Far-Red Fluorescent Liposomes for Folate Receptor-targeted

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Far-red Fluorescent Liposomes for Folate Receptor-targeted Bioimaging Sheng Dong, Joshua Teo, Li Yan Chan, Chi-Lik Ken Lee, and Keitaro Sou ACS Appl. Nano Mater., Just Accepted Manuscript • DOI: 10.1021/acsanm.8b00084 • Publication Date (Web): 27 Feb 2018 Downloaded from http://pubs.acs.org on February 27, 2018

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ACS Applied Nano Materials

Far-red Fluorescent Liposomes for Folate Receptor-targeted Bioimaging

Sheng Dong†, Joshua Teo‡, Li Yan Chan‡, Chi-Lik Ken Lee‡, Keitaro Sou*†#§

† Waseda Bioscience Research Institute in Singapore (WABIOS), 11 Biopolis Way, #05-02, Helios, Singapore 138667, Singapore. ‡ Department for Technology, Innovation and Enterprise (TIE), Singapore Polytechnic, 500 Dover Road, Singapore 139651, Singapore. # Organization for University Research Initiatives, Waseda University, 513 Wasedatsurumaki-cho, Shinjuku-ku, Tokyo 162-0041, Japan.

Keywords: bioimaging, click chemistry, folate receptor, folic acid, liposomes, nanoparticles, ovarian cancer cells, squaraine dye

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ABSTRACT: In this paper, we describe the newly designed liposomes modified with amphiphilic far-red squaraine dye and folic acid for its application in folate receptor-targeted bioimaging. Enhanced intracellular uptake of the engineered liposomes has been demonstrated on SKOV-3 ovarian cancer cells.

Folate, or folic acid (FA) is an essential vitamin in eukaryotic cells for biosynthesis of nucleotide bases.1-3 Previous studies showed that the expression of folate receptors (FRs) is highly dependent on cell types and localization of cells in tissue.4-5 Although some normal tissues also express FRs, receptor localization is limited to their apical membrane surfaces (not exposed to blood).6 Detectable amount of FRs are generally expressed only on the membrane of certain cancer cells (such as epithelial, ovarian, cervical, breast, lung, kidney, colorectal, and brain tumors) and activated macrophages (cause inflammations and autoimmune diseases).7-18 Therefore, folate can be used as a cheaper and more accurate probe than most other targeting molecules for in vivo labelling and detection of cancer cells19. Human studies were done in ovarian cancer patients to examine the feasibility of cancer therapy using the folate receptor approach.20 In these studies, FA conjugated with a fluorescence molecule, such as fluorescein isothiocyanate (FITC), was a common

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design of the prototype diagnostic tool. However, small molecules, such as FA-FITC, are rapidly eliminated from systemic circulation through renal extraction and/or distribution into normal tissues, resulting in poor distribution of the fluorescent probe to the tumor. Liposomes, on the other hand, have higher stability and survivability in circulation and hence greater odds of successful passive distribution into the tumor.21,22 Liposome-based drug delivery systems are increasingly promising in anti-cancer therapies over the past decades.23 The organic surface of liposomes can be modified for the attachment of targeting molecules. This enables the liposome vehicles to home in on specific targets in cancer therapeutic treatment. Systematic studies have been done to ensure that folate is sufficiently specific to accurately deliver liposomes to respective target cells. The length of the polyethylene glycol (PEG) spacer between the liposome and the attached folate is the main factor that determines the affinity towards the folate receptor, as discovered by Low and co-workers. They reported that a PEG linker of 250 Å length (M.W. ≈ 3350) may have aided in overcoming steric hindrance of PEG-DSPE (DSPE: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine), hence enabling the folate to bind to more receptors. Consequently, this may reduce non-specific uptake by non-cancerous tissue and hence improve bioavailability in circulation. This optimized design will also allow the lowering of percentage of bound FA on the liposome to 0.1

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mol%.24, 25 However, the large FA-PEG-DSPE probe requires multi-step synthesis and subsequent challenging purification, which may result in an overall lower yield. In this study, we describe novel FA-tethered liposomes, incorporated with far-red fluorescent dye (SQR23), that specifically identify FRs on the cell membrane (Figure 1).

Figure 1. Fluorescing and functionalized liposome targeting at cancer cells with overexpressed folate receptors. The surface of the liposome was remotely modified with folic acids by click chemistry. Squaraine dyes have attracted scientists’ attention since its invention in 1965.26 Their applications in the field of photodynamic therapy, organic solar cells, and metal ion recognition, have been thoroughly studied.27-29 In contrast, its relevance and application in the bioimaging field was significantly lesser. The two main problems that limit the effective use of squaraine dyes in biological applications are: 1) squaraine dye tends to aggregate in a fluorescence-quenching form in an aqueous environment; 2) the dye is 4


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vulnerable to thio-containing nucleophiles that naturally exist in cells, which may result in a loss of its fluorescent properties. To circumvent both issues, several strategies, such as hydrophilic squaraine dyes, rotaxanes, serum albumins and nanoprobes encapsulation of squaraine dyes, have been developed.30-38

Kim

and

co-workers

discussed

the

use

of

poly(maleic

anhydride-alt-octadec-1-ene) (PMAO) as the structural material with double layers formed by the aliphatic chains, that could protect the hydrophobic squaraine dye within the layer.39 By applying a similar approach, we hypothesize that the squaraine dye could also be embedded inside the lipid bilayers of liposomes. Moreover, the fatty shield of the liposomes can act as a protective layer of the dye, to prevent unwanted side reactions by nucleophiles present in the aqueous milieu outside the liposome. Firstly, it is important to customise a new squaraine dye for this context of application. We have successfully designed and synthesized an asymmetric and amphiphilic squaraine dye, SQR23, which could be anchored inside the lipid bilayer membrane of liposomes (Figure 2). The hydrophobic properties of the amphiphilic fluorescent dye played a significant role in order to be incorporated into the membrane of liposomes. The detailed synthetic procedure can be found in the Supporting Information. The spectroscopic properties of SQR23 were measured by preparing a series of solutions in

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different solvents (10 µM for absorbance spectrum and 1 µM for fluorescence spectrum). The fluorescence of SQR23 was quenched in DMF, DMSO and DI water, while the quantum yield can be as high as 0.1-0.4 in other low-polarity solvents. Maximum excitation wavelength was observed to be around 630 nm, while maximum emission wavelength varied from 640 to 665 nm (Figure S8 and Table S1). The advantages of using far-red/near infrared SQR23 include minimal interfering absorption and fluorescence from biological samples, inexpensive diode excitation, reduced scattering and enhanced tissue penetration depth. A feasibility test was carried out by mixing 0.1 mol%

SQR23

with

a

mixed

1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine

lipid (DPPC),

powder

containing

L-glutamic

acid,

N-(3-carboxy-1-oxopropyl)-, 1,5-dihexadecyl ester (SA), PEG-DSPE, and SQR23 (DPPC/SA/PEG-DSPE/SQR23 = 90/10/0.3/0.1, molar ratio) in phosphate buffered saline (PBS). As expected, confocal microscopic analysis demonstrated that SQR23 was incorporated into the liposome membrane (Figure 2B). The maximum emission wavelength was 619 nm (Figure S11B). The resulting liposome suspension is stable at room temperature or 4 oC for at least two weeks without the formation of precipitates.

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Figure 2. Amphiphilic squaraine dye (SQR23) for labeling of liposome membrane. (A) Chemical structure of SQR23, (B) Confocal fluorescence image of liposomes containing 0.1 mol% SQR23 in lipid bilayer membrane. The scale bar represents 5 µm.

After confirming the successful fluorescence labeling of liposomes with SQR23, we proceeded to functionalize SQR23-incorporated liposomes with FA. Figure 3 displayed the synthetic scheme of FA-DBCO-PEG5-G16 (DBCO: dibenzocyclooctyl; G16: 1,5-dihexadecyl-L-glutamate). This new spacer design addressed the issue of steric hindrance and challenging synthetic procedures faced by Low and colleagues previously. The liposome was first tagged with DBCO, before the attachment of FA via copper-free click chemistry. It is especially important to assemble FA at the last step as this affords the versatility of ligand screening using different targeting molecules for other potential applications. Furthermore, bioactive drug payloads could first be pre-loaded inside the liposome core using this strategy, hence minimizing undesirable side reactions during downstream liposome surface modification. 7



α-isomer) FA-N3 (α

DBCO-PEG5-G16

FA-DBCO-PEG5-G16

Figure 3. Molecular components for remote modification of preformed liposome with folic acids by click chemistry. FA-N3 was synthesized according to previously described protocols in literature, yielding both α- and γ- isomers (Figure S7).40 The mixture acquired was used without further separation, since both isomers could bind similarly to the FRs on cell membrane.41 DBCO-PEG5-G16 was achieved simply by a one-step coupling reaction (Figure S4). Liposomes (DPPC/SA/PEG-DSPE/SQR23 = 90/10/0.3/0.1, molar ratio) containing three different amounts of DBCO-PEG5-G16 (0.3, 3, and 5 mol% to total lipids) were prepared by the extrusion method, and the diameter of resulting liposomes was determined by dynamic light scattering to be 160 nm in average (Figure S11A). FA-N3 (0.5 equiv. to DBCO-PEG5-G16) in PBS solution was then added and stirred overnight at room temperature in the dark to achieve the desired functionalized liposomes (FA-liposomes). The SKOV-3 ovarian cancer cell line was known to overexpress FR and thus was selected to be the cell model for cell staining experiments (Figure S12). SKOV-3 cells 8


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were first seeded in 96-well plates overnight till 100% confluency. FA-liposome was then added to the SKOV-3 cells incubated in 37 oC for 2.5 h. After incubation, the liposome suspension was aspirated from the cells and the cells were washed with sterile 1× PBS thrice. Washed cells were analyzed with an automated microplate reader at room temperature to obtain fluorescence intensity measurements (excitation at 630 nm; emission at 660 nm). The loading amount of DBCO-PEG5-G16 in the FA-liposomes is crucial and affects the uptake by SKOV-3 cells. FA-liposomes containing 5 mol% DBCO-PEG5-G16 showed significantly higher uptake by SKOV-3 cells as compared to the negative control of SKOV-3 cells incubated with unmodified liposomes (p=0.001, Figure 4A). No significant difference, compared to the negative control, was detected when 0.3 or 3 mol% of DBCO-PEG5-G16 FA-liposomes were used instead. Further confocal microscopic analyses provided direct visualization of fluorescence in labelled SKOV-3 cells and demonstrated the practical applications of FA-liposomes in diagnostic detection of cancer cells (Figures 4B and S13). The fluorescence suggested uptake of the liposomes into the cancer cells via endocytosis pathway after binding with the FRs located on the cellular surface. Further experiments will employ time-point confocal imaging to validate, in a mechanistic manner, this intracellular transportation pathway in

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mediating the uptake of FA-liposomes. We will also further explore the possibility of testing the newly designed FA-liposomes towards drug payload encapsulation and efficacy as a theranostic approach. In conclusion, we have successfully designed and synthesized an asymmetric amphiphilic squaraine dye SQR23. This dye was embedded within the liposome membrane and served as a promising diagnostic imaging tool. The fluorescing liposomes were further functionalized with folic acid to target cancer cells with overexpression of folate receptors, as demonstrated using SKOV-3 ovarian cancer cells. Our works provided a new solution to the solubility and stability issues of squaraine dyes commonly encountered in bioimaging. The synthetic route is universal and enabled the liposomes to be easily functionalized with folic acid or other molecules as ligands for different receptors of interest. The promising results obtained provide growing confidence that this new fluorescing FA-liposomes, when encapsulated with drug, will serve as a good tool for theranostic applications.

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Figure 4. Fluorescence observation of SKOV-3 ovarian cancer cells using FA-modified liposomes (5 mol%) incorporating 0.1 mol% SQR23. (A) Fluorescence intensity of SKOV-3 treated with unmodified liposomes and FA-liposomes. Data are mean ± SD (n=3). Statistical analysis for two group comparisons was done with a two-tailed unpaired t-test. (B) Confocal images of SKOV-3 cells treated with PBS (background), unmodified liposomes, and FA-liposomes. The scale bars represent 20 µm. ASSOCIATED CONTENT Supporting Information 11



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This material is available free of charge via the Internet at http://pubs.acs.org. Materials

and

detailed

experimental

procedures

including

synthesis

and

characterization of SQR23, DBCO-PEG5-G16, and FA-N3, spectroscopic properties of SQR23, liposome preparation and characterization, cell culture, and cellular uptake experiments.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Present Addresses § Research Institute for Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan

Notes The authors declare no competing financial interests. ACKNOWLEDGMENT This work was partly supported by JSPS KAKENHI (JP16H03844) and SP R&D (TIEFA) grant from Singapore Polytechnic (R225).

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Far-Red Fluorescent Liposomes for Folate Receptor-targeted

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