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Published in final edited form as: Adv Ther (Weinh). 2020 Jun 8;3(8):2000029. doi: 10.1002/adtp.202000029

Maltotriose Conjugated Metal–Organic Frameworks for Selective Targeting and Photodynamic Therapy of Triple Negative Breast Cancer Cells and Tumor Associated Macrophages

Yoshie Sakamaki †, John Ozdemir †, Alda Diaz Perez †, Zachary Heidrick †, Olivia Watson †, Miu Tsuji †, Chirstopher Salmon †, Joseph Batta-Mpouma ‡, Anthony Azzun †, Valerie Lomonte †, Yuchun Du §, Julie Stenken †, Jin Woo-Kim ‡, M Hassan Beyzavi †
PMCID: PMC7567337  NIHMSID: NIHMS1624017  PMID: 33072859

Graphical Abstract

Herein, we report a nano-MOF conjugated to maltotriose as a new DDS. MA-PCN-224-0.1Mn/0.9Zn showed its ability to target cancer and TAM. This novel MOF is an effective PDT agent and shows little dark toxicity, MA-PCN-224-0.1Mn/0.9Zn uptakes selectively into cancer cells. A well-suited size control methodology was used so that the nano-scaled MOFs may take advantage of the EPR effect. This development of a nano-scale MOF for PDT that is conjugated to a cancer targeting ligand represents a meaningful development for the use of MOFs as drug delivery systems.

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Keywords: photodynamic therapy (PDT), metal-organic framework (MOF), passive and active targeting, triple-negative breast cancer (TNBC), tumor-associated macrophage (TAM), MOFs for Photodynamic Therapy

Metal–organic frameworks (MOF) are a well-suited platform for drug delivery systems that can affect photodynamic therapy (PDT). A well-designed PDT delivery system to treat cancer can overcome some problems of current photodynamic therapy such as prolonged photosensitivity and tumor specificity. Triple negative breast cancer (TNBC) is difficult to treat with existing chemotherapy and often requires surgery because it quickly metastasizes throughout the body. Tumor associated macrophages (TAMs) are known to promote angiogenesis, matrix remodeling, and metastases. Considerable evidence suggests that most TAMs are more similar to M2-polarized macrophages and although some TAMs are known to be M1 polarized there is evidence that most are M2-like the selective targeting of M2 polarized macrophages would be a necessary breakthrough in developing effective nanomedicine.[1] One possible route to target the M2 over the M1 macrophages is to take advantage of the overexpression of CD206 (mannose receptor) on the surface of the M2 macrophages.[2] MOF nanoparticles of dimensions around 50 nm were synthesized by a solvothermal reaction of Mn(III)-tetrakis(4-carboxyphenyl) porphyrin, tetrakis(4-carboxyphenyl) porphyrin and ZrOCl2. Through post-synthetic modification, Zn(II) was incorporated to the tetrakis(4-carboxyphenyl) porphyrin sites and potassium maltotrionate was conjugated to the empty coordination sites on the Zr(OH)4O4. The resultant maltotriose-PCN-224-0.1Mn/0.9Zn was able to specifically target tumor cells and M2-polarized macrophages. Upon irradiation by an LED light MA-PCN-224-0.1Mn/0.9Zn treated triple negative breast cancer (TNBC) and the M2-polarized macrophages selectively by actively targeting via the GLUT and CD206 receptors. The MA-PCN-224-0.1Mn/0.9Zn showed no toxicity towards normal cell lines and no dark toxicity.

Since triple negative breast cancer (TNBC) cells lack the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2); it is difficult to treat with receptor targeting drugs. TNBC comprises 15–20% of all breast cancers, and its clinical course is frequently characterized by early relapse and poor overall survival.[3] Cytotoxic chemotherapy remains the only approved treatment. More than 80% of women with triple negative breast cancer are treated with chemotherapy regimens that include anthracyclines such as doxorubicin (DOX).[4] However, doxorubicin is ineffective in the treatment of TNBC, and can cause cardiotoxicity as a serious side effect.[5] Furthermore, chemotherapy treatment of breast cancer cell lines using either 5-FU, cisplatin, paclitaxel, doxorubicin, or etoposide showed multi-drug resistance.[6] Tumor subtypes and cell types are similar. MDA-MB231 cell lines are classified as triple negative breast cancer (TNBC).[7] The MDA-MB-231 cancer cell line is a highly aggressive TNBC which express high P-glycoprotein (P-gp) to reduce the effects of anti-cancer drugs.[6] MDA-MB-231 is also known for its high invasive potential, which is related to its high expression of the GLUT receptor. 6

PDT is cancer treatment which relies on a photosensitizer (PS) that upon irradiation by light will generate toxic reactive oxygen species (ROS), such as singlet oxygen (1O2) that cause apoptosis in cancer cells.[8] PDT is garnering attention due to its ability to treat tumors without surgery, radiotherapy or chemotherapy. The porphyrin macrocycle is a known PS that has seen clinical use in the European Union under the name Foscan.[9] However, these PS do not target specific cancers, which results in less effective treatment and a prolonged photosensitivity. In 2014, porphyrin containing MOFs were reported to treat head and neck cancers for PDT.[10] MOFs can deliver a PS via two strategies: either loading of the PS within the porous MOF framework or by incorporating the PS into the MOF as the organic linker between the metal rich secondary building units (SBUs). The latter strategy of rigid fixation of a PS into a MOF as the organic linker within the crystal structure prevents aggregation of the PS which increases ROS generation as aggregation results in quenching.[8] MOF platforms for PDT also take advantage of the heavy atom effect wherein a heavy atom incorporated into the PS change the intersystem crossing during ROS production.[8] The heavy atom in a MOF may be either the metal in porphyrin center or the metals in the SBU.

Through a phenomenon known as the Warburg effect, cancer cells are known to have an increased the demand of glucose.[11] Maltotriose is a chain of three glucose molecules which can be used as a cancer targeting moiety in PDT.[12] The modification with maltotriose aimed to target cancer cells and tumor-associated macrophages (TAM) via GLUT and CD206 receptors, respectively. Tumor-associated macrophages (TAM) are known to be associated with M2-like phenotype roles, such as angiogenesis, matrix remodeling, and metastases.[13] M2 macrophages are known to be characterized by a specific marker such as macrophage scavenger receptor (CD204 and CD163) and also mannose receptor-1 (CD206)[14] The ability to target TAMs is an ability that often used to determine the effectiveness of therapeutic agents in targeted cancer therapy.[2, 15] However, many of these trials have revealed that the therapies indiscriminately target tumor specific M2-like and M1-like phenotypes. The activated macrophages (M1 phenotype) are important because they serve important roles in the defense mechanisms against bacteria, virus, parasites and so on and so it could be beneficial to inhibit the unintentional destruction of M1-polarized macrophages.[2, 16] Thus, nonspecific targeting of all macrophages can make the body immunocompromised. MA-PCN-224-0.1Mn/0.9Zn can target the M2-polarized macrophages by the use of maltotriose conjugation to the MOF surface. By targeting M2 macrophages with maltotriose, we can more effectively treat different cancers. Using size-control methodologies the PCN-224-0.1Mn/0.9Zn particles had dimensions within the 50–200 nm regime. Nanoparticles within this size range accumulate in the poor vasculature of tumors by a phenomena known as the enhanced permeability and retention (EPR) effect.[17] This maltotriose-conjugated MOF was designed to be a new novel drug delivery system (DDS) able to target cancer and the CD206 receptor while reducing ROS damage to normal cells and macrophages.

5,10,15,20-Tetrakis (4-carbomethoxyphenyl)porphyrin (H2TMP) was synthesized and hydrolyzed to 5,10,15,20-Tetrakis (4-carboxyphenyl)porphyrin (H2TCPP) with known procedures.[18] Metal insertion with Mn(III) of the H2TCPP gave MnTCPP. The MOFs were synthesized by mixing the ratio (1:9) of MTCPP (M = Mn) and TCPP with ZrOCl2 in a size-control methodology[19] to produce nano-scale MOFs PCN-224-0.1Mn. The MOFs were then treated with ZnCl2 for insertion of Zn into the H2TCPP ligands for enhanced 1O2 generation by the heavy atomic effect. The heavy atom effect is known to enhance intersystem crossing (ISC) of PS and generate more singlet oxygen.[8] The resultant PCN-224-0.1Mn/0.9Zn was conjugated to maltotrionic acid (MA) in potassium maltotrionate acid solution. MA was synthesized from maltotriose as reported with some modifications.[20] The PCN-224 structure consists of six connected Zr6-oxo nodes that has another 6 coordination sites still available for conjugation to -COOH moieties.[18b] Maltotrionic acid in an aqueous solution chelates to the Zr6 node of the PCN-224-0.1Mn/0.9Zn to give the MA-PCN-224-0.1Mn/0.9Zn. Conformation of the maltotrionic acid chelation is performed by measurement of zeta-potential and TEM analysis. The initial concentrations of MnTCPP to H2TCPP in the reaction mixture along with final Mn:Zn ratios along with particle size of the resultant MA-PCN-224-0.1Mn/0.9Zn MOFs are depicted in Figure 1.

Figure 1.

Figure 1.

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The different kinds of PCN-224-0.1Mn/0.9Zn with size and metal.

The MOF samples were characterized using powder X-ray diffraction (pXRD), transmission electron microscopy (TEM), inductively couple plasm mass spectrometry (ICP-MS), and UV-vis, and MA-PCN-224-0.1Mn/0.9Zn was characterized by TEM, zeta-potential, UV-vis, and fluorescence. Structural elucidation of the PCN-224-0.1Mn was performed by matching the pXRD pattern of the synthesized samples with the calculated pXRD patterns of the PCN-224-0.1Mn as shown in Figure 2d.[21] The Mn:Zn metal ratios in the MA-PCN-224-0.1Mn/0.9Zn samples were determined to be 1:10.1 (Supporting Information section S4) a using inductively coupled plasma mass spectroscopy (ICP-MS) this result indicates an increased incorporation of H2TCPP over Mn-H2TCPP into the PCN-224-0.1Mn framework. Comparison of particle size and morphology of the MOF particles before and after post-synthetic modification with Zn and MA using TEM can be seen in Figure 2 a–b; this analysis reveals that the median particle size of the nMOFs increases from the 40–50 nm range before modification to 50–60 nm after with MA. This ~10nm increase is attributed to a thick layer of MA around the nMOF particles after conjugation with MA. Modification with MA was also analyzed by zeta potential (Supporting Information section S4). Before modification with MA, the surface charge of PCN-224-0.1Mn/0.9Zn was measured to be is −4.22 mV (stv is 0.1173), after modification with MA the surface of PCN-224-0.1Mn/0.9Zn is −32.4 mV (stv is 0.4706). The large negative shift in zeta-potential is also indicative of a large layer of MA in the MA-PCN-224-0.1Mn/0.9Zn; moreover, this increase in negative surface charge will increase electrostatic dispersion in water. Saccharide-conjugated porphyrin displays a widening in the UV-vis absorption spectra[22] which was observed in the collected UV-vis absorption of MA-PCN-224-0.1Mn/0.9Zn. (Figure 2e) The change in surface electronics also leads to a widening of the UV-Vis absorption of MA-PCN-224-0.1Mn/0.9Zn.

Figure 2.

Figure 2.

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TEM images. a) shows PCN-224-0.1Mn images of before modification. b) shows its image of after post-metalation with Zn and modification with MA. c) shows size distribution before after modification of PCN-224-0.1Mn/0.9Zn and MA-PCN-224-0.1Mn/0.9Zn d) shows pXRD data of PCN-224-0.1Mn. e) shows UV absorbance of Mn-tmp, H2tmp, MA-PCN-224-0.1Mn/0.9Zn, and PCN-224.

The selective antitumor effect of MA-PCN-224-0.1Mn/0.9Zn was tested in-vitro by comparing the cell toxicity of MA-PCN-224-0.1Mn/0.9Zn towards two cancer cell lines, MDA-MB231 (TNBC) and HeLa (epithelial from cervix) cells, as well as one normal cell line, MCF10a (epithelial from breast). Incorporation of MA onto the PCN-224-0.1Mn/0.9Zn particles target the GLUT receptor of cancer cells. MA-PCN-224-0.1Mn/0.9Zn solutions were prepared in phosphate-buffered saline (PBS). MA-PCN-224-0.1Mn/0.9Zn was well dispersed in phosphate buffered saline (PBS) stably. (Supplementary information Figure S2)

For bio-imaging, the fluorescence spectra of MA-PCN-224-0.1Mn/0.9Zn in PBS was measured at 420 nm excitation with the resultant spectrum shown in Figure 3. MA-PCN-224-0.1Mn/0.9Zn has large excitation wavelength of 400 to 440 nm, and 560 nm (Supplementary information Figure S1).

Figure 3.

Figure 3.

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The fluorescence emission of MA-PCN-224-0.1Mn/0.9Zn in PBS λex=420 nm.

The PDT effect of MA-PCN-224-0.1Mn/0.9Zn and H2TCPP against MDA-MB231, Hela, and MCF-10a cells were measured by WST-8 assay. The number of live cells is directly proportional to the amount of formazan produced. The WST-8 assay was carried out as follows: the three cell lines underwent 24 hours treatment with H2TPP and MA-PCN-224-0.1Mn/0.9Zn respectively then the cells were washed by PBS three times and irradiated by while LED light (100 mW/cm2) for 15 minutes. The comparison of PDT effect for MA-PCN-224-0.1Mn/0.9Zn between cancer cell lines and normal cell lines is shown in Figure 4a. MDA-MB231 and Hela cancer cell lines exposed to MA-PCN-224-0.1Mn/0.9Zn and irradiated with LED light were effectively killed 73% and 87% respectively but under the same conditions MA-PCN-224-0.1Mn/0.9Zn showed limited toxicity towards the MCF10a cell lines.

Figure 4.

Figure 4.

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Bio-activity data. a) PDT effect (LED irradiation for 15 mins 100mW/cm2) of MA-PCN-224-0.1Mn/0.9Zn on MDA-MB231, Hela, and MCF10a b) dark toxicity of MA-PCN-224-0.1Mn/0.9Zn on MDA-MB231, Hela, and MCF10a. c) PDT effect (LED irradiation for 15 mins 100mW/cm2) of H2TCPP on MDA-MB231, Hela, and MCF10a. d) Caspase-3 activity of MDA-MB231 treated by MA-PCN-224-0.1Mn/0.9Zn (LED irradiation for 15 mins 100mW/cm2). One-way ANOVA was performed with a p<0.05 and Tukey as a post-test in N=3. Significant differences were determined by comparing against control sample. The data represent mean ± SD, n=3.

To demonstrate that toxicity is dependent on irradiation with LED light the dark toxicity of MA-PCN-224-0.1Mn/0.9Zn was also tested against all three cell lines used in the study and the results are shown in Figure 4b. The dark toxicity of MA-PCN-224-0.1Mn/0.9Zn against all three cell lines was minimal suggesting that the toxicity of MA-PCN-224-0.1Mn/0.9Zn is arising from the irradiation of the PS MOF with light and subsequent ROS generation. Also, the lack of dark toxicity indicates that cellular toxicity of the MA-PCN-224-0.1Mn/0.9Zn could be localized to effected areas by the selective irradiation of those areas with LED light. To determine the effectiveness of the targeting by MA conjugation the all three cell lines were also exposed to the H2TCPP linker and irradiated, as suspected; without a targeting moiety all cell lines were indiscriminately killed (Figure 4c). The apoptosis effect by MA-PCN-224-0.1Mn/0.9/Zn on MDA-MB231 cells was also analyzed by caspase-3 assay as seen in Figure 4d. Caspases are crucial mediators of programmed cell death (apoptosis). Among them, caspase-3 is a frequently activated death protease which catalyzes the cleavage of many key cellular proteins.[23] In addition to cell viability tests caspase-3 activity was detected in to determine the amount of apoptosis among MDA-MB231 cells exposed to MA-PCN-224-0.1Mn/0.9Zn. The caspase-3 assay data shown in Figure 4d correlates with the cell viability tests and shows that as the amount of MA-PCN-224-0.1Mn/0.9Zn is increased more apoptosis is observed.

Further study of MA-PCN-224-0.1Mn/0.9Zn selectivity was performed by detecting cellular uptake of the PS MOF into cancer cells with bio-imaging. By detecting the emission of MA-PCN-224-Mn, the cellular uptake of MA-PCN-224-0.1Mn/0.9Zn on HeLa, MDA-MB231, and MCF10a were observed. MA-PCN-224-0.1Mn/0.9Zn was not detected in MCF10a but was observed in the Hela and MDA-MB231 as seen in Figure 5. These images indicate that a MOF functionalized with MA can be a suitable agent for actively targeting cancer cells. The ability to forgo uptake into normal cells is essential for the ensuring that PS MOFs can not show a prolonged photosensitivity. It also increases the efficiency of the MOF PS such that less material can be administered in treatment when compared to a PS that will not actively target cancer cells.

Figure 5.

Figure 5.

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Bio-imaging of MDA-MB231, Hela, and MCF10a cells. The emission of MA-PCN-224-0.1Mn/0.9Zn was shown as a red color.

In addition to tumor cells the specific targeting of the M2-like macrophage was attempted. The choice to target M2 macrophages which overexpress the CD206 macrophage was done in part to make the MOF particles more selective to TAMs. Most cancer chemotherapy is not selective and thus also affects M1 phenotype macrophage which are crucial components in the immune defense mechanism (Figure 6a). It has previously been reported that TAM expresses more of the mannose receptor (CD206) than the M1 macrophage does.[2, 14] From THP-1 cell line, M1-polarized and M2-polarized macrophages were transformed by following the reported way.[2] THP-1 cells are immortalized monocyte-like cells derived from the peripheral blood of a 1-year old male child with acute monocytic leukemia. They have been used in the investigation function during a healthy and/or diseased stage.[24] THP-1 cells are known to differentiate into macrophage-like cells using phorbol 12-myristate 13-acetate (PMA).[25] Similar to macrophage cells, THP-1 cells stimulated with PMA have been shown to be used to induce NF-κB in response to lipopolysaccharide (LPS) with an increase of secretion of tumor necrosis factor alpha (TNF-α).[25a, 26] For this experiment, CCL2 and IL-10 were measured to confirm the presence of M1/M2 phenotype. Human CCL2 (C-C motif chemokine ligand 2) is known to be involved during a pro-inflammatory response, phagocytosis and monocytic infiltration. Macrophage induced with LPS have shown an increase of the presence of M1 phenotype and also the secretion of CCL2. [27] On the other hand, IL-10 is known to reduce pro-inflammatory response and express M2-like phenotype.[27d, 28] For this experiment, IL-4/IL-13 are known modulator to release IL-10 which is known to be secreted by M2 phenotype.[29] Moreover, IL-10, IL-4 and IL-13 is known to down regulated the CCl2 production in activated macrophages.[30]

Figure 6.

Figure 6.

Figure 6.

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THP-1 cells were activated to macrophage-like by using phorbol 12-myristate 13-acetate. After activation, LPS/IFNγ was added to induce the M1 phenotype or IL-4/IL-13 was added to induce the M2 phenotype. a) The roles of M1 and M2 macrophages. b) Macrophage-like cells induced with LPS/IFNγ and IL-14/IL-13. The culture was incubated for 24 hours at 37 °C in 5% CO2. One-way ANOVA was performed with a p<0.05 and Tukey as a post-test in n=3. Significant differences were determined by comparing against control sample. c) PDT effect (LED irradiation for 15 mins, 100 mW cm−2) of MA-PCN-224-0.1Mn/0.9Zn on M1 and M2 phenotype. The data represent mean ± SD, n = 3.

As shown in Figure 6b, LPS/IFNγ shown a significant increase of CCL2 comparing with control. Also, it is possible to observe a significant decrease of CCL2 in macrophage-like cells induced with IL-4/IL-13. Moreover, IL-10 was ran in this experiment; however, the sample were below of the detection limit. Even though, the concentration of IL-10 were below of the detection limit, it is possible to observe that CCL2 concentration were lower for IL-4/IL-13 than the control. Previous research have shown that the activation of M2 can be shown due to the decrease of pro-inflammatory cytokines such as CCL2, and IL-4/IL-13 have been used in the expression of M2-like phenotype.[27d, 30–31] After these confirmation, by WST-8 assay, MA-PCN-224-0.1Mn/0.9Zn showed that it has an ability to kill only the M2 polarized macrophages without killing M1 macrophage (Figure 6c).

We have reported that a nano-scaled MOF MA-PCN-224-Mn can selectively target cancer cell lines and tumor associated macrophages due to the action of maltotrionic acid conjugated. MA-PCN-224-0.1Mn/0.9Zn is a well-designed drug delivery system that has been proven to actively two kinds of cancer cell lines while showing minimal toxicity toward the normal MCF10a cell lines. MA-PCN-224-0.1Mn/0.9Zn has also shown its ability to target M2 polarized macrophages without killing M1-polarized macrophages. This work lays an essential foundation for utilizing cancer targeting moieties on the surface of MOF for the targeted delivery of a PS to effected cells. In future studies it would be beneficial to perform targeting tests using specifically TAMs that have been polarized as M2 macrophages following the procedure recently developed by Benner et. al.[32] The characterization of MA-PCN-224-0.1Mn/0.9Zn surface charge with zeta potential confirms that there is the dispersive effect of MOF particles can be enhanced by surface functionalization. MA-PCN-224-0.1Mn/0.9Zn should be tested in a living mouse model in future studies to determine if the MA conjugation to the surface of the MOF can sustain cancer targeting effect within the circulation of a living sample. In vivo studies are also necessary in the future so that the metal toxicity of the MOFs can be determined. The degree of ROS generation by monitoring 1O2 phosphorescence at 1270 nm also warrants further study so that the heavy atom effect on ROS production compared to the free H2TCPP is better understood. However, it is clear that the MA-PCN-224-0.1Mn/0.9Zn represents a major proof of concept that molecular targeting of receptors on the surface of cancer cells will mitigate the indiscriminate cellular death associated with PDT. To date most efforts in the synthesis of MOFs for PDT attempt to increase the effectiveness by utilizing different organic PS molecules within the MOF framework. This work is the first to actively target cancer cells and M2-polarized macrophages through a specific receptors (CD206). This is a much more efficient approach that must be used in future explorations of MOFs as PDT agents as it brings the PS directly to the cancer cells. Active targeting will also increase the potency of a PS so that less of the MOF needs to be administered reducing any prolonged photosensitivity. Since MA-PCN-224-0.1Mn/0.9Zn also contains the paramagnetic Mn(III) metal is will be an excellent MRI agent.[18a, 33] that has a cancer targeting effect. The MOF synthesis developed in this work also showcase an excellent procedure of controlling the size of porphyrinic PCN-224 MOF particles.

Supplementary Material

supp info

Acknowledgements

M.H.B. gratefully acknowledges the financial support through the startup funds from the University of Arkansas and the NIH-NIGMS (GM132906). We thank Center for Advanced Surface Engineering (CASE) under the National Science Foundation (NSF) grant number OIA-1457888 and the Arkansas EPSCoR program, ASSET III.

Footnotes

Supporting Information

Supporting Information is available from the Wiley Online Library or from the author.

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