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. 2016 Feb 15:6:21459.
doi: 10.1038/srep21459.

A nanoparticulate pre-chemosensitizer for efficacious chemotherapy of multidrug resistant breast cancer

Shengrong Guo  1 , Li Lv  1 , Yuanyuan Shen  1 , Zhongliang Hu  2 , Qianjun He  3 , Xiaoyuan Chen  4
Affiliations

A nanoparticulate pre-chemosensitizer for efficacious chemotherapy of multidrug resistant breast cancer

Shengrong Guo et al. Sci Rep. .

Abstract

Small-molecule chemosensitizers can reverse cancer multidrug resistance (MDR), thus significantly improving the in vitro effect of chemotherapy drugs for MDR cancer cells, however, their in vivo effects are not always very good, because they are difficult to effectively accumulate in tumor and enter the same cancer with chemotherapy drugs after systemic administration due to individual biopharmaceutical properties. To overcome these limitations, here we study a novel nanoparticular pre-chemosensitizer which can be also used as nanocarrier of chemotherapy drugs. We take an 'all in one' approach to develop a self-assembled nanoparticle formula of amphiphilic poly(curcumin-dithiodipropionic acid)-b-poly(ethylene glycol)-biotin. The nanoparticle is capable of tumor-targeted delivery, responsive degradation at the intracellular level of glutathione and subsequent intracellular co-release of the chemosensitizer curcumin and the encapsulated chemotherapeutic drug doxorubicin to maximize a synergistic effect of chemosensitization and chemotherapy. We demonstrate that the antitumor efficacy of nanoparticle is much superior to that of doxorubicin in the multidrug resistant MCF-7/ADR xenografted nude mice.

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Figures

Figure 1
Figure 1. Schematic illustration of the treatment of multidrug-resistant cancer with the DOX@PCDA-PEG-Biotin NPs.
After intravenous injection, the DOX@PCDA-PEG-Biotin NPs accumulate at the site of tumor through passive targeting (EPR effect) (a), and then are taken up by MDR cancer cells through active targeting (biotin acceptor-mediated endocytosis) (b). Subsequently, the DOX@PCDA-PEG-Biotin NPs are liable to escape from endosome/lysosome and then enter cytosol, where they will encounter relatively high level of GSH and thus decomposing into CUR followed by the release of encapsulated DOX (c). The released CUR can down-regulate the P-gp expression on MDR cancer cells and inhibit their ATP activity in favor of the intracellular and intranuclear accumulation of released DOX and CUR (d), playing a role as pre-chemosensitizer.
Figure 2
Figure 2. Synthesis routes of PCDA-PEG and PCDA-PEG-Biotin by a poly(active pharmaceutical ingredients) (PAPI) strategy.
Figure 3
Figure 3
GSH-triggered degradation of the PCDA-PEG-Biotin nano-carrier (A‒E), and drug release behaviors of the DOX@PCDA-PEG-Biotin NPs (F). GPC (A,B) and DLS (C,D) profiles of the PCDA-PEG-Biotin in pH 7.4 PBS at 10 μM (A,C) and 5 mM GSH (B,D), respectively. (E) A LC-HR-MS spectrum showing the degraded species (CUR) and its assignment (M+H)+ peaks after treatment of the biotin-PEG-PCDA with 5 mM GSH and esterase (100 ) in PBS for 24 h. (F) DOX release profiles of the DOX@PCDA-PEG-Biotin NPs in pH 7.4 PBS at 10 μM and 5 mM GSH, respectively.
Figure 4
Figure 4
Reversal effects on MDR in MCF-7/ADR cells: the level of P-gp expression (A) and the ATP inhibition rate (B) on MCF-7/ADR cells after 48 h incubation with various formulas at an equivalent concentration of DOX; the accumulation of DOX fluorescence within MCF-7/ADR cells incubated for different duration of time (C); the retention percentage of intracellular DOX after removing extracellular DOX (D); schematic illustration of the reversal of MDR in MCR-7/ADR cells by the DOX@PCDA-PEG-Biotin NPs (E).
Figure 5
Figure 5. Tumor targeting capability and antitumor activity.
(A) In vivo fluorescence images of the MCF-7/ADR tumor-bearing nude mice at 2, 6 and 24 h after intravenous injection of free DiR (left) and the DiR-labeled DOX@PCDA-PEG-Biotin NPs (right). The arrow indicates the sites of tumor. Ex vivo fluorescence Images of the tumor and normal tissues harvested from the euthanized MCF-7/ADR tumor-bearing nude mice at 24 h post injection, where a–f inset images represent heart, liver, spleen, lung, kidneys and tumor, respectively. The MCF-7/ADR tumor growth curves (B) and the body weight variation (C) after intravenous injection of free DOX, the DOX@PCDA-PEG-Biotin NPs at a DOX dose of 2 mg/kg each week, or saline with the equivalent volume (0.2 mL) as control. The appearances (D) and weights (E) of the tumors harvested from euthanized MCF-7/ADR tumor-bearing nude mice at 8 weeks. Significant differences: * (p < 0.01, compared to saline control); #(p < 0.01, compared to free DOX).
Figure 6
Figure 6
H&E, Ki67, TUNEL and P-gp images of tumor tissues dissected from the MCF-7/ADR tumor-bearing nude mice sacrificed at 8 weeks after intravenous injection of free DOX at a dose of 2 mg/kg each week (B), the DOX@PCDA-PEG-Biotin NPs at an equivalent DOX dose of 2 mg/kg each week (C), or an equivalent volume of saline as control (A).
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