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. 2021 Aug 13;12(9):1459–1463. doi: 10.1021/acsmedchemlett.1c00283

Porphyrin-Based Tumor-Targeting Theranostic Agent: Gd-TDAP

Soyeon Kim †,‡, Ji-ung Yang †,‡, Jae Hun Ahn †,§, In Ok Ko †, Jung Young Kim †, Yong Jin Lee †, Ji-Ae Park †,*
PMCID: PMC8436409  PMID: 34531954

Abstract

graphic file with name ml1c00283_0007.jpg

The aim of this work was to evaluate a tumor-targeting porphyrin-based gadolinium complex (Gd-TDAP) for use as an MR/optical imaging agent and potential therapeutic agent. Gd-TDAP had higher longitudinal relaxivity (11.8 mM–1 s–1) than a commercial MRI contrast agent (Omniscan; 3.7 mM–1 s–1) in HSA solution (0.67 mM) at 3 T. The tumor-targeting characteristics were confirmed by T1-weighted MR imaging and optical imaging using an orthotopic brain tumor mouse model, which showed 1.3-fold higher uptake in tumor compared to normal brain tissues. The cell fraction data using U87MG glioblastoma cells indicated the potential for gadolinium neutron capture therapy (Gd-NCT), which requires gadolinium to be inside the cell nucleus. In addition, porphyrin derivatives can be used for photodynamic therapy (PDT), and the results demonstrated that Gd-TDAP has great potential not only as a bimodal imaging agent but also for treatment.

Keywords: Porphyrin, MRI contrast agent, Fluorescence imaging, PDT, Gd-NCT

Porphyrin and its derivatives have been widely applied in the medical field as diagnostic and therapeutic agents. They provide good cell permeability, high tumor absorption, low toxicity, and blood-brain barrier (BBB) penetration.1,2 Porphyrin has its own fluorescence, so it is used not only as an optical imaging agent but also as a radiopharmaceutical and magnetic resonance imaging contrast agent (MRI CA) because it can form complexes with metals.3−599mTc, 111In, 68Ga, and 64Cu are the main metallic radioisotopes for single-photon emission computed tomography (SPECT) or positron emission tomography (PET), and Gd(III) is the main metal for MRI CAs.6,7 When these metals are combined with porphyrin, they act as a corresponding imaging agent and naturally exhibit fluorescence, acting as multimodal agents.1,8,9

In addition, porphyrin derivatives have been widely applied in cancer therapy, such as photodynamic therapy (PDT), chemotherapy, and neutron capture therapy (NCT). Consequently, they were applied as a formulation capable of implementing both diagnostic imaging and multiple therapeutic techniques.10−13 As an example of recent research, Gd/Pt bifunctionalized porphyrin was used for MRI-guided tumor chemo-photodynamic therapy.14

Whether diagnostic or therapeutic, an overriding requirement in theranostics is the targeting ability of the drug. In particular, the concentration of the drug should be low in normal cells and high in tumor cells. To increase intracellular accumulation or tumor uptake, numerous modifications and conjugations of various molecules have been attempted.15,16 As part of that effort, we introduce a compound that binds N,N-dimethyl-p-phenylenediamine (DMPD) to a porphyrin. DMPD is potentially BBB permeable and has antioxidant activity similar to that of a water-soluble vitamin E analogue. In addition, DMPD has moderate metabolic stability and could be suitable for in vivo application due to its low concentration in liver microsomes.17

In developing theranostic drugs, it is important to design a platform that can perform multiple functions simultaneously. This can reduce the side effects caused by unnecessary ingredients from a clinical point of view. To this end, we present the gadolinium complex of 5,10,15,20-(tetra-N,N-dimethyl-4-aminophenyl)porphyrin (TDAP) (Gd-TDAP, Chart 1) as a multimodal theranostics platform for brain tumors [optical/MRI and NCT/PDT]. Ultimately, advanced treatments such as NCT and PDT are required for the treatment of brain tumors, and for successful treatment, more accurate diagnosis is required. Although numerous types of gadolinium-porphyrin derivatives have been developed, their application to brain tumors is rare.11,18

Chart 1. Structure of Gd-TDAP Used in This Study.

Chart 1

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To verify the functions of Gd-TDAP, we here report the photophysical characterization, magnetic properties, brain tumor targeting ability, in vivo MRI contrast enhancement and optical imaging capability.

The relaxivity values for Gd-TDAP are summarized in Table 1 with Omniscan for comparison. The values of Gd-TDAP in water were similar to those of Omniscan. However, in human serum albumin (HSA) solution, the relaxivities of Gd-TDAP were significantly higher than those of water, which was not observed for Omniscan. These results indicated that Gd-TDAP interacts with HSA and consequently produces good MR images in vivo. The interaction of the Gd complex and HSA was further demonstrated by the change in relaxation rate with increasing Gd-TDAP concentration at a fixed concentration of HSA.19 After these measurements, the binding constant (Ka) with HSA can be calculated by eq 1 in the Supporting Information (see the Materials and Methods section). The Ka of Gd-TDAP (71 M–1) is approximately three times higher than that of Dotarem (21 M–1), which explains why Gd-TDAP has high relaxivities in HSA solutions.20

Table 1. Relaxivity and Log P Values for Gd-TDAP and Omniscan in Water or HSA at 25 °C.

  r1 (mM–1 s–1)
 r2 (mM–1 s–1)
  
  water HSAa water HSAa log Po/w
Gd-TDAP 3.6 ± 0.1 11.8 ± 0.1 14.0 ± 0.1 41.7 ± 2.3 1.09
Omniscan 3.7 ± 0.1 3.7 ± 0.1 4.5 ± 0.1 4.6 ± 0.1 –2.13b
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a

Human serum albumin (HSA) = 0.67 mM in water.

b

Data obtained from ref (25).

Since this kind of protein interaction is often observed in lipophilic molecules, the octanol–water partition coefficient (log Po/w) was measured to determine the lipophilicity.21,22 According to a report by Bannwarth et al., the binding affinity of cephalosporin derivatives to HSA depends on their lipophilic character.22 The log Po/w value for Gd-TDAP is 1.09, indicating that Gd-TDAP is much more lipophilic than commercial MRI contrast agents such as Dotarem or Omniscan. It also corresponds to a suitable range for passing through the blood-brain barrier (BBB). Several studies of the relationship between lipophilicity and BBB penetration predicted that log Po/w values greater than 0 and less than 3.5 could pass the BBB.23,24 Therefore, Gd-TDAP is expected to be a suitable agent for brain imaging.

Since porphyrin can act as a fluorophore as well as a ligand for Gd chelation, absorption and emission spectra were obtained to determine its optical properties (Figure 1). The Soret absorption band of Gd-TDAP was observed at 440 nm, and Q bands were observed at 562 and 606 nm. Figure 1 also shows a significant redshift (440 to 680 nm), which is an advantage in a fluorescent probe because the excitation light can be easily separated from the emission light.26

Figure 1.

Figure 1

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Absorption and emission spectra of Gd-TDAP.

Furthermore, we measured the kinetic stability of Gd-TDAP by using its optical properties due to the difference in emission patterns between the ligand and the Gd complex. Kinetic stability is a highly important factor because dechelated free Gd ions can lead to health disorders such as nephrogenic systemic fibrosis (NSF).27 As shown in the inset in Figure 2, two large peaks are observed at approximately 500 and 680 nm in HSA solution for the ligand, but there are no peaks near 500 nm for the Gd complex. However, HSA-containing solutions exhibited 500 nm emission when excited at 430 nm. Several papers have reported that the binding between the porphyrin derivative and HSA could inhibit the intrinsic fluorescence of the protein.28−30 Thus, when the Gd complex was decomplexed, it was expected that the emission of HSA would be restored. Unlike the dissolution of the Gd complex in water, the addition of HSA produced a very slight change in the emission spectrum at approximately 500 nm. However, during 1 h of incubation in HSA solution at 37 °C, a significant spectrum change was not observed; therefore, the solution was considered to be stable during the test. The rigidity of the porphyrin ring was expected to contribute to improving the stability of the Gd complex.31

Figure 2.

Figure 2

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Evolution of the emission spectrum of Gd-TDAP in HSA solutions (incubation at 37 °C) as a function of time.

To confirm the potential of Gd-TDAP as a Gd-NCT agent, U87MG cells were fractionated after incubation with Gd-TDAP for 24 h. Placing gadolinium in the DNA helix is essential for effective NCT because the range of auger electrons in aqueous solutions is only several nanometers, much smaller than the size of a single cell.32,33 The cell fraction cultured only in medium (without contrast agent) was used as a control, and the concentration of gadolinium in each fraction was estimated using T1-weighted images. As shown in Figure 3, the signal intensity of the cytoplasm and nucleus was greater than that of the control, which indicates that Gd-TDAP can enter the nucleus and implies its potential for use as a Gd-NCT drug.

Figure 3.

Figure 3

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(a) T1-weighted MR images of U87MG cell fractions incubated with Gd-TDAP (100 μM, 24 h). (b) Change in signal intensity of MR images for each cell fraction. ΔSI = SIGd-TDAP/SIcontrol. Statistical analysis was performed using the Mann–Whitney U test with SPSS software (*P ≤ 0.05).

The target-specific nature of Gd-TDAP can be further validated by 3 T MR imaging. For the experiment, the tumor-bearing mice were injected with Gd complex (0.05 mmol/kg) into the tail vein and T1-weighted images were acquired over 60 min. Comparison of the pre- and post injection (p.i.) MR images showed distinct differences between the brain tumor region and normal tissues, whereas Omniscan did not reveal any significant differences (Figure 4a). In tumors, the contrast-to-noise ratio (CNR) value of Gd-TDAP was more than 2–3 times higher than that of Omniscan 15–30 min p.i.; it is probably because the relaxivity of Gd-TDAP was higher than that of Omniscan. In the normal brain, the CNR profile of Gd-TDAP is significantly higher for as long as 60 min p.i.; a similar pattern was observed in normal mouse brains (data not shown), which indicates the BBB permeability of Gd-TDAP (Figure 4b). In addition, Omniscan is discharged after reaching a peak at 15 min p.i., whereas Gd-TDAP exhibits a signal increase lasting up to 30 min p.i. and a slow discharge. Here, the steady signal of Gd TDAP indicates specific molecular binding to brain tumors. We additionally performed a pharmacokinetic study of Gd-TDAP in normal nude mouse, showing signal enhancement in the hepatic and renal excretion pathways (Figure S1).

Figure 4.

Figure 4

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(a) Axial T1-weighted MR images pre and post injection of Gd-TDAP or Omniscan (0.05 mmol/kg, i.v. injection). (b) CNR of tumor and normal regions p.i. of the Gd complex as a function of time. CNR = SNRpost – SNRpre. Data are shown as the mean ± SD (n = 3, *P ≤ 0.05, Mann–Whitney U-test).

The fluorescence properties and target-specific nature of Gd-TDAP can be further evaluated by fluorescence imaging equipment (Maestro and IVIS). As shown in Figure 5, strong and concentration-dependent fluorescence imaging (Figure 5a) was observed. Since fluorescence imaging offers less penetration than MRI, tumors were isolated from the brain at 15 min p.i., which was the time of the highest MRI signal, and tumor-targeted fluorescence images of Gd-TDAP were obtained. As shown in Figure 5b and c, a markedly stronger signal was observed in the tumor than in normal brain tissues. Therefore, it was confirmed that Gd-TDAP can be used as a contrast agent for both MR and fluorescence imaging. ICP-MS was additionally performed to measure the concentration of Gd in the separated normal and tumor brain tissues and to determine whether the signal change actually came from Gd-TDAP or from dechelated TDAP. The fluorescence signal intensities and the amount of Gd from brain tumors increased by 1.3-fold higher than those from normal brain tissues (Figure 5c and 5d). Although there were differences in values among different mice, a difference of approximately 30% was found in both the fluorescence and ICP-MS data, confirming that a Gd complex exists stably in vivo.

Figure 5.

Figure 5

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(a) Fluorescence images of Gd-TDAP at various concentrations. The white letters are the Gd concentration values for each sample. (b) Coronal T1-weighted MR image and fluorescence image 15 min p.i. of Gd-TDAP (0.05 mmol/kg, i.v. injection). (c) Ratio of fluorescence signal intensity of normal and tumor brain tissue isolated at 15 min p.i. of Gd-TDAP. (d) Ratio of the Gd amounts in normal and tumor brain tissue isolated at 15 min p.i. of Gd-TDAP (*P ≤ 0.05, Mann–Whitney U-test).

In summary, the porphyrin-based gadolinium complex Gd-TDAP has shown high relaxivities, lipophilicity, and stability. T1-weighted MR imaging showed that brain tumors could be detected within 20 min p.i., and Gd-TDAP persisted longer than Omniscan. In addition, after injection, the fluorescence images showed a clear difference between the extracted tumor and normal brain tissues. Furthermore, the accumulation of Gd-TDAP in the nucleus after cell fractionation demonstrated potential application for Gd-NCT.

Glossary

Abbreviations

BBB

blood-brain barrier

MRI CAs

magnetic resonance imaging contrast agents

SPECT

single-photon emission computed tomography

PET

positron emission tomography

PDT

photodynamic therapy

NCT

neutron capture therapy

DMPD

N,N-dimethyl-p-phenylenediamine

TDAP

5,10,15,20-(tetra-N,N-dimethyl-4-aminophenyl)porphyrin

HSA

human serum albumin

NSF

nephrogenic systemic fibrosis

p.i.

postinjection

CNR

contrast-to-noise ratio

SNR

signal-to-noise ratio

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00283.

  • Details regarding materials and methods, synthetic characterization, relaxivity, determination of binding constant with HSA, octanol–water partition coefficient, in vitro, ex vivo fluorescence imaging, cell culture, cell fractions, brain tumor model, in vitro, in vivo MR imaging protocols and additional MR in vivo data (PDF)

Author Contributions

Experiments, data curation, and draft manuscript preparation, S.K.; preparing animal model, image acquisition, J-U.Y., J.H.A. and S.K.; MR image acquisition, I.O.K. and S.K.; writing-review and editing, J.Y.K. and J-A.P.; project supervision, Y.J.L. and J-A.P.; funding acquisition, J-A.P. All authors have read and agreed to the published version of the manuscript.

This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (No. 2020R1A2C200790611). This work was also supported by a grant of the Korea Institute of Radiological and Medical Sciences(KIRAMS), funded by MSIT, Republic of Korea (No. 50536-2021).

The authors declare no competing financial interest.

Supplementary Material

ml1c00283_si_001.pdf (1.2MB, pdf)

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Supplementary Materials

ml1c00283_si_001.pdf (1.2MB, pdf)

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