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. 2021 Dec;28(1):776-786.
doi: 10.1080/10717544.2021.1902022.

Precise engineering of hybrid molecules-loaded macromolecular nanoparticles shows in vitro and in vivo antitumor efficacy toward the treatment of nasopharyngeal cancer cells

Dongmei Liu  1 , Wenguang Zhang  2 , Xinju Liu  1 , Rongliang Qiu  1
Affiliations

Precise engineering of hybrid molecules-loaded macromolecular nanoparticles shows in vitro and in vivo antitumor efficacy toward the treatment of nasopharyngeal cancer cells

Dongmei Liu et al. Drug Deliv. 2021 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 gemcitabine (GEM) and cisplatin (PT) exhibits a great anticancer potential, as GEM enhances the effect of PT treatment of human cells by providing stability of the microenvironment. However, encapsulation of GEM 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 GEM and PT core and the macromolecular 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 GEM to stimulate excellent anticancer property. The occurrence of the PT suggestively enhanced the encapsulations of GEM into PLGA NPs (GEM-PT NPs). Further, the morphology of GEM NPs, PT NPs, and GEM-PT NPs and nanoparticle size was examined by transmission microscopy (TEM), respectively. Furthermore GEM-PT NPs induced significant apoptosis in human nasopharyngeal carcinoma CNE2 and SUNE1 cancer cells by in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assays (AO-EB, nuclear staining, and annexin V-FITC). In a xenograft model of nasopharyngeal cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose. Our results suggest that a macromolecular hydrophobic and highly toxic drug can be rationally converted into a pharmacologically efficient and self-deliverable of nanotherapy.

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

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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 GEM and PT into amphiphilic polymers to form GEM-PT NPs for the treatment of cancer therapy.
Figure 2.
Figure 2.
Characterization of the nanoparticles. (A–F) Morphology and particle size of GEM NPs, PT NPs, and GEM-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 GEM NPs, PT NPs, and GEM-PT NPs analyzed by dynamic light scattering via a Zetasizer. (G–I) Stability of the GEM NPs, PT NPs, and GEM-PT examined by the dynamic light scattering.
Figure 3.
Figure 3.
(A) Drug release profiles (GEM and PT) from the GEM NPs, PT NPs, and GEM-PT NPs against PBS containing 0.3% polysorbate 80%. (B) Enlarged figure of drug release profiles (GEM and PT) from the GEM NPs, PT NPs, and GEM-PT NPs.
Figure 4.
Figure 4.
In vitro cytotoxicity of free PT, free GEM, PT NPs, GEM NPs, and GEM-PT NPs were evaluated in CNE2 and SUNE1 cancer cells. Cell viability was examined by the MTT assay after 24 h of drug incubation. Cell viability of non-cancerous HUVEC cells after treatments with different samples for 24 h.
Figure 5.
Figure 5.
Dual AO/EB staining assay for examining Free PT, Free GEM, PT NPs, GEM NPs, and GEM-PT NPs-induced cell death in CNE2 cells. The cells were treated with Free PT, Free GEM, PT NPs, GEM NPs, and GEM-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 GEM, PT NPs, GEM NPs, and GEM-PT NPs-induced cell death in CNE2 cells. The cells were treated with Free PT, Free GEM, PT NPs, GEM NPs, and GEM-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 CNE2 cells using flow cytometry. The cells were treated with free PT, free GEM, PT NPs, GEM NPs, and GEM-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 CNE2 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: 50 μm.
Figure 9.
Figure 9.
In vivo antitumor activity of free PT, free GEM, PT NPs, GEM NPs, and PT-GEM NPs compared to saline. CNE2 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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