hpma-docetaxel or gemcitabine conjugates and uses thereof
一种吉西他滨、多西他赛的技术，应用在HPMA-多西他赛或吉西他滨缀合物及其用途领域，能够解决肿瘤转移性疾病等问题
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Embodiment 1
[0100] Example 1: Synthesis of HPMA-gemcitabine or docetaxel conjugates for drug delivery
[0101] HPMA comonomer drug conjugates were synthesized by polymerization of HPMA monomer and activated MA-GFLG-drug (SEQ ID NO: 1 ) comonomer in different molar ratios.
[0102] 1) Synthesis of HPMA comonomer
[0103] The synthesis of HPMA monomer was carried out as previously described (Kopecek and Bazilova, Eur. Polym. J., 9: 7-14 (1973)), as figure 1 shown. The MA-GG-ONp comonomer was prepared by a modified multistep reaction (Kopecek et al., Ann. N Y Acad. Sci., 446:93-104 (1985)).
[0104] plan 1
[0105]
[0106] To a solution of 1-amino-2propanol (65.6ml, 0.84mol) in 250ml of acetonitrile was added dropwise freshly distilled methacryloyl chloride (MACl) (41ml, 0.42mol, in 20ml of acetonitrile) at -5°C with vigorous stirring . A small amount of the inhibitor tert-octylcatechol was added to the solution. The reaction mixture was stirred at room temperature for an additional ...
Embodiment 2
[0148] Embodiment 2: biological test
[0149] 1) Growth of cancer cell lines
[0150] Cancer cell lines used to assay the effects of HPMA-drug conjugates were obtained from the following sources: human MDA-MB-231 (breast), HCT116 (colon) and PANC-1 (pancreas) from the American Standard Culture Center (ATCC) ( Manassas, VA). UMRC2 (kidney) was from the National Cancer Institute (Bethesda, MD). Cells were maintained in Dulbecco's Modified Eagle's Medium ("DMEM", Invitrogen) supplemented with 10% FBS, P / S and 10 mM HEPES. All cells were incubated at 37°C in humidified 5% CO 2 incubate.
[0151] 2) In vitro cell proliferation assay for human tumor cell lines
[0152] Growth inhibition assays of HPMA-drug conjugates against human cancer cell lines were performed using the sulforhodamine B ("SRB") method (Skehan et al., J. National Cancer Institute, 82: 1107-1112 (1990)). Briefly, exponentially growing cancer cells were treated with 2-3x10 3 Cells / well were seeded in 96-well ...
Embodiment 3
[0159] Example 3: Xenotransplantation Studies
[0160] To observe tumor growth inhibition in animal models, HPMA-conjugated docetaxel or gemcitabine was used on nude mouse xenograft models as described below.
[0161] Mia-Paca human pancreatic cancer cell or HCT116 cell suspension (3x10 6 cells) were subcutaneously injected into the lower flank of six-week-old female FoxN1 nude mice. When the tumor reaches an appropriate size (eg, about 50-60mm 3 volume), the mice were injected intravenously with phosphate-buffered saline (PBS) alone or the drug conjugate of the invention every 4-5 days. Animals are monitored for several weeks until control tumors reach, eg, about 1 cm in diameter, at which point animals are euthanized. Tumor size and tumor composition were determined and reported as fold change in tumor size ( Figure 1-Figure 3 ).
[0162] Using the model described in this example, it was shown that drug conjugates of the invention, such as those described in Example 1,...
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