means the API is not able to pass across biological barriers. There are several options for solving this issue: (i) change of the lipid bilayer composition, (ii) addition of a permeability enhancer, or (iii) modification of the chemical structure of the API to design a prodrug. The latter approach was taken in the present work, and the effect of small changes in the molecular structure of the API on its permeation rate across a lipidic bilayer was systematically explored utilizing computer simulations. An in silico methodology for prodrug design based on the COSMOperm approach has been proposed and applied to four APIs (abiraterone, cytarabine, 5-fluorouracil, and paliperidone). It is shown that the addition of aliphatic hydrocarbon chains via ester or amide bonds can render the molecule more lipophilic and increase its permeability by approximately 1 order of magnitude for each 2 carbon atoms added, while the formation of fructose adducts can provide a more hydrophilic character to the molecule and reduce its lipid partitioning. While partitioning was found to depend only on the size and type of the added group, permeability was found to depend also on the added group location. Overall, it has been shown that both permeability and lipid partitioning coefficient can be systematically shifted into the desired liposome formulability window by appropriate group contributions to the parental drug. This can significantly increase the portfolio of APIs for which liposome or lipid nanoparticle formulations become feasible.

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“…Cytarabine is a chemotherapy drug used for the treatment of acute as well as chronic myeloid leukemia. 53,54 The systemic elimination of cytarabine is rapid and follows a biphasic elimination profile, with an initial plasma half-life of 7-20 min followed by a terminal half-life of 2-3 h. 55 5-fluorouracil is also a chemotherapy drug used for the treatment of cancer, especially colorectal cancer. 56 The elimination of 5-fluorouracil after parenteral administration occurs fast with an apparent terminal half-life of ~8-20 min.…”

Section: S1s2mentioning

confidence: 99%

Three-Dimensional Covalent Organic Frameworks with pts Topology for Controlled Anticancer Drug Delivery

Zhao

Irie

et al. 2023

Preprint

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Noted for their unique structural and functional attributes including especially high surface areas, open interconnected nanochannels and rich active sites, three-dimensional (3D) covalent organic frameworks (COFs) have emerged as frontier materials for energy, environmental and biomedical research. However, the limited options of 3D organic building blocks, poor reversibility in covalent linkage formation and highly complicated crystal structure analysis raise several challenges to the construction of new 3D COFs for which the number of 3D COF structures is still restricted to a few. In this contribution, we report the designed synthesis of two new 3D COFs, namely TUS-440 and TUS-441, with two- and three-fold interpenetrated pts topology, respectively, by combining a Td-symmetric tetrahedral vertex with two C2-symmetric rectangular linkers. The resulting COFs demonstrate well-defined crystalline porous structures and Brunauer−Emmett−Teller surface areas of 1320 and 940 m2 g-1. In vitro drug delivery studies substantiate these COFs as efficient nanocarriers with good loading and sustained release of anticancer drugs (cytarabine and 5-fluorouracil), showing great potential for increasing therapeutic efficacy and reducing dosing frequency.

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Rational design of a new cytarabine-based prodrug for highly efficient oral delivery of cytarabine

Abstract: To overcome the drawbacks of cytarabine such as bad liposolubility and low bioavailability, we rationally designed a new cytarabine-based prodrug for oral cytarabine delivery, realizing significantly enhanced bioavailability for cancer therapy.

Cited by 13 publications

References 27 publications

pH Sensitive Pluronic Acid/Agarose-Hydrogels as Controlled Drug Delivery Carriers: Design, Characterization and Toxicity Evaluation

pH Sensitive Pluronic Acid/Agarose-Hydrogels as Controlled Drug Delivery Carriers: Design, Characterization and Toxicity Evaluation

Computational Prodrug Design Methodology for Liposome Formulability Enhancement of Small-Molecule APIs

Three-Dimensional Covalent Organic Frameworks with pts Topology for Controlled Anticancer Drug Delivery

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