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Application of the Tumor Site Recognizable and Dual-Responsive Nanoparticles for Combinational Treatment of the Drug-Resistant Colorectal Cancer

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Abstract

Purpose

Combination of PCI and chemotherapy represents a promising strategy for combating drug resistance of cancer. However, poor solubility of photosensitizers and unselectively released drugs at unwanted sites significantly impaired the treatment efficacy. Therefore, in the present study, we aimed to develop a nano-platform which could efficiently co-entrapping photosensitizers and chemotherapeutics for active targeting therapy of drug resistant cancers.

Methods

Two pro-drugs were respectively developed by covalently linking the Ce6 with each other via the GSH-sensitive linkage and the PTX with mPEG-PLA-COOH through the ROS sensitive-linker. The dual-responsive nanoparticles (PNP-Ce6) was developed by emulsion/solvent evaporation method and further modified with tLyp-1 peptides. Physicochemical properties of nanoparticles were determined by the TEM and DLC. Cellular uptake assay was investigated with the Ce6 acting as the fluorescent probe and cell growth was studied by the MTT experiment. In vivo tumor targeting and anti-tumor assay was investigated on the colorectal cancer-bearing mice.

Results

The developed tPNP-Ce6 were stable enough under the normal physiological conditions. However, free Ce6 and PTX were completely released when exposed the tPNP-Ce6 to the redox environment. Excellent tumor-targeting drug delivery was achieved by the tPNP-Ce6, which in turn resulted in satisfactory anit-tumor effect. Of great importance, super inhibition effect on tumor progress was achieved by the combination therapy when compared with the group only received with chemotherapy..

Conclusion

The results obtained in the present study indicated that the developed tPNP-Ce6 may have great potential in enhancing the therapeutic efficacy of drug-resistant colorectal cancer.

Left: Targeting delivery of drug to tumor site by the tumor recognizable and dual-responsive nanoparticles and penetrating into tumor inner via the mediation of irradiation. Right: Nanoparticle distribution within tumor tissues with green represents the blood vessels stained with CD31, blue signal represents the cell nuclei stained with DAPI and red shows fluorescence of Ce6 as the indicator of the nanoparticles.

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Abbreviations

Ce6:

Chlorin e6

DAPI 40,6:

Diamidino-2-phenylindole

DCC 1, 3:

Dicyclohexyl carbodiimide

DLC:

Dynamic light scattering detector

DMAP:

4-Dimethylaminopyridine

DMSO:

Dimethyl sulfoxide

EE:

Encapsulation efficacy

GSH:

γ-glutamylcysteinyl-glycine

HCT-15:

Human colorectal cancer cells

HPLC:

High performance liquid chromatography

LC:

Loading capacity

M-β-CD:

methyl-β-cyclodextrin

NRP:

1 neuropilin-1

PCI:

Photodynamic internalization

PDT:

Photodynamic therapy

P-gp:

P-glycoprotein

PS:

Photosensitizers

PTX:

Paclitaxel

ROS:

Reactive oxygen species

SOG:

Singlet oxygen generation

TEM:

Transmission electron microscope

TK:

Thioketal groups

-SS-mal:

Maleimide thioether

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Acknowledgments and Disclosures

This work was supported by Sichuan University Talent Introduction Start-up Fund (Jingyuan Xiong) and also the Public Health and Preventive Medicine Provincal Experiment Teaching Center at Sichuan University, as well as the Food Safety Monitoring and Risk Assessment Key Laboratory of Sichuan Province.

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Author notes

  1. Ying Shi and Shufang Shan contributed equally to this work.

Authors and Affiliations

  1. Healthy Food Evaluation Research Center, West China School of Public Health and West China Fourth Hospital, Sichuan University, 16 Renminnan Road 3rd Section, Chengdu, 610041, Sichuan, China

    Ying Shi, Shufang Shan, Chenghui Li, Xuejiao Song, Chaoxiong Zhang, Jiayi Chen, Jia You & Jingyuan Xiong

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  1. Ying Shi
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Correspondence to Jia You or Jingyuan Xiong.

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Shi, Y., Shan, S., Li, C. et al. Application of the Tumor Site Recognizable and Dual-Responsive Nanoparticles for Combinational Treatment of the Drug-Resistant Colorectal Cancer. Pharm Res 37, 72 (2020). https://doi.org/10.1007/s11095-020-02791-2

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