Elsevier

Biomaterials

Volume 284, May 2022, 121467
Biomaterials

Supramolecular organic frameworks improve the safety of clinically used porphyrin photodynamic agents and maintain their antitumor efficacy

https://doi.org/10.1016/j.biomaterials.2022.121467Get rights and content

Abstract

Despite that photodynamic therapy (PDT) has been applied for the treatment of cancer and skin diseases for more than two decades, all clinically used photodynamic agents (PDAs) suffer the drawback of skin phototoxicity of PDAs, which requires patients to avoid exposure to natural light for weeks after treatment, but has so far lacked effective suppression methods. Here, we report that three-dimensional diamondoid supramolecular organic frameworks (SOFs), that possess well-defined 2.1-nm porosity, can be used to suppress the skin phototoxicity of Photofrin, HiPorfin and Talaporfin, three porphyrin-based PDAs which clinically receive the most wide applications by injecting SOF after PDT, via an adsorption and retention mechanism. Fluorescence and dynamic light scattering experiments confirm that the SOFs have strong interaction with PDAs, and can adsorb PDAs at a micromolar concentration, whereas dialysis experiments support that the adsorption leads to an important retention effect. In vitro and in vivo experiments reveal that SOFs have high biocompatibility. Studies with healthy and tumor-bearing mouse models demonstrate that, when the PDAs are administrated at a dose comparable with the clinical one, SOF can remarkably suppress sunlight-induced skin phototoxicity, whereas the PDT efficacy of mice treated with SOF post-PDT is maintained. This work provides an efficient strategy for the improvement of the safety of clinically used PDAs.

Introduction

Since the approval of Photofrin by U.S. Food and Drug Administration for clinical treatment of esophageal cancer in 1995 [1], photodynamic therapy (PDT) has been developed as one of the major treatment modalities for cancer and skin diseases due to its unique advantages, including good controllability, non-invasiveness, spatiotemporal selectivity, and minimal systemic toxicity [[2], [3], [4], [5], [6], [7]]. To date, all clinically approved PDT agents are porphyrin or chlorin derivatives that bear different number of carboxylate anions [8,9], whereas a number of porphyrin-derived photosensitizers are also being investigated on different phases of clinical trials. 5-Aminolevulinic acid, with clinical approval for PDT of actinic keratosis and fluorescence-guided visualization of malignant tissue during glioma surgery and high-grade gliomas, is also converted to protoporphyrin IX as photosensitizer in body [10,11]. However, clinically used porphyrin photosensitizers all suffer the drawback of body accumulation, which results in the horrendous adverse effect of long-lasting skin photosensitivity [[12], [13], [14]]. Patients are thus required to avoid exposure of skin and eyes to sunlight or indoor light for up to 6 weeks after treatment [[15], [16], [17]], which brings great inconvenience and lowered quality of life for patients treated. Since the practical application of PDT in 1995, this post-treatment phototoxicity of porphyrin photosensitizers has been a major limitation of the modality, but remains an unsettled challenge clinically. Thus, there is a clinical demand for the development of synthetic agents that are able to suppress the phototoxicity of PDAs and simultaneously allow for the maintainability of their antitumor efficacy.

Recently, several attempts have been made to reduce the photosensitivity of PDAs. One strategy involves the development of activatable photosensitizers (aPSs) which minimize skin phototoxicity by “turning off” the activity of photosensitizers in normal tissues and “turning on” it in the tumor area [[18], [19], [20], [21], [22], [23], [24], [25]]. For this aim, aPSs can be activated by tumor-specific endogenous stimuli (e.g. pH, enzymes, GSH, hypoxia and H2O2) [[26], [27], [28], [29], [30]], or extracorporeal stimuli (e.g. temperature and NIR) [23,31]. Nevertheless, aPSs also suffer some drawbacks. For example, PDT nanosystems prepared using aPSs may not precisely distinguish normal tissues from tumors. For some cases, the “turning on” pH values are not within the pH region of tumor microenvironments, which thus results in low PDT efficacy. Moreover, the introduction of stimuli-responsive groups or linkers generally complicates the preparation of PDT systems, leading to increased cost and challenges for production control. Recently, Chen et al. constructed a nucleic-acid-responsive assembled architecture to overcome the drawback of a zinc (II) phthalocyanine-based PDA [32]. Zhang et al. also designed a self-degradable supramolecular photosensitizer for the improvement of the safety of a boron dipyrromethene (BODIPY)-derived PDA [33]. However, the development of efficient strategies for the improvement of the safety of clinically used PDAs has not been addressed.

The last decades have witnessed great achievements of host-guest chemistry, which has promoted the development of supramolecular hosts as antidotes for in vivo sequestration or reversal of detrimental drugs [[34], [35], [36], [37], [38], [39]]. In this category, cyclodextrins, calixarenes, (acyclic) cucurbiturils and pillararenes have been investigated for efficient encapsulation of neuromuscular blockers, drugs of abuse, anesthetics, neurotoxins, and the highly toxic pesticide paraquat [[37], [38], [39]]. Sugammadex, a biocompatible γ-cyclodextrin derivative, has been approved as a neuromuscular blocking reversal agent and yet obtained remarkable clinical success [40]. We have recently constructed a family of three-dimensional diamondoid supramolecular organic-frameworks (SOFs) [[41], [42], [43]], which is driven hydrophobically via cucurbit [8]uril (CB [8])-encapsulation-enhanced intermolecular aromatic dimerization [[44], [45], [46]]. The regular nano-scale pores of diamondoid SOFs have been utilized to adsorb antitumor agents and DNA for efficient intracellular delivery [47,48]. For suppressing the phototoxicity of PDAs after PDT, here we describe a post-PDT strategy, i.e., injecting a biocompatible reagent after PDT treatment to adsorb or sequester the remaining PDAs in body. In this paper, we report that biocompatible diamondoid SOFs can work as in vitro and in vivo sequestration agents for clinically applied porphyrin PDAs, including Photofrin, the first and most widely used photosensitizer,1 HiPorfin, which is approved in China for the treatment of superficial cancers [49], and Talaporfin, which is approved in Japan for early-stage endobronchial cancer [50]. We demonstrate that SOFs can efficiently adsorb and retain the PDAs through cooperative hydrophobicity and ion electrostatic attraction. We show that, for mice and rats administrated with PDAs at a dose comparable with the clinical one, one of the SOFs can remarkably suppress simulated sunlight-induced, PDA-caused skin lesion at the identical or less dose and allow for the maintainability of the PDT efficacy of the PDAs.

Section snippets

Materials and measurements

All reagents and solvents were purchased from commercial suppliers and used without further purification. 1H NMR spectra were recorded on a Bruker AVANCE III HD (400 MHz). UV–Vis spectroscopy was recorded on a Cary 100 spectrometer (Agilent). Fluorescence spectroscopy was conducted on a RF-6000 fluorescence spectrometer (Shimadzu). The SAXS data were collected at the SIBYLS Beamline 12.3.1 of the Advanced Light Source (Lawrence Berkeley National Laboratory). Powder X-ray diffraction

The characterization of 3D supramolecular structures

Our previous work showed that 1:2 mixture of tetracationic monomers and CB [8] give rise to 3D diamondoid SOF in water [41]. In the present study, T1 and T2, which bear four hydrophilic 2-aminoethoxy or aminoacetamidyl groups, were prepared, which were expected to endow the corresponding SOF-1 and SOF-2 with increased water-solubility (Fig. 1a). The synthesis details of T1 and T2 are provided in Supplementary Information. T3 and T4 have a solubility of ca. 2.0 mM in water, whereas T1 and T2 are

Conclusion

Taken together, we have developed and successfully demonstrated that supramolecular organic frameworks can adsorb clinically used porphyrin photodynamic agents by in vitro and in vivo experiments. Through this strategy, remarkable suppression of the phototoxicity of PDAs post-treatment at a clinical dose is achieved. What is more, the antitumor activity of PDAs maintains highly effective while skin phototoxicity is reduced by SOF. The results herein establish SOFs as broad-spectrum agents to

Data availability

The authors declare that all data supporting the findings of this study are available within the paper and its supplementary information, source data for the figures in this study are available from the online version.

Credit author statement

Zhan-Ting Li: Conceptualization, Funding acquisition, Methodology, Supervision, Data curation, Writing – review & editing, Da Ma: Conceptualization, Methodology, Supervision, Writing – original draft, Yun-Chang Zhang: Funding acquisition, Validation, Yamin Liu: Data curation, Methodology, Visualization, Writing – original draft, Chuan-Zhi Liu: Methodology, Investigation, Ze-Kun Wang: Formal analysis, Validation, Wei Zhou: Validation, Hui Wang: Validation, Dan-Wei Zhang: Validation.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

This work was financially supported by National Natural Science Foundation of China (Project No. 21921003, 21890730 and 21890732) and sponsored by Shanghai Sailing Program (Project No.20YF1458000).

References (56)

  • D. Chen et al.

    Photothermal-pH-hypoxia responsive multifunctional nanoplatform for cancer photo-chemo therapy with negligible skin phototoxicity

    Biomaterials

    (2019)
  • Y. Zhang et al.

    Switchable PDT for reducing skin photosensitization by a NIR dye inducing self-assembled and photo-disassembled nanoparticles

    Biomaterials

    (2016)
  • H. Kim et al.

    ROS-responsive activatable photosensitizing agent for imaging and photodynamic therapy of activated macrophages

    Theranostics

    (2013)
  • H. Yin et al.

    Macrocycles and related hosts as supramolecular antidotes

    Trends. Chem.

    (2021)
  • J. Tian et al.

    In situ-prepared homogeneous supramolecular organic framework drug delivery systems (sof-DDSs): overcoming cancer multidrug resistance and controlled release

    Chin. Chem. Lett.

    (2017)
  • Z. Huang

    An update on the regulatory status of PDT photosensitizers in China

    Photodiagnosis Photodyn. Ther.

    (2008)
  • D. Kessel

    Photodynamic therapy: a brief history

    J. Clin. Med.

    (2019)
  • Z. Jiang et al.

    Antiangiogenesis combined with inhibition of the hypoxia pathway facilitates low-dose, X-ray-induced photodynamic therapy

    ACS Nano

    (2021)
  • J. Gao et al.

    Biomarker displacement activation: a general host-guest strategy for targeted phototheranostics in vivo

    J. Am. Chem. Soc.

    (2018)
  • W. Fan et al.

    Overcoming the Achilles' heel of photodynamic therapy

    Chem. Soc. Rev.

    (2016)
  • X. Zhao et al.

    Recent progress in photosensitizers for overcoming the challenges of photodynamic therapy: from molecular design to application

    Chem. Soc. Rev.

    (2021)
  • S.I. Ogura et al.

    Development of phthalocyanines for photodynamic therapy

    J. Porphyr. Phthalocyanines

    (2006)
  • D.A. Bellnier et al.

    Mild skin photosensitivity in cancer patients following injection of Photochlor (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a; HPPH) for photodynamic therapy

    Cancer Chemother. Pharmacol.

    (2006)
  • T.J. Dougherty et al.

    Cutaneous Phototoxic occurrences in patients receiving Photofrin

    Laser Surg. Med.

    (1990)
  • W.G. Roberts et al.

    Skin photosensitivity and photodestruction of several potential photodynamic sensitizers

    Photochem. Photobiol.

    (1989)
  • X. Li et al.

    Activatable photosensitizers: agents for selective photodynamic therapy

    Adv. Funct. Mater.

    (2017)
  • J.F. Lovell et al.

    Activatable Photosensitizers for imaging and therapy

    Chem. Rev.

    (2010)
  • Z. Dong et al.

    Synthesis of hollow biomineralized CaCO3-polydopamine nanoparticles for multimodal imaging-guided cancer photodynamic therapy with reduced skin photosensitivity

    J. Am. Chem. Soc.

    (2018)
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