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Synthesis of indocyanine green functionalized comblike poly(aspartic acid) derivatives for enhanced cancer cell ablation by targeting endoplasmic reticulum

Abstract

Undesired gene expression can lead to severe disease such as cancers. Oncogenic proteins or survival factors encoded by oncogenes can sustain cancer cell survival and proliferation. Considering proteins are manufactured and transported by endoplasmic reticulum (ER), the destroying of oncogenic proteins within ER could cut off the process of undesired gene expression. In this study, a new type of ER targeting strategy was developed based on the coordination interaction of Ca(II) ion rich ER lumen with carboxyl group of poly(aspartic acid) (PAsp). The comblike polymer PAsp-g-(PEG-ICG) was rationally designed and successfully prepared by grafting azido-modified polyethylene glycol (PEG) and azido-modified photosensitizer indocyanine green (ICG) onto alkynyl-modified PAsp through the copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC). Among that, ICG not only shows its importance as an imaging agent that reveals the distribution of PAsp-g-(PEG-ICG) micelles both at tissue and subcellular levels, but also takes full advantage as a protein destructive agent to generate reactive oxygen species (ROS) resulting in protein denaturation. Moreover, chemotherapeutic drug, such as paclitaxel, enables to be easily encapsulated into PAsp-g-(PEG-ICG) (PTX@PAsp-g-(PEG-ICG)) up to 28 % of drug loading capacity with excellent stability. The experimental results proved that the as-prepared PTX@PAsp-g-(PEG-ICG) micelles exhibited selectively accumulation in the ER lumen of cancer cells. Thus, 10-fold enhancement of ROS was generated by incubating cancer cell with PAsp-g-(PEG-ICG) micelles at PTX concentration of 1.0 μg/ml under laser irradiation (0.2 W/cm2, 785 nm, 30 s) upon 24 h, leading to disruption of proteins in ER that caused ER stress-induced cancer cell apoptosis up to 76 % . In cytotoxicity test, U-87 MG glioma cells incubated with PTX@PAsp-g-(PEG-ICG) at the PTX concentration of 2.5 μg/ml were reduced to nearly 0 % of cell viability upon 24 h under laser irradiation (2 W/cm2, 785 nm, 30 s), in comparison with free PTX that showed 60 % of cell viability at the same condition, indicating that photodynamic therapy (PDT) remarkablely enhanced chemotherapeutic effects. With the good combination of PDT and chemotherapy, the PTX@PAsp-g-(PEG-ICG) micelles offer unprecedented advantages to effectively targeting ER that displayed a prolonged retention time in tumors of U-87 MG bearing nude mice, opening up a great promise of manipulating biomaterial design to achieve the intended ER targeted delivery for non-invasive cancer therapy.

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Publication details

The article was received on 27 Nov 2017, accepted on 05 Feb 2018 and first published on 06 Feb 2018


Article type: Paper
DOI: 10.1039/C7PY01994G
Citation: Polym. Chem., 2018, Accepted Manuscript
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    Synthesis of indocyanine green functionalized comblike poly(aspartic acid) derivatives for enhanced cancer cell ablation by targeting endoplasmic reticulum

    J. Wan, L. Sun, P. Wu, F. Wang, J. Guo, J. Cheng and C. Wang, Polym. Chem., 2018, Accepted Manuscript , DOI: 10.1039/C7PY01994G

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