Integration of metal-organic framework with a photoactive porous-organic polymer for interface enhanced phototherapy

Abstract

Porphyrin-based porous organic polymers are highly potential candidates for cancer theranostics. However, un-controllable particle size and unclear photoactive mechanisms have been deemed to be “Achilles’ heels” for their biomedical application. Herein, a facile self-template strategy has been applied to integrate two types of porous materials to build the MOF@POP-PEG nanocomposite (named HUC-PEG). As-synthesized HUC-PEG exhibited controllable particle shape and size, good biocompatibility, and better colloidal stability. Importantly, synergy “0 + 1 > 1” interface effects have been demonstrated to simultaneously enhance both the generation of more singlet oxygen (¹O₂) for photodynamic therapy (PDT) and local hyperthermia for photothermal therapy (PTT), thus to achieve favorable proliferation inhibition of tumor cell both in vitro and in vivo. Moreover, the strong X-ray attenuating ability of Hf element and excellent photothermal conversion efficacy endow this nanocomposite with computed tomography (CT)/photothermal imaging functions. We believe that our ingenious design may open a new horizon for the preparation of nanoscale POP-based therapeutic agents and also realize a paradigm shift in the understanding of photoactive mechanism in porous materials.

Introduction

For nearly half a century, porphyrins and their derivatives have been used as photodynamic agents to treat skin-related tumors [1]. Under light irradiation, porphyrin-contained nanomaterials could produce cytotoxic reactive oxygen species (ROS) for photodynamic therapy (PDT) [[2], [3], [4], [5], [6], [7], [8], [9]], but the hypoxic tumour microenvironment usually down-regulated the therapeutic effect [[10], [11], [12], [13]]. Adjusting the hydrophobic and π-π interaction of porphyrin molecules within their nano-assembly could largely change the photophysical properties to induce local hyperthermia through nonradiative transition for photothermal therapy (PTT). It is speculated that the photosensitizers (PSs) capable of simultaneous PDT and PTT can eliminate the respective limits of PDT and PTT, thus facilitating excellent antitumor efficacy [[14], [15], [16]]. Additionally, although advanced nanotechnology has highly revolutionized the current drug delivery strategy, the native hydrophobic feature and unclear photoactive mechanism of the majority of PSs hinder their further bioapplication [17,18]. Therefore, it is still desirable to develop controllable PSs-based nano-systems, enabling overcoming these Achilles’ heels in subsequent clinical translation.

Porous organic polymers (POPs) or covalent organic frameworks (COFs), which were constructed by organic building blocks through covalent bonds, have gained tremendous interests for their low skeleton density, periodic structure, and tunable pore size [[19], [20], [21], [22]]. As one of the new subclass of porous materials, POPs could serve as an alternative medium for using in catalysis [23,24], sensors [25], and gas adsorption and storage [26,27]. Meanwhile, the periodic connection of those organic building blocks in POPs can isolate photoactive molecules from each other to increase the intermolecular distance and to refine the molecular vibration, and thus avoiding the aggregation-caused quenching (ACQ). It would benefit for the subsequent design and application of smart fluorescent sensors and the elevation of photodynamic performance in photocatalysis [[28], [29], [30], [31]]. For biological applications, these porous structures in POPs could be filled with medical molecules as drug delivery system for cancer treatments in vitro and in vivo [[32], [33], [34]]. But it is still in its infancy, and elaborate efforts should be devoted to the controllable particle size and shape, the enhancement of dispersion and stability under physiological environments, and also imperative chemical modification. Numbers of synthetic approaches have been developed to control the morphology and size of POP by adjusting synthesis parameters, surfactant-assisted synthesis [35], and template strategy [36,37]. In the latter approach, the morphology of resultant nanocomposites largely depends on the selected “templates”, and the thickness of POPs layers can be manipulated by facilely controlling the ratio of two components in nanocomposites. Of note, nanoscale metal-organic frameworks (MOFs) with abundant cavities and defect sites on the outersurface could be selected as “self-template” to construct MOF-POP composites. Besides the introduction of distinctive properties from MOF core itself, synergy interface effects between the two porous materials have also been demonstrated. For example, the COF-MOF composite membranes exhibited higher selective separation of the H₂/CO₂ mixtures than each individual ZIF-8 and COF-300 counterparts [38]. Recently, Zhang and Lan reported the construction of MOF/COF hybrid photocatalysts for efficient hydrogen evolution by the efficient charge separation across the covalent heterojunction interface in the hybrid materials [39]. And a microspherical MOF@COF composite with synergistic enhancements in both N₂ and H₂O uptake was synthesized by two-step process [40]. Regarding these highlighted works, we are motivated to explore the synergy effects of MOF@COF composite on the biomedical field.

We have previously confirmed the successful usage of Zr-UiO typed NMOF templates to construct photoactive MOF-POP with desired particle size available for endocytosis by cancer cells [41]. Unsurprisingly, after endocytosis, the porphyrin-contained nanocomposite exhibited strong ability to generate cytotoxic singlet oxygen (¹O₂) for PDT in vitro, but the short excitation wavelength and low molar extinction coefficient of porphyrin hampered their further in vivo application. Moreover, we have also observed the spatial-arrangement-dependent photochemical behaviour in tetratopic chlorin doped Hf-UiO-66 with both PDT and PTT activity [42]. Herein, Hf-UiO-AM@POP-PEG nanocomposite (HUC-PEG) was one-pot synthesized by growing tetrakis (4-aminophenyl)-21H,23H-chlorin (TAPC) [4] (Figs. S1–2), terephthalaldehyde and PEG5k-NH₂ on the outersurface of amine-functional Hf-UiO-66 (Hf-UiO-AM) for ‘‘proof of principle’’ (Scheme 1a). The PEG capping could guarantee the good dispersibility and physiologic stability of HUC-PEG in the blood circulation system, thus improving intratumoral drug accumulation. The usage of chlorin-based building blocks could boost the photon utilization efficiency and expand the therapeutic depth to achieve better in vivo performances. Both in vitro and in vivo experiments indicated that HUC-PEG nanocomposite, which was composed of non-photoactive Hf-UiO-AM (0) and photoactive POPs (1), possessed “0 + 1 > 1” [43] amplification effect as demonstrated in simultaneous enhanced PDT and PTT performances (Scheme 1b). To the best of our knowledge, this work is the first example of chlorin-based POP with controllable photoproperties for therapy.