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. 2020 Dec 1;5(49):31700–31705. doi: 10.1021/acsomega.0c04213

Fluorescent Nanoparticles for Targeted Tumor Imaging and DNA Tracking Gene Delivery In Vitro/In Vivo

Wan Sun †,‡, Fang Tang ‡, Jing-Xue Cui ‡, Zhong-Lin Lu ‡,*
PMCID: PMC7745405  PMID: 33344822

Abstract

graphic file with name ao0c04213_0010.jpg

Fluorescence detection is desirable to track the gene transfer process in order to explain the mechanism. Here, a fluorescent nanoparticle, diketopyrrolopyrrole-based liposome (DPL), was prepared for DNA delivery and tumor imaging in vitro and in vivo. The process to deliver DNA into cells was detected in real time by DPL according to the fluorescent property. The transfection efficacies (TEs) for luciferase and enhanced green fluorescent protein (EGFP) analysis of DPL were 1.5 times those of the commercial transfection agent Lipo 2000. Importantly, the DPL/DNA system has high EGFP TE in vivo with tumor targeting ability. This work provided an effective strategy for monitoring transfection processes.

1. Introduction

Gene therapy is hurdled by the complicated extracellular and intracellular barriers.1−4 During the transfection process, it is necessary to use a gene delivery system that can protect the transgene from destruction in lysosomes because of the abundance of enzymes there and pass through the cell membrane by electrostatic repulsion.5−9 In nature, viruses were first used in gene vectors and were highly efficient in gene transfection.10 However, viral vectors were potentially infectious, and it is necessary to use a gene delivery system that can protect the transgene from destruction in lysosomes because of the abundance of enzymes there and pass through the cell membrane by electrostatic repulsion driving the search for alternative nonviral gene delivery strategies.11−13 Although nonviral gene delivery systems have more safety in vivo, the poor transfection efficiency of the vector has hindered their development in clinical application. To improve the efficiency of gene delivery, understanding the key steps in this transfection process is very important. Considering the abovementioned data, high-efficiency gene vectors with the ability of visually tracking the gene delivery process are still urgently needed.

The fluorescent nanomaterials prompt the growing interests in the application of biomedicine.14−17 Compared to conventional fluorescent dyes, fluorescent nanomaterials have stronger fluorescent brightness, better photostability, water dispersibility, and biocompatibility, making fluorescent nanomaterials to have a great significance for cancer diagnosis and treatment.18−22 At the same time, the fluorescence characteristics of fluorescent nanomaterials can better achieve visual monitoring of cellular processes.23,24 In addition, the enhanced permeability and retention (EPR) effect of nanomaterials can achieve precise tumor treatment with fewer potential side effects.25 Therefore, a nonviral gene vector with tumor targeting and imaging ability for gene therapy is greatly significant in medicine and clinic.

Inspired by the above-described concerns, a fluorescent nanocarrier with tumor targeting ability, low cytotoxicity, and high transfection efficiency needs to be urgently researched. In our previous work,26 the electron donor–acceptor–donor (D–A–D) fluorescent molecule diketopyrrolopyrrole-based liposome (DPL) was designed for siRNA delivery. Herein, DPL was adapted for tracking the process of DNA delivery (Figure 1). According to the method in the literature, the compound was mixed with dioleoylphosphatidylethanolamine (DOPE) in a molar ratio of 2:1 to form a new lipid complex.27 The present work demonstrated that DPL showed good fluorescent responses toward DNA, and the fluorescence intensity of DPL showed an approximately sevenfold enhancement. Complete retardation of DNA (10 μg/mL) can be achieved at 20 μM. Luciferase or enhanced green fluorescent protein (EGFP) expression analysis suggested that DPL was a successful gene vector for delivery of DNA than Lipo 2000 in HeLa cells and realized fluorescent tracking gene transfection in vitro and in vivo.

Figure 1.

Figure 1

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Schematic illustration of the gene delivery process of DPL/DNA. (1) Cellular uptake of DPL/DNA, (2) endosomal escape (triggered by a pH decrease of endosome), and (3) releasing DNA from DPL and nuclear trafficking.

2. Experimental Section

2.1. Cellular Uptake and Release

To investigate the cellular uptake efficacies of DPL/DNA, A549 cells were seeded in glass-bottom dishes, the densities of cells reached 30%, and the cells were treated with DPL/DNA. Here, DNA was labeled with fluorescein isothiocyanate (FITC), and the concentration of DPL and DNA was 40 μM and 10 μg/mL, respectively. After incubation for 4, 8, 12, and 24 h, the cells were washed with phosphate-buffered saline solution more than three times. All the samples were visualized and imaged using confocal laser scanning microscopy (CLSM).

3. Results and Discussion

3.1. Characterization of DPL for DNA Transfer

3.1.1. Agarose Gel Retardation Assay

The condensing abilities of DPL toward plasmid DNA were evaluated using agarose gel electrophoretic analysis (Figure 2). The naked compound could completely condense DNA at 40 μM [58 μg/mL (mass ratio = 5.8:1)]. The effective condensation ability can be attributed to the strong electrostatic interactions between the two triazole-[12]aneN3 units and DNA and the hydrophobic interactions with DNA from the rigid DPP and the aliphatic chain. DPL could completely condense DNA at 20 μM [29 μg/mL (mass ratio = 2.9:1)] under the help of DOPE, improving the DNA condensation ability of the naked compound.28−30

Figure 2.

Figure 2

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Agarose gel electrophoretic analysis for retarding the DNA protective capability of DPL and DPL/DOPE with varying concentrations ([DNA] = 10 μg/mL).

3.1.2. Particle Size and Zeta Potential

As shown in Figure 3A,B, the sizes of the DPL/DNA decreased and zeta potentials of the DPL/DNA increased with increasing concentration of DPL. The DNA was completely retarded by DPL at 20 μM. At this concentration, the zeta potential of DPL/DNA was positive, and the size was much smaller than that when the concentration of DPL was 10 μM. When the concentration of DPL was increased, the sizes and zeta potentials of DPL/DNA only changed slightly, indicating that DPL/DNA formed stable nanostructures. The morphology of DPL was in the shape of a liposome, which was ellipsoidal after forming nanoparticles with DNA, as shown in Figure 3C,D.

Figure 3.

Figure 3

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(A) Sizes and (B) zeta potentials of the DPL/DNA with different concentrations; morphology of the DPL (C) and DPL/DNA (D) characterized by transmission electron microscopy. ([DNA] = 10 μg/mL).

3.1.3. Interaction between DPL and DNA

The DNA binding ability of DPL was studied by ethidium bromide (EB) analysis, based on the competitive binding between EB and DPL with DNA. As shown in Figure 4A, the EB produced strong fluorescence at 608 nm after binding to ct DNA. After gradually adding DPL, the fluorescent intensity of EB was gradually decreased and quenched. As indicated by the inset plot of Figure 4B, the apparent binding constants (Kapp) of compound DPL were calculated to be 6.7 × 106 M–1, which suggests that the intercalative binding of DPL with ct DNA was considerably strong.31

Figure 4.

Figure 4

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(A) Emission spectra of EB bound to DNA in the presence of DPL ([EB] = 5 μM, [DNA] = 40 μM, [DPL] = 0–20 μM, and λex = 530 nm); (B) plots of emission intensity I0/I vs [DPL] in Tris-HCl buffer; (C) effect of increasing amounts of EB and DPL on the relative viscosity of ct DNA at 20 (±0.1) °C [ct DNA]: 30 μM. (SD = 3). (D) Fluorescence spectra of DPL (10 μM) upon the addition of ct DNA (0–20 μM) at 5 mM Tris (pH 7.2).

Viscosity measurements were carried to study the effect of DPL on the viscosity of DNA. As shown in Figure 4C, by increasing the amounts of DPL, the relative viscosity of DNA increased steadily, similar to EB. The results suggest that DPL can bind to DNA through intercalation and electrostatic interaction.32

The fluorescence properties of DPL interacting with DNA were investigated through fluorescence titration experiments. The fluorescence intensity of DPL showed an approximately sevenfold enhancement in the presence of ct DNA (Figure 4D).

3.2. Cytotoxicity and Cellular Uptake and Release Studies

DPL showed low cytotoxicity at a concentration from 10 to 60 μM toward different cancer cells (A549, HepG2, HeLa, and MCF-7) (Figure S1), which is suitable for biological applications.

With good DNA condensation ability and biocompatibility, DPL was used to track the process of DNA delivering into HeLa cells. The FITC-labeled DNA (green fluorescence) was packaged with DPL (red fluorescence) to afford the complexes and incubated with cells. LysoTracker blue and DAPI were used to locate DNA. The uptake processes were observed at different times by laser scanning confocal microscopy (LSCM).33−36 As shown in Figure 5, the green fluorescence was found mainly on the cell membrane and some punctate green fluorescence entered the lysosome within 4 h, suggesting that the DPL/DNA vehicle had started to be taken up by cells. After incubation for 8 h, higher green fluorescence was observed in the lysosome and some green fluorescence was released from the carrier, indicating DPL/DNA escape from the endosome (triggered by a pH decrease within the endosome),37 and the DNA began to be released from the vector; then, some punctate green fluorescence was observed in the nucleus after 12 h. At 24 h, higher green fluorescence was found in the nucleus. The results clearly show the process of transfer DNA by DPL into the cell nucleus successfully.

Figure 5.

Figure 5

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LSCM images of HeLa cells after treatment with DPL/DNA under different incubation times. The DNA was labeled with fluorescein amidite (FITC). [DPL] = 40 μM, [DNA] = 4 μg/mL, blue channel: LysoTracker blue (4, 8 h) and DAPI (12, 24 h). Merge1: merger of the blue channel and green channel; Merge2: merger of the blue channel, green channel, and red channel. Scale bars = 10 μm.

3.3. Transfection Efficacies of DPLIn Vitro and In Vivo

In vitro transfection efficacies (TEs) of DPL on different cells were conducted using both luciferase and EGFP reporter genes. Lipo 2000, a commercial transfection reagent, was used as a contrast vector (10 μM) (Figure 6). With increasing concentrations of DPL from 10 to 60 μM, the luciferase expression of DPL increased and then decreased in all cell lines. As shown in Figures 6A, S2, at 50 μM DPL, the transfection efficiency in HeLa cells is 1.5 times that of Lipo 2000, and it is almost the same in A549; however, the transfection efficiencies of DPL in HepG2 and MCF-7 cell lines are poorer than those of Lipo 2000. The EGFP transfection by DPL measured by flow cytometry and LSCM are shown in Figures 6B, S3. It can be seen that the transfection of GFP was greatly achieved at 40 or 50 μM in the four cell lines, suggesting that DPL achieves more efficient EGFP transfection than Lipo 2000 in HeLa, A549, and HepG2 cell lines.

Figure 6.

Figure 6

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(A) Transfection efficiencies of pGL-3 DNA by DPL at varied concentrations in four cells by luciferase assays; (B) EGFP expressions in four cells measured by flow cytometry (n = 3). [DNA] = 10 μg/mL.

EGFP gene delivery and imaging were further carried out under in vivo; after intraperitoneal injection of the DPL/DNA complexes for 72 h, an obvious fluorescence signal occurred, as shown in Figure 7A–C, indicating that higher gene expression was shown at the tumor site. Semiquantitative fluorescence intensity of organs is shown in Figure 7D, also indicated that almost all of the EGFP was located at the tumor site.

Figure 7.

Figure 7

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(A–C) EGFP expressions in nude mice’s organs bearing HeLa tumor xenografts; (D) fluorescent emission intensity of different organs for EGFP (n = 3).

3.4. Tumor Targeting In Vivo

To assess DNA delivery in tumors, DPL/DNA nanoparticles were injected intraperitoneally into HeLa tumor xenograft nude mice for 24 h, and the biodistribution was evaluated by living fluorescence imaging. As shown in Figure 8, the fluorescence intensity at the tumor site was significantly higher than that of the surrounding tissue, and tumors and major organs were excised for further living imaging, indicating long retention of DPL/DNA nanoparticles in the tumor tissue, and few accumulated in the liver because of tumor targeting through the EPR effect.

Figure 8.

Figure 8

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In vivo imaging of tumor-bearing mice and mice’s organs at 24 h after intraperitoneal injection of DPL/DNA.

4. Conclusions

We have designed and synthesized a DNA delivery system. With the efficient DNA condensation abilities, DPL was able to show the process of DNA delivery in real time by CLSM. The TE for luciferase or EGFP was better than that of Lipo 2000 in HeLa cells. Furthermore, the DNA delivery system realized the expression of DNA in vivo and showed higher expression at the tumor site with tumor targeting ability. This work provides new insights into realizing real-time tracking of the gene delivery process in vitro and in vivo.

Acknowledgments

This article was financially supported by the National Natural Science Foundation of China (21372032 and 21778012), the National Key R&D Program of China (2016YFE0205400-005), the Fundamental Research Funds for the Central Universities, Beijing Municipal Commission of Education, and the Dezhou University Research Project Funding (2019xjrc335).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c04213.

  • Detailed experimental conditions and methods, synthesis, structural characterization, spectroscopic data, and biological experiments and analysis (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao0c04213_si_001.pdf (312.7KB, pdf)

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Supplementary Materials

ao0c04213_si_001.pdf (312.7KB, pdf)

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