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. 2020 Dec;27(1):1319-1328.
doi: 10.1080/10717544.2020.1815897.

Co-drug delivery of regorafenib and cisplatin with amphiphilic copolymer nanoparticles: enhanced in vivo antitumor cancer therapy in nursing care

Zhe Zhou  1
Affiliations

Co-drug delivery of regorafenib and cisplatin with amphiphilic copolymer nanoparticles: enhanced in vivo antitumor cancer therapy in nursing care

Zhe Zhou. Drug Deliv. 2020 Dec.

Abstract

Cancers continue to be the second leading cause of death worldwide. Despite the development and improvement of surgery, chemotherapy and radiotherapy in cancer management, effective tumor ablation strategies are still in need due to high cancer patient mortality. Hence, we have established a new approach to achieve treatment-actuated modifications in a tumor microenvironment by using synergistic activity between two potential anticancer drugs. Dual drug delivery of Regorafenib (REGO) and Cisplatin (PT) exhibits a great anticancer potential, as REGO enhances the effect of PT treatment of human cells by providing stability of the microenvironment. However, encapsulation of REGO and PT fanatical by methoxypoly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-PLA in termed as NPs) is incompetent owing to unsuitability between the binary Free REGO and PT core and the polymeric system. Now, we display that PT can be prepared by hydrophobic coating of the dual drug centers with dioleoylphosphatidic acid (DOPA). The DOPA-covered PT can be co-encapsulated in PLGA NPs alongside REGO to stimulate excellent anticancer property. The occurrence of the PT suggestively enhanced the encapsulations of REGO into PLGA NPs (REGO-PT NPs). Further, the morphology of REGO NPs, PT NPs, and REGO-PT NPs and nanoparticle size was examined by transmission microscopy (TEM), respectively. Furthermore REGO-PT NPs induced significant apoptosis in human lung A549 and ovarian A2780 cancer cells by in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assayes (AO-EB, Nuclear Staining and Annexin V-FITC). In a xenograft model of lung cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose. Our results suggest that a hydrophobic and highly toxic drug can be rationally converted into a pharmacologically efficient and self-deliverable nursing care of nanotherapy. Highlights Dual drug delivery of Regorafenib (REGO) and Cisplatin (PT) exhibits a great anticancer potential, as REGO enhances the effect of PT treatment of human cells by providing stability of the microenvironment. REGO-PT NPs induced significant apoptosis in human lung A549 and ovarian A2780 cancer cells by in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assayes. In a xenograft model of lung cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose.

Keywords: Combinational delivery; apoptosis; cancer; in vivo antitumor efficacy.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
A graphic representation of the encapsulation of REGO and PT into amphiphilic polymers to form REGO-PT NPs for the treatment of cancer therapy.
Figure 2.
Figure 2.
Characterization of the nanoparticles. (A–F) Morphology and particle size of REGO NPs, PT NPs and REGO-PT NPs under a transmission electron microscope after negative staining with sodium phosphotungstate solution (2%, w/v). Scale bar: 20 nm. Particle size distribution of REGO NPs, PT NPs and REGO-PT NPs analyzed by dynamic light scattering via a Zetasizer. (G-I) Stability of the REGO NPs, PT NPs and REGO-PT examined by the dynamic light scattering.
Figure 3.
Figure 3.
Drug release profiles (REGO and PT) from the REGO NPs, PT NPs, and REGO-PT NPs against PBS containing 0.3% polysorbate 80.
Figure 4.
Figure 4.
In vitro cytotoxicity of Free PT, Free REGO, PT NPs, REGO NPs, and REGO-PT NPs were evaluated in A549 and A2780 cancer cells. Cell viability was examined by the MTT assay after 24 h of drug incubation.
Figure 5.
Figure 5.
Dual AO/EB staining assay for examining Free PT, Free REGO, PT NPs, REGO NPs, and REGO-PT NPs-induced cell death in A549 cells. The cells were treated with Free PT, Free REGO, PT NPs, REGO NPs, and REGO-PT NPs at 2.5 µM concentration for 24 h. B) Quantification of apoptosis ratio. The cells were quantified by image J software.
Figure 6.
Figure 6.
Nuclear (Hoechst 33258) staining assay for examining Free PT, Free REGO, PT NPs, REGO NPs, and REGO-PT NPs-induced cell death in A549 cells. The cells were treated with Free PT, Free REGO, PT NPs, REGO NPs, and REGO-PT NPs at 2.5 µM concentration for 24 h. B) Quantification of apoptosis ratio. The cells were quantified by image J software.
Figure 7.
Figure 7.
A) Apoptotic analysis of A549 cells using flow cytometry. The cells were treated with Free PT, Free REGO, PT NPs, REGO NPs, and REGO-PT NPs at 2.5 µM concentration for 24 h and then stained with FITC annexin V/PI for flow cytometry analysis. B) Apoptosis ratio of A549 cells.
Figure 8.
Figure 8.
H&E staining of the major organs (kidney, liver, lung, spleen and heart) excised from different treatment mice groups. Scale bar: 100 μm.
Figure 9.
Figure 9.
In vivo antitumor activity of Free PT, Free REGO, PT NPs, REGO NPs, and PT-REGO NPs compared to saline. A549 tumor xenograft-bearing Balb/c nude mice were administered with various drugs via intravenous injection at days 0, 3 and 6. A) Changes in tumor volumes. B) Body weights. C) Represent tumor photograph. D) Tumor weights. The data are presented as the means ± SD (n = 7).
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