Dendron-polymer hybrid mediated anticancer drug delivery for suppression of mammary cancer

doi:10.1016/j.jmst.2020.02.089

Abstract

Abstract:

Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity. Here we report a dendronized polymer-doxorubicin (DOX) hybrid (DPDH) with an improved in vivo drug delivery efficiency for cancer therapy compared with a linear polymer-DOX conjugate (LPDC). The in vitro drug release profile of DOX indicates that DPDH displays pH-responsive drug release due to cleavage of hydrazone bonds since a greater amount of DOX is released at pH 5.2 at a faster rate than at pH 7.4. DPDH efficiently enters 4T1 cells and releases DOX to induce cytotoxicity and apoptosis. Owing to the dendronzied structure, DPDH has a significantly longer blood circulation time than LPDC. DPDH substantially enhances the therapeutic efficacy to suppress tumor growth in a 4T1 mammary cancer model than LPDC as well as free drug, evidenced from tumor growth inhibition, TUNEL assessment and histological analysis. Biosafety of DPDH is also confirmed from hemolysis, body weight shifts during treatment and pathological analysis. This study demonstrates the use of dendronized polymer-DOX hybrids for specific drug molecules is a promising approach for drug delivery.

Key words: Polymer-drug conjugate, Dendrimers, Hybrid, Stimuli-responsive, Drug delivery system, Cancer therapy

Dayi Pan, Xiuli Zheng, Miao Chen, Qianfeng Zhang, Zhiqian Li, Zhenyu Duan, Qiyong Gong, Zhongwei Gu, Hu Zhang, Kui Luo. Dendron-polymer hybrid mediated anticancer drug delivery for suppression of mammary cancer[J]. J. Mater. Sci. Technol., 2021, 63: 115-123.

Figures/Tables 6

Fig. 1. Illustration of the structure of DPDH (A) and LPDC (B); size distribution (C), stability of hydrodynamic sizes under simulated physiological conditions of DPDH and LPDC (D); the cumulative DOX release of DPDH and LPDC at pH 5.2 and pH 7.4 (E).

Fig. 2. Fluorescence spectra of DPDH (A), LPDC (B) and DOX (C); UV absorbance spectra of DPDH (D), LPDC (E) and DOX (F) in different solutions.

Fig. 3. Cytotoxicity of DPDH, LPDC and DOX against 4T1 cells (A); caspase-3 activation to mediate apoptosis of cancer cells (B); cell uptake of DPDH, LPDC and DOX in 4T1 cells by flow cytometer (C) and CLSM (D, scale bars for 25 μm); cellular internalization of DPDH and LPDC in 4T1 cells after incubation with different inhibitors (E). Statistical significance compared to the DPDH group (*P < 0.05, **P < 0.01).

Fig. 4. Apoptotic 4T1 cells induced by the treatment of DPDH, LPDC and DOX and untreated cells as a control (A); chromatin condensation and nuclear fragmentation from apoptotic cells treated by DOX, DPDH and LPDC (B, scale bars for 25 μm).

Fig. 5. In vivo blood concentration at different durations after injection of DPDH, LPDC and DOX into mice.

Fig. 6. Tumor volume (A), tumor weight (B), TGI (C)and body weight shift (D) in mice receiving different treatments by saline (control), DOX, DPDH and LPDC, and tumor metastasis (E, the red circles note the metastatic 4T1 tumors; scale bars for 100 μm) and in situ apoptosis (F, scale bars for 50 μm). Statistical significance compared to the DPDH group (*P < 0.05, **P < 0.01; ***P < 0.001).

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