Growth inhibition, drug load, and degradation studies of gelatin/methotrexate conjugates

Ofner, Clyde M.; Pica, Karen; Bowman, Bill J; Chen, Chao-Sheng

doi:10.1016/j.ijpharm.2005.10.037

Cited by 28 publications

(26 citation statements)

References 25 publications

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“…In recent decades some methods have been developed to overcome these limitations that polymer conjugation has been of more importance. Conjugation of methotrexate with natural and synthetic long chain polymers like human and rabbit serum albumins, 3,4) poly L-lysine, 5,6) dextran, 7) poly hydroxyethyl methacrylate (HEMA), 8) poly spartamide 9) and gelatin 10,11) proves the importance of methotrexate as an strategic drug and its necessities of polymer conjugation. 29) Polyethylene glycol (PEG) is the most common polymer ever used for conjugation.…”

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confidence: 99%

Synthesis and Characterization of Methotrexate Polyethylene Glycol Esters as a Drug Delivery System

et al. 2010

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147Methotrexate (amethopterin, 4-amino-N 10 -methyl petroyl glutamic acid, MTX) is a drug that has been used clinically since 1953 for treatment of many tumors especially acute lymphoblastic anemia. It has also been used for several other diseases like choriocarcinoma, psoriasis, sarcoidosis and trophoblastic tumors. 1,2) However some limitations restrict the use of methotrexate including high toxicity due to its low specificity and short plasma half life. In recent decades some methods have been developed to overcome these limitations that polymer conjugation has been of more importance. Conjugation of methotrexate with natural and synthetic long chain polymers like human and rabbit serum albumins, 3,4) poly L-lysine, 5,6) dextran, 7) poly hydroxyethyl methacrylate (HEMA), 8) poly spartamide 9) and gelatin 10,11) proves the importance of methotrexate as an strategic drug and its necessities of polymer conjugation. 29) Polyethylene glycol (PEG) is the most common polymer ever used for conjugation. The researchers have mentioned many rationales for conjugation with PEG (pegylation) including increased water solubility, controlled permeability through biological barriers, longevity in blood stream, controlling of release, overcoming tumor resistance, increased antitumor effect and reduced protein immunogenicity. [12][13][14][15] Among the small molecules, anticancer and antiviral drugs have been in priority for pegylation such as paclitaxel, 16,17) podophyllotoxin 18) and 6-mercaptopurin 19) for increasing water solubility, amphotericin B for decreasing drug toxicity and side effects, 20) doxorubicin for increasing efficacy 21) and in case of campthotecin for increasing solubility, efficacy and plasma circulation half life.22,23) PROTHECAN ® , the ester of campthotecin and mPEG40000D is a typical conjugate that is under clinical phase II. 24)In despite of extensive researches on physicochemical properties of produced pegylated forms of other drugs including water solubility, in vitro and in vivo bond stability (the study of different linkages and spacers between drug and PEG) 17,[25][26][27] and in vivo fate of conjugates, 12,21,28) there is no enough information about different polymer conjugates of methotrexate.29) Furthermore, as the most of polymer conjugates contain a link between a-carboxyl group of methotrexate and amino or hydroxyl group of synthetic or natural polymers, it is expected to obtain the similar physicochemical properties including partitioning and solubility in different conjugates. In the current study, as part of our aim to improve physicochemical and biopharmaceutical properties of MTX to achieve a better drug delivery system, synthesis of esters of MTX with PEGs of different molecular weight (at low, medium and high molecular weight) and evaluation of the physicochemical properties of MTX-PEGs were described. To the best of our knowledge, no reports on the synthesis and application of the esters of MTX-PEGs as novel drug delivery for MTX has been published. Methotrexate (MTX) is one...

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Synthesis and Characterization of Methotrexate Polyethylene Glycol Esters as a Drug Delivery System

et al. 2010

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“…This is a continuation of our previous work with these conjugates for cellular drug delivery (24). Growth inhibition was measured in the current investigation by a modified MTT assay based on cellular metabolism while growth measurement in the previous study was measured by the trypan blue dye exclusion method based on membrane integrity.…”

Section: Discussionmentioning

confidence: 69%

“…Cationic poly-L-lysine-MTX conjugates have shown a greater cytotoxicity against rat hepatoma cells and L1210 leukemia cells when the MTX load per conjugate was lower (23). An anionic gelatin-MTX conjugate has demonstrated that different drug load affects the in vitro growth inhibition of HL-60 cells (24). Therefore, a molecular weight effect on in vitro cytotoxicity is not clear and may be affected by the macromolecule, drug load, and cell type.…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Molecular Weight, Drug Load, and Charge of Gelatin–MTX Conjugates on Growth Inhibition of HL-60 Leukemia Cells

Chen

Ofner

2008

Pharm Res

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“…Methotrexate is known as a strong classic anticancer agent and used as monotherapy or in combination with other anticancer drugs in multidrug chemotherapy regimens (3). It has a wide range of activities in cytostatic activities, especially when high doses are associated with the release of folinic acid (4)(5)(6). Serum concentrations of methotrexate quickly drop when it is directly injected into the bloodstream (7).…”

Section: Introductionmentioning

confidence: 99%

Preparation, Characterization, and Optimization of Folic Acid-Chitosan-Methotrexate Core-Shell Nanoparticles by Box-Behnken Design for Tumor-Targeted Drug Delivery

et al. 2016

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Abstract. The objective of this study was to investigate the combined influence of independent variables in the preparation of folic acid-chitosan-methotrexate nanoparticles (FA-Chi-MTX NPs). These NPs were designed and prepared for targeted drug delivery in tumor. The NPs of each batch were prepared by coaxial electrospray atomization method and evaluated for particle size (PS) and particle size distribution (PSD). The independent variables were selected to be concentration of FA-chitosan, ratio of shell solution flow rate to core solution flow rate, and applied voltage. The process design of experiments (DOE) was obtained with three factors in three levels by Design expert software. Box-Behnken design was used to select 15 batches of experiments randomly. The chemical structure of FA-chitosan was examined by FTIR. The NPs of each batch were collected separately, and morphologies of NPs were investigated by field emission scanning electron microscope (FE-SEM). The captured pictures of all batches were analyzed by ImageJ software. Mean PS and PSD were calculated for each batch. Polynomial equation was produced for each response. The FE-SEM results showed the mean diameter of the core-shell NPs was around 304 nm, and nearly 30% of the produced NPs are in the desirable range. Optimum formulations were selected. The validation of DOE optimization results showed errors around 2.5 and 2.3% for PS and PSD, respectively. Moreover, the feasibility of using prepared NPs to target tumor extracellular pH was shown, as drug release was greater in the pH of endosome (acidic medium). Finally, our results proved that FAChi-MTX NPs were active against the human epithelial cervical cancer (HeLa) cells.

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Growth inhibition, drug load, and degradation studies of gelatin/methotrexate conjugates

Cited by 28 publications

References 25 publications

Synthesis and Characterization of Methotrexate Polyethylene Glycol Esters as a Drug Delivery System

Synthesis and Characterization of Methotrexate Polyethylene Glycol Esters as a Drug Delivery System

The Effect of Molecular Weight, Drug Load, and Charge of Gelatin–MTX Conjugates on Growth Inhibition of HL-60 Leukemia Cells

Preparation, Characterization, and Optimization of Folic Acid-Chitosan-Methotrexate Core-Shell Nanoparticles by Box-Behnken Design for Tumor-Targeted Drug Delivery

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