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Small Peptide-Doxorubicin Co-Assembly for Synergistic Cancer Therapy.

ABSTRACT: Design of elaborated nanomaterials to improve the therapeutic efficacy and mitigate the side effects of chemotherapeutic anticancer drugs, such as Doxorubicin (Dox), is significant for cancer treatment. Here, we describe a co-assembled strategy, where amphiphile short peptides are co-assembled with Doxorubicin to form nanoscale particles for enhanced delivery of Dox. Two kinds of short peptides, Fmoc-FK (FK) and Fmoc-FKK (FKK), are synthesized. Through adjusting the component ratio of peptide and Dox, we obtain two kinds of co-assembled nanoparticles with homogeneous size distributions. These nanoparticles show several distinct characteristics. First, they are pH-responsive as they are stable in alkaline and neutral conditions, however, de-assembly at acidic pH enables selective Dox release in malignant cancer cells. Second, the nanoparticles show an average size of 50-100 nm with positive charges, making them effective for uptake by tumor cells. Moreover, the side effects of Dox on healthy cells are mitigated due to decreased exposure of free-Dox to normal cells. To conclude, the co-assembled peptide-Dox nanoparticles exhibit increased cellular uptake compared to free-Dox, therefore causing significant cancer cell death. Further apoptosis and cell cycle analysis indicates that there is a synergistic effect between the peptide and Doxorubicin.

SUBMITTER: Li S

PROVIDER: S-EPMC7036863 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Small Peptide-Doxorubicin Co-Assembly for Synergistic Cancer Therapy.

Li Shuangfei S Chen Xianglan X Chen Huirong H Peng Jiaofeng J Yang Xuewei X

Molecules (Basel, Switzerland) 20200123 3

Design of elaborated nanomaterials to improve the therapeutic efficacy and mitigate the side effects of chemotherapeutic anticancer drugs, such as Doxorubicin (Dox), is significant for cancer treatment. Here, we describe a co-assembled strategy, where amphiphile short peptides are co-assembled with Doxorubicin to form nanoscale particles for enhanced delivery of Dox. Two kinds of short peptides, Fmoc-FK (FK) and Fmoc-FKK (FKK), are synthesized. Through adjusting the component ratio of peptide an ...[more]

PMID: 31979298

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Project description:Small cell lung cancer (SCLC) at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment. Anthracyclines, such as doxorubicin, have definite activity in this disease, and ganetespib has shown promising activity in preclinical models but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that ganetespib (IC50: 31 nM) was much more potent than 17-allylamino-17-demethoxygeldanamycin (17-AAG), a geldanamycin derivative (IC50: 16 μM). Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and Caspase 3-dependent cell death. MTS assay revealed that ganetespib synergized with both doxorubicin and etoposide, two topoisomerase II inhibitors commonly used in SCLC chemotherapy. Expression of receptor-interacting serine/threonine-protein kinase 1 (RIP1), a protein that may function as a pro-survival scaffold protein or a pro-death kinase in TNFR1-activated cells, was induced by doxorubicin and downregulated by ganetespib. Depletion of RIP1 by either RIP1 small interfering RNA (siRNA) or ganetespib sensitized doxorubicin-induced cell death, suggesting that RIP1 may promote survival in doxorubicin-treated cells and that ganetespib may synergize with doxorubicin in part through the downregulation of RIP1. In comparison to ganetespib or doxorubicin alone, the ganetespib+doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immunocompromised mice. We conclude that ganetespib and doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that ganetespib and doxorubicin combination therapy may be an effective strategy for SCLC treatment, which warrants clinical testing.

Project description:The limited clinical efficacy of monotherapies in the clinic has urged the development of novel combination platforms. Taking advantage of light-triggered photodynamic treatment combined together with the controlled release of nanomedicine, it has been possible to treat cancer without eliciting any adverse effects. However, the challenges imposed by limited drug loading capacity and complex synthesis process of organic nanoparticles (NPs) have seriously impeded advances in chemo-photodynamic combination therapy. In this experiment, we utilize our previously synthesized porphyrin-grafted lipid (PGL) NPs to load highly effective chemotherapeutic drug, doxorubicin (DOX) for synergistic chemo-photodynamic therapy. Methods: A relatively simple and inexpensive rapid injection method was used to prepare porphyrin-grafted lipid (PGL) NPs. The self-assembled PGL NPs were used further to encapsulate DOX via a pH-gradient loading protocol. The self-assembled liposome-like PGL NPs having a hydrophilic core were optimized to load DOX at an encapsulation efficiency (EE) of ~99%. The resultant PGL-DOX NPs were intact, highly stable and importantly these NPs successfully escaped from the endo-lysosomal compartment after laser irradiation to release DOX in the cytosol. The therapeutic efficacy of the aforementioned formulation was validated both in vitro and in vivo. Results: PGL-DOX NPs demonstrated excellent cellular uptake, chemo-photodynamic response, and fluorescence imaging ability in different cell lines. Under laser irradiation, cells treated with a low molar concentration of PGL-DOX NPs reduced cell viability significantly. Moreover, in vivo experiments conducted in a xenograft mouse model further demonstrated the excellent tumor accumulation capability of PGL-DOX NPs driven by the enhanced permeability and retention (EPR) effect. Through fluorescence imaging, the biodistribution of PGL-DOX NPs in tumor and major organs was also easily monitored in real time in vivo. The inherent ability of porphyrin to generate ROS under laser irradiation combined with the cytotoxic effect of the anticancer drug DOX significantly suppressed tumor growth in vivo. Conclusion: In summary, the PGL-DOX NPs combined chemo-photodynamic nanoplatform may serve as a potential candidate for cancer theranostics.

Dataset Information

Small Peptide-Doxorubicin Co-Assembly for Synergistic Cancer Therapy.

Publications

Small Peptide-Doxorubicin Co-Assembly for Synergistic Cancer Therapy.

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