Porphyrin-Based Nanomedicines for Cancer Treatment - Bioconjugate

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Porphyrin-Based Nanomedicines for Cancer Treatment Xiangdong Xue, Aaron Lindstrom, and Yuanpei Li Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.9b00231 • Publication Date (Web): 26 Apr 2019 Downloaded from http://pubs.acs.org on April 26, 2019

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Bioconjugate Chemistry

Porphyrin-Based Nanomedicines for Cancer Treatment Xiangdong Xue, Aaron Lindstrom, Yuanpei Li* Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA. Corresponding author: Y. Li, [email protected] Abstract As unique molecules with both therapeutic and diagnostic properties, porphyrin derivatives have been extensively employed for cancer treatment. Porphyrins not only show powerful phototherapeutic effects (photodynamic and photothermal therapies), but also exhibit excellent imaging capacities, such as nearinfrared fluorescent imaging (NIRFI), magnetic resonance imaging (MRI), photoacoustic imaging (PAI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT), etc. Taking advantage of their robust phototherapeutic effects and excellent imaging capacities, porphyrins can be used to create nanomedicines with effective therapeutic and precise diagnostic properties for cancer treatment. In this review, we summarize porphyrin-based nanomedicines which have been developed recently, including porphyrin-based liposomes, micelles, polymeric nanoparticles, peptide nanoparticles and small-molecule nano-assemblies, and their applications on cancer therapy and diagnosis. The outlook and limitation of porphyrin-based nanomedicines are also reviewed.

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Introduction Despite the substantial manpower and resources that have been allocated to the fight against cancer, it remains one of the leading causes of human death.1 So far, the treatment efficacy of traditional approaches for cancer therapy, such as surgery2, chemotherapy3,

4

and radiotherapy5, 6, remains

unsatisfactory for many cancer types. New treatment modalities, such as phototherapy7,

8

and

immunotherapy9, 10, are exploited for cancer treatment. Phototherapy provides a straightforward way to ablate tumor tissues in a highly controllable manner, which is an ideal complementary regimen to the traditional therapeutics. Immunotherapy takes advantage of the immune system to combat both primary and metastatic cancer and several therapies are currently FDA-approved. However, the heterogeneity of a tumor makes it difficult for a single therapeutic model to reach its desired efficacy. Combinations of different therapeutics in a synergistic way may lead to a better response rate to heterogeneous tumors in a compensatory mechanism. To precisely fight a complex and heterogeneous tumor, novel diagnostic approaches are urgently needed. As Sun Tzu said in “The Art of The War”, know yourself as well as the enemies, you will never be defeated. If we can accurately differentiate tumors from normal tissues, figure out the tumor developing stages, and even understand biological behaviors of the administrated therapeutics, the odds of winning the battle against cancer can be largely improved. The combination of diagnostic and therapeutic approaches will help us to fight cancer precisely and effectively. The diagnostics could vividly delineate tumor-development process and biological behaviors of therapeutics, and the therapeutics learn the information that is feedbacked from diagnostics and gain better skills to fight with cancer. As unique molecules that intrinsically possess multiple diagnostic and therapeutic functions, porphyrin derivatives have enormous merits for cancer diagnosis and therapy.11-13 Porphyrin molecules absorb light energy and transform it into powerful therapeutic effects. They can be activated by light energy and react with surrounding oxygens to produce reactive oxygen species (ROS). ROS are highly energized and cytotoxic substances, which endows porphyrins with excellent photodynamic therapeutic (PDT) effects.1416

Porphyrins can also create hyperthermia by taking advantage of the photon energy released in as

molecular vibration which leads to photothermal therapeutic (PTT) effect.17, 18 Tumor cells are generally more vulnerable to hyperthermia than normal cells. Unlike PDT, the occurrence of PTT only needs incident light, but not oxygen, which allows PTT to work effectively in tumor tissue that has developed an oxygen-exhausted anoxic or hypoxic microenvironment.19 PTT and PDT are highly controllable because they only ablate areas exposed to a directed light. Such selectivity guarantees the safety of phototherapies and largely alleviates side effects. PTT and PDT also enable porphyrins to synergistically combine with other therapeutic models in highly controllable, non-invasive and localized manners.


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The diagnostic uses of porphyrins are as versatile as their therapeutic utility. Porphyrins develop excellent optical imaging ability by radiatively decaying the incident energy to near-infrared fluorescence (NIRF).20,

21

As thermoelastic expansion transforms to vibrations which can be detected in forms of

sound, PTT concomitantly triggers photoacoustic imaging (PAI) to porphyrins.22-24 NIRFI and PAI render porphyrins capable of powerful imaging-guided surgery and vividly delineate the biological behaviors of porphyrin-related materials or chemicals in vivo.25-27 However, these two photo-mediated imaging functions may be hindered by limited light penetration. Deeper tissue penetration with imaging techniques like MRI, PET or SPECT can be achieved on porphyrins through metal chelation. Metal chelation gifts porphyrins with copious imaging functionalities and different metal-porphyrin complexes can be coupled with different imaging techniques. For instance, porphyrin chelation with manganese (II) or gadolinium (III) can be used as contrast agents in MRI28-30, while porphyrin chelated 64Cu and

99mTc

can be utilized

for PET and SPECT, respectively.31, 32 Although porphyrins show “all-in-one” theranostic functionalities, their clinic applications are impeded by the poor water solubility. Porphyrin molecules tend to form agglomerates or aggregates in an aqueous solution which lead to low bioavailability. Moreover, systemic administration incurs phototoxicity to skin because generic porphyrins do not selectively accumulate in tumors.33, 34 Advances in nanomedicine bring new hope to porphyrin-based cancer treatments. Nanomedicine offers i) Improved bioavailability. Nanomedicine loads or carries therapeutics and makes them suspend well in aqueous solution; ii) Better pharmacokinetics. Nanomedicine protects therapeutics from being prematurely inactivated or cleared during blood circulation; iii) Targeted therapy. Nanomedicine passively accumulates in tumors by enhanced permeability and retention (EPR) effect35, 36 or targets tumors by integration of tumor targeting ligands, therefore, largely decreases non-specific damage to normal cells and alleviates side effects; iv) Multifunctionality. Nanomedicine engages different functional modules, like imaging contrast agents, functional peptides, multi-therapeutics, etc., in one single nanoparticle. So far, various forms of nanomedicines have been developed, which include liposomes37-40, micelles41-44, nano-assemblies45-49, polymeric nanoparticles50-53, that have already achieved remarkable success in developing cancer therapies. Thus, nanotechnology can be used to improve the bioavailability, selectivity and activities of porphyrins. So far, numerous types of porphyrin-based nanomedicines have been established with superior anti-cancer therapeutic effects and excellent imaging properties. In this review, we highlight recent works on porphyrin-based nanomedicines (Figure 1), including liposomes, micelles, polymeric nanoparticles and nano-assemblies. These nanomedicines are constructed by porphyrin-based building blocks like porphyrin-lipid conjugates, porphyrin-polymer conjugates, porphyrin-peptide conjugates and porphyrin-drug conjugates. We will include the advanced therapeutic



and diagnosis functionalities of these porphyrin-based nanomedicines on cancer treatments in our discussion in addition to the future trends and potential limitations of porphyrin-based nanomedicines. We hope to provide an overall review of porphyrin-based nanomedicines and inspire scientists to develop the next-generation nanomedicines with multi-modal therapeutic and imaging capacities, which can treat the cancers precisely and effectively.

Figure 1. Schematic illustration of different porphyrin-based nanomedicines. Acronyms: MRI, magnetic resonance imaging; SPECT, single-photon emission computed tomography; PET, positron emission tomography; NIRFI, near-infrared fluorescence imaging; PAI, photoacoustic imaging; PDT, photodynamic therapy; PTT, photothermal therapy; M, metal.

Porphyrin-based liposome (Porphysome) Liposomes are one of the most successful paradigms of nanomedicines for cancer treatment. Multiple liposomes have already been developed for commercial use with examples like Doxil®, DaunoXome®, Depocyte®, Mepact® and Marqibo®. Liposomes are generally composed of phospholipids, like phosphatidylcholine (PC) and phosphatidylethanolamine (PE), which endow liposomes with high biocompatibility and biodegradability. Despite these successful applications, the efficacy and extensibility of current liposomal formulations are still limited by their simple functionality. Normally, single modal therapeutics like conventional liposomes cannot cope with the complicated physiological conditions present in heterogeneous tumors which prevent them from achieving therapeutic utility. Furthermore, liposomes typically require the addition of fluorescent tags to be traceable and to measure their pharmacokinetics and biodistributions, though the leakage of these tags from liposomes may mislead the results.


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To solve these shortcomings, Zheng’s group developed a multifunctional, porphyrin-based liposome, termed as porphysome.54 The porphysome was assembled by porphyrin-lipid conjugates (Fig. 2a) and showed an ideal particle size (~100 nm) for drug delivery (Fig. 2b). The porphysome exhibited PAI and NIRFI properties that allowed for excellent imaging of the lymph nodes and tumors on rodent models (Fig. 2c). The NIR fluorescence of porphyrin is quenched when porphysome is intact, but could be restored upon dissociation of the liposome. With this unique “OFF” and “ON” property, the NIRFI was more accurate, as background fluorescence of the optical imaging was maximally diminished, only the tumor site was lit up by NIRFI (Bottom images in Fig. 2c). Since porphyrin molecules can absorb energy from the incident laser and rapidly convert the energy to hyperthermia, intact porphysomes exhibited powerful PTT effect which completely ablated the subcutaneous tumors on mice (Fig. 2d and 2e), and largely prolonged the survival time in comparison to non-laser-treated mice (Fig. 2f). The porphysomes were enzymatically degradable and induced minimal acute toxicity in mice with intravenous doses of 1,000 mg/kg. The porphysome is also capable of loading the drug doxorubicin (DOX) with a high encapsulation rate. Zheng and co-workers also employed a similar porphyrin-lipid conjugate to construct microbubbles which showed ultrasound imaging, PAI, and NIRFI capacities.

22, 23, 55

These convertible microbubbles

could be stimulated by a low-frequency ultrasound that converted into nanoscale, liposomal nanoparticles (Fig 3a, 3b and 3c).55 This unique “from microscale to nanoscale” conversion allowed the microbubble to bypass the EPR effect and showed better accumulations in the tumor site, thus present long-lasting and clearer imaging than its non-transformable counterpart (Fig. 3d).



Figure 2. Examples of the porphysome and its diagnostic and therapeutic functionalities. a) Construction of a porphysome. b) Morphology of porphysomes observed by electron microscopy. c) Top, lymphatic mapping of porphysome-treated rat by PAI; Bottom, accumulation of porphysomes at the site of a tumor indicated by the activatable fluorescence. The PBS-treated mice were set as control. In PAI, the cyan arrow points out secondary lymph vessels, the red arrow points out the lymph node, yellow is inflowing lymph vessel. The scale bar is 5 mm. d) Time-dependent PTT effect of porphysome on mice. Laser dose (1.9 w/cm2, 60 s). e) Photographs showing the PTT effect on tumor-bearing mice that treated with porphysome with or without the laser. The PBS with laser treatment was set as control. f) The overall survival rate of tumor-bearing mice that treated with PBS with laser, porphysome alone and porphysome with laser. Adapted with permission from Ref. 54. Copyright 2011 Nature Publishing Group.


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Figure 3. Porphyrin-lipid based microbubble. a) Schematic illustration of the formation of porphyrin microbubbles with a perfluorocarbon gas core. b) Structural conversion of microbubble by low-frequency, high-duty-cycle ultrasound. c) Optical and electron microscopic graphs showing the structural conversion. d) Ultrasound imaging and PAI of microbubble on tumor-bearing mice. The left panel showed that the microbubble was not treated with conversion ultrasound, mice in the right panel were treated with conversion ultrasound. The scale bar is 2 mm. Adapted with permission from Ref. 55. Copyright 2015 Nature Publishing Group.

As aforementioned, porphysomes showed NIRFI capacity due to the embedded porphyrin molecule and the fluorescence quenching of porphyrin creates NIRF images with minimal background. However, the quenching behaviors may confuse the imaging feedbacks because the real biodistributions of porphysomes are not always visualized. Moreover, the increased fluorescence caused by the dissociation of the porphysome may be mistaken for increased accumulation of porphysomes. To solve these drawbacks, Zheng’s group developed a Förster resonance energy transfer (FRET) based porphysome (FRETysome), which could fluorescently report the structural state of the porphysome by FRET in a realtime manner.56 They doped a porphyrin-based FRET pair into a single porphysome (Fig. 4a). In this way, the fluorescence readouts were mainly from acceptor if the FRETysome was intact, while the donor’s fluorescence would dominate the imaging results if the FRETysome dissociated. In comparison with the porphysome described in Fig. 2, the FRETysome showed better NIRFI in mice model and the FRETysome was deemed superior for in vivo imaging (Fig. 4b). In a tumor-bearing mice model, the



NIRF signal of FRETysome tapered off over time, which vividly reported the location and structural status of liposomes in a real-time manner (Fig. 4c and 4d). In comparison, the porphysome showed no fluorescence changes and was not able to indicate the real status of the nanostructure. By integration of FRET into a porphysome, Zheng’s group created a novel imaging technique to vividly visualize the liposome structural degradation kinetics in a mouse model. Porphyrin molecules smartly revitalized the liposomes with excellent therapeutic efficacy and myriad of extensibilities. The porphysome was a fascinating, multifunctional theranostic regime for cancer treatments, Zheng and co-works have successfully implemented them into various kinds of tumor models for phototherapies (photodynamic and photothermal therapy)19, 54, 56-59, NIRFI56, 60-62, MRI57, 63, 64, PAI61, 65, 66, SPECT63, and PET60, 62, 67.

Figure 4. The FRETysome and its imaging properties. a) Schematic illustration of the energy transfer in FRETysome. b) Subcutaneous imaging of FRETysomes. P, Porphysomes; BP, Bchl-lipid doped porphysomes. Dashed circle, Matrigel control. c) Ratiometric fluorescence of tumor-bearing mice treated with FRETysome (upper panel) and porphysome (lower panel). d) The plot of fluorescence ratio over time in animals treated with FRETysomes or porphysomes (red). *, p < 0.001, ∥, p < 0.005. Reproduced with permission from Ref. 56. Copyright 2015 American Chemical Society.

Porphyrin-based Micelles Nanomedicinal micelles are commonly assembled by a cluster of amphiphile compounds in aqueous solution, in which the hydrophobic head tends to avoid water phase, while the hydrophilic tail faces to


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water, thus form a stable core-shell nanostructure. The major differences between micelle and liposomes are i) micelles are monolayer in structure while liposomes are generally formed by bilayer or even multilayer lipids. ii) micelles are capable of loading hydrophobic drug due to the hydrophobic core, whereas liposomes are usually employed for the delivery of hydrophilic payloads. Generally, micelles are more stable and smaller in size than liposome. Since many chemotherapeutics are water-insoluble, the hydrophobic core of micelles represents an optimal reservoir for the formulation and delivery of these drugs. Therefore, micelles have enormous potential for clinical use but most micelles face problems like traceability and single drug loading that limit their anti-tumor activities. As hydrophobic molecules, porphyrins are ideal building blocks for micellar structure construction and can add their excellent photodynamic/photothermal therapeutic effects and powerful imaging capacities onto the drug delivery abilities of micelles. By incorporating porphyrins as its hydrophobic building blocks, a multifunctional micelle can be constructed like porphysome. To this end, our group developed an “all-in-one” micelle (nanoporphyrin) with powerful therapeutic and imaging capacities by integrating porphyrin molecules into nanostructure (Fig. 5).68 To build nanoporphyrin, we replaced four cholic acid molecules with porphyrin derivative (pyropheophorbide a, Fig. 5a) in the telodendrimer we developed.6972

In a spontaneous breast cancer model, the NIRF from porphyrin molecules indicated that

nanoporphyrin preferentially accumulated in spontaneous tumors (Fig. 5b). The tumor-oriented NIRF clearly differentiated the boundary between the normal tissue and tumor tissue with high resolution; even a tiny tumor with a size of 0.006 mm2 could be fluorescently delineated. As an ideal metal chelator, porphyrin can chelate different metals for high-resolution imaging. By chelating Gd(III) to nanoporphyrin for MRI, the bright T1 MR signal delineated a time-dependent tumor accumulation behavior of nanoporphyrin (Fig. 5c). By chelation of

64Cu,

PET imaging showed similar tumor accumulation

behaviors to that MRI observed (Fig. 5d). We also achieved dual-modal imaging of MRI and PET, and MRI-PET combinatorial imaging by chelating both

64Cu

and Gd (III) in the building blocks (Fig. 5e).

Nanoporphyrin also showed excellent PTT (Fig. 5f) and PDT (Fig. 5g) on tumor-bearing mice. To pursue the synergistic effect between the chemotherapy and phototherapies, the chemotherapeutic drug DOX was encapsulated in nanoporphyrin. The nanoporphyrin-DOX combination produced a remarkable obstruction of tumor progression (Fig. 5h). Thus, porphyrin-based micelles exhibit promising capabilities and exciting potentials as highly versatile multimodal theranostic agents for use against cancers. The nanoporphyrin micelle is a successful cancer treatment paradigm which has been employed to treat different tumor models, like prostate cancer73, bladder cancer74-76 and colon cancer77.



Figure 5. The porphyrin-based telodendrimer micelle (nanoporphyrin) is a promising theranostic agent. a) Schematic illustration of the nanoporphyrin and the functionalities of each component. b) NIRFI of the spontaneous mammary cancer on transgenic mice. c) MRI, d) PET imaging and e) PET-MRI combinatorial imaging of the tumor-bearing mice that treated with nanoporphyrin (chelated with Gd (III) or 64Cu). f) Photoinduced hyperthermia (PTT) and g) ROS production (PDT) of nanoporphyrin on transgenic mice. h) Tumor volume changes in tumor-bearing mice (n=6) treated with porphyrin-based telodendrimer micelles and the controls. The red arrows denote light treatments, and the black arrows indicate the intravenous injections. White arrows point out the tumor sites. Reprinted with permission from Ref. 68. Copyright 2014 Nature Publishing Group.


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Porphyrin-based micelles exhibit excellent stability because porphyrin molecules are highly hydrophobic, and their planar molecular structure tends to strongly pack together by “π-π” stacking and hydrophobic force. These properties also aid in the encapsulation of hydrophobic drugs. Nie’s group developed a porphyrin-based micelle (PM-DOX-TAX)78 that co-loaded two chemotherapeutics (DOX and docetaxel) to achieve excellent imaging and synergistic therapeutic effects (Fig. 6a). PM-DOX-TAX was able to report its own subcellular distributions and in vivo biodistributions by NIRFI (Fig. 6b). The PM-DOXTAX also showed photo-induced hyperthermia (Fig. 6c), which could effectively abate the tumor in mice models by the synergistic therapeutic effect with chemotherapies.

Figure 6. The assembly, imaging and therapeutic effects of the porphyrin-based, dual-drug loaded micelle (PM-DOX-TAX). a) The self-assembly of the PM-DOX-TAX. b) Optical imaging of the micelle in vitro and in vivo. c) Photothermal effect of the PM-DOX-TAX. Reprinted with permission from Ref. 78. Copyright 2016 Elsevier B.V.

As discussed previously, porphyrins suffer from fluorescence quenching when they are trapped in a highly stacked nanostructure or quenched by metal chelation, which greatly hinders the applications of porphyrins in multi-modal imaging. Porphyrin-based micelles can solve this problem by employing other loaded dyes to pursue multi-modal imaging abilities. Liu’s group developed a multifunctional nanomicelle (IR825@C18PMH-PEG-Ce6)79 by introducing a NIRF dye (IR825) into porphyrin-based micelle (Fig. 7a). IR825@C18PMH-PEG-Ce6 showed intriguing multi-modal imaging functionalities (Fig. 7b, 7c and 7d), in which the porphyrin chelated with Gd(III) offers MRI contrast enhancement, and IR825 contributed to bright NIRFI and high-resolution PAI. The triple modal imaging capabilities in one single micelle could precisely reflect the in vivo biological behaviors of IR825@C18PMH-PEG-Ce6. With a combination of porphyrin and IR825, the micelle also achieved controllable PDT and/or PTT, which effectively ablated tumors in a mouse model (Fig. 7e and 7f).



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Figure 7. Porphyrin-based multifunctional micelle (IR825@C18PMH-PEG-Ce6). a) Design of the IR825@C18PMH-PEG-Ce6. b) NIRFI, c) MRI and D) PAI of IR825@C18PMH-PEG-Ce6 micelle. The white arrows in c) point out heart. White dashed circle denotes tumors. e) PTT effect of IR825@C18PMH-PEG-Ce6. f) Anti-tumor effect of IR825@C18PMH-PEG-Ce6 with controllable PDT and/or PTT. Adapted with permission from Ref. 79. Copyright 2016 Wiley-VCH.

Porphyrin-based polymeric nanoparticles Polymeric nanoparticles are one of the most investigated nanomedicines for cancer therapy. They are generally constructed from different biocompatible polymers and have shown a great versatility for drug loading, imaging tags, and surface modifications amongst numerous capabilities. Knowing the in vivo behaviors of the polymeric nanoparticles can guide them achieving precisely medicinal applications on cancer therapy. As multifunctional molecules with various imaging capabilities, porphyrins have intensively evaluated as components of polymeric nanoparticles to render nanoparticles with intriguing diagnostic functionalities. Cai and co-workers employed a

64Cu

chelated porphyrin derivative (meso-

tetra(4-carboxyphenyl)porphyrin, TCPP) as a core on which to attach PEG polymers with different molecular weights (Fig. 8a).80 As designed, the polymeric nanoparticles with different PEGylations exhibited varied sizes but identical surfaces. TEM micrograph showed that sizes of the polymeric nanoparticles were 3.6, 5.4, 8.8, and 14.2 nm for TCPP-PEG2K, TCPP-PEG5K, TCPP-PEG10K, and TCPPPEG30K, respectively (Fig. 8b). These nanoparticles were employed to systemically investigate the in vivo behaviors that impacted by size. With PET imaging, they found TCPP-PEG10K NPs exhibited the best pharmacokinetics (Fig. 8c), higher tumor accumulation (Fig. 8d) and lower restraint in the reticuloendothelial system (Fig. 8e). The NIRF imaging from porphyrin also showed that the accumulation of TCPP-PEG10K NPs was lower in the liver and kidneys, but higher in the tumor. The


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TCPP-PEG10K NPs also showed potent tumor ablation by photodynamic therapy. By virtue of the PET imaging capabilities of the

64Cu-chelated

porphyrin, the detailed behaviors of the nanoparticles were

precisely unveiled at in vivo level. This provided bio-information that optical imaging is hard to precisely obtain and showed great potential for guiding the future designing of the clinic-bound nanomedicine.

Figure 8. The porphyrin-based polymeric nanoparticles (TCPP-PEG) and their PET imaging-guided biological behaviors. a) The design and synthesis of the TCPP-PEG. b) TEM micrographs showing the morphology and size of the porphyrin-based polymeric nanoparticles with different PEGylations. Time-activity curves of 64CuTCPP-PEG (2k, 5k, 10k and 20k) in different major organs of c) blood, d) tumor, and e) liver. Adapted with permission from Ref. 80. Copyright 2017 Wiley-VCH.

Porphyrin molecules have been widely employed for phototherapeutic design, as their absorption distributes within the NIRF range which is feasible to the tissue penetration. For photo-active therapeutics and diagnostics, longer absorption wavelengths are beneficial because they penetrate deeper into tissue and are less likely to be photobleached. However, the absorption of porphyrins is generally below 700 nm,81-86 which still have large space to be improved. Researchers have tried to redshift the absorption beyond 700 nm to improve the photostability of porphyrins, increase their tissue penetration, and strengthen their phototherapeutic effects. To this end, Liu’s group employed porphyrin derivatives as building blocks to synthesize a conjugated copolymer (PorCP) with improved properties.87 Intramolecular charge transfer (ICT) dominated the optical properties of the PorCP polymer which redshifted the absorbance of the complex to ~800 nm and increased its photothermal conversion efficiency (PCE). They



assembled PorCP into nanoparticles with DSPE-PEG (Fig. 9a), which showed spherical morphology (Fig. 9b) with ~800 nm UV absorption (Fig. 9c). The porphyrin molecules within the PorCP NPs exhibited good photostability, a high extinction coefficient, and strong PCE. The PorCP NPs also exhibited an effective PTT effect on tumor ablation both in vitro and in vivo in a zebrafish model (Fig. 9d and 9e). Thus, they greatly improved the photophysical properties of the porphyrin with a smart energy transfer system and created a powerful cancer treatment. Overall, this is a good example of a model for the development of porphyrin-based nanomedicines with more powerful photo-mediated functionalities.

Figure 9. Porphyrin-based polymeric nanoparticles (PorCP NPs). a) Schematic illustration of the PorCP NPs; b) Size distributions (DLS) and morphology (TEM) of the PorCP NPs. c) UV–vis spectrum of PorCP NPs in an aqueous medium. d) 3D fluorescence images of zebrafish liver tumor groups before and after 1 day of different treatments. Group 1: blank control without NPs injection and NIR laser irradiation, Group 4: treated with PorCP-Tat NPs and 5 min of NIR laser irradiation. Group 5: treated with PorCP-Tat NPs and 10 min of NIR laser irradiation. Laser dose: 808 nm, 0.5 w/cm2. e) The relative tumor volume changes in each group. Adapted with permission from Ref. 87. Copyright 2016 Wiley-VCH.

Porphyrin-peptide based nanoparticles


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Peptides can realize different chemical and biological functions by changing the sequence and composition of amino acids. Through these amino acid modifications, peptides can be tailored to various kinds of self-assemblies and exhibit various active biological functionalities. In light of these intriguing merits, peptides were conjugated with porphyrins to construct versatile, cancer-targeting nanomedicines. Peptides not only provide the driving force for self-assembly to improve the bioavailability and biocompatibility of porphyrins, but also contribute their unique biological activities to the overall nanoparticle. Zhang’s group developed porphyrin-peptide based nanoparticles (PPK), which contained a porphyrin conjugated with a mitochondria-targeted, proapoptotic peptide (Fig. 10a).88 In PPK nanoparticles, the porphyrin provided the hydrophobic driving force and the peptide provided the hydrophilic driving force for self-assembly. The porphyrin portion of the structure also contributed NIRF for optical imaging and PDT effect for anti-cancer activity to the PKK. The peptides could target the nanoparticle to the mitochondria and added cell apoptosis activities to the PKK. This created a PKK nanoparticle where the combination of the porphyrin and peptide lead to a synergistic activity that was greater than either portion alone. Their pharmacokinetics were also highly improved and the intrinsic NIRF from porphyrins clearly delineated the tumor accumulation and biodistributions of PPK (Fig. 10b and 10c). The PKK was able to effectively slow tumor progression on a mouse model, due to the powerful synergistic effects of porphyrin-induced PDT and peptide-mediated targeting and proapoptotic functions (Fig. 10d).

Figure 10. The porphyrin-peptide based nanoparticle (PPK). a) Schematic illustration of the self-assembly and biological functionalities of the PPK; b) NIRFI of the PPK in tumor-bearing mice. The white arrows indicate tumors; c) Biodistributions of the PPK indicated by NIRF of the porphyrin. d) Anti-tumor effect of the PPK. The black arrows denote the administration of PPK. Adapted with permission from Ref. 88. Copyright 2015 Wiley-VCH.



Enhancement of the PTT effects alone can be used to create powerful therapies that will be effective in hypoxic tumor microenvironments where other activities like PDT cannot work. Yan and the co-workers developed photothermal peptide-porphyrin nanodots (PPP-NDs) by conjugating porphyrin derivative with a short peptide (Fig. 11a and 11b).89 In PPP-NDs, peptide (FF) provided the driving force for selfassembly and porphyrin contributed to the photoacoustic imaging (Fig. 11c) and PTT effect (Fig. 11d). The peptide-driven self-assembly process tightly packed the porphyrin subunits together which maximized the energy released by the PTT effect. With the powerful PTT and EPR-mediated tumor accumulation, PPP-NDs showed excellent anti-tumor effect both in vitro (Fig. 11e) and in vivo (Fig. 11f).

Figure 11. Porphyrin-peptide nanodots (PPP-NDs) created by Yan and coworkers exhibit powerful PTT effects. a) Self-assembly of the PPP-NDs. b) TEM image of PPP-NDs. c) PAI of PPP-NDs on tumor-bearing mice. Tumor sites were indicated by white circles. d) PTT of PPP-NDs on tumor-bearing mice. e) Cell viability of MCF-7 cells treated PPP-NDs with or without laser. f) anti-tumor effect of PPP-NDs. Reproduced with permission from Ref. 89. Copyright 2017 American Chemical Society.

Porphyrin derivatives covalently conjugated to peptides can readily form nanoparticles which improves tumor targeting and blood circulation. Nonetheless, the PDT and NIRFI properties are largely blunted if the porphyrin molecules are trapped in a nanostructure. The development of controllable porphyrin-based nanomedicines which remain stable during systemic circulation but responsively release the porphyrin in specific locations could realize more theranostic functionalities. Inspired by metalloproteins that exist in


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nature, Yan and the co-workers smartly “conjugated” porphyrins and peptides with metal coordination and developed porphyrin-based supramolecular metallo-nanodrugs90. The metallo-nanodrugs can be made by cooperative coordination of small peptides (Fmoc-H or Z-HF) and porphyrin (chlorin e6, Ce6) with Zn2+ (Fig. 12a). Promisingly, the metallo-nanodrugs were stable in physiological conditions and showed excellent stability during blood circulation. The metallo-nanodrugs also exhibited high susceptibility to certain stimulation in tumor cells and rapidly released the Ce6 in a burst manner in the presence of acidic pH (Fig. 12b) and GSH (Fig. 12c). By virtue of the controllable stability, the nanodrugs showed prolonged blood circulation time than the free Ce6 (Fig. 12d). Strikingly, the metallo-nanodrugs, exhibited an extremely effective therapeutic effect and they could completely eradicate the tumor in a short time due to the unleashed PDT effect (Fig. 12e). Yan and the coworker have also developed numerous other porphyrin-peptide based nanomedicines. They introduced Mn2+ coordination in between Ce6 and Fmoc-L-lysine and developed a minimalist multifunctional theranostic nanoplatform which showed excellent MRI-guided tumor photodynamic therapy91. By doping different short-peptides with porphyrin (Ce6), they also fine-tuned the self-assembly of the nanostructures, which yielded nanoparticles with tunable size, adjustable photosensitizer loading, and controllable responsiveness.92

Figure 12. Porphyrin-peptide based supramolecular metallo-nanodrugs (Fmoc-H/Zn2+/Ce6 and ZHF/Zn2+/Ce6 nanoparticles). a) Schematic illustration of the self-assembly of the porphyrin-peptide based



supramolecular metallo-nanodrug. b) pH and c) GSH responsiveness of the metallo-nanodrugs. d) Pharmacokinetics of the supramolecular metallo-nanodrugs in comparison with free Ce6. e) Anti-tumor efficacy of the metallo-nanodrugs. Adapted with permission from Ref. 90. Copyright 2018 American Chemical Society.

With the simple conjugation of porphyrin and peptide, the possible applications of the nanoparticles are greatly expanded. The porphyrins provided the driving force of assembly and versatile theranostic functions to the nanoparticles and the peptides contributed the driving force to fine-tune the self-assembly and their unique biological functions (targeting, penetration, cytotoxicity, etc.). Taken together, these combined properties synergistically improved the efficacy of the porphyrin-peptide conjugates towards cancer therapy. Porphyrin-based small molecule nanomedicines Despite the aforementioned nanomedicines have achieved great success in drug delivery for cancer treatment but they rarely reach high drug loading efficiency (DLE93). Generally, the DLE of traditional nanomedicines, such as liposome and micelles, doesn’t exceed 20%, which means the formulations are composed of 80% non-pharmaceutical ingredients or more to deliver less than 20% active pharmaceutical ingredients.72,

94, 95

To improve DLE, some drug-drug conjugated amphiphiles have been developed to

construct small molecule nanomedicines.96-100 These small molecule nanomedicines have shown nearly 100% DLE, but these studies have mostly been done with a single therapeutic model and have shown less efficacy toward heterogeneous tumors. Once again, these nanomedicines lack of traceability and their biodistribution and pharmacokinetics are not easily measured. Porphyrin derivatives are mostly hydrophobic and their rigid, planar structures tend to stack together, which is optimal to provide the driving force for self-assembly. As the porphyrins show excellent photomediated therapeutic effect, they also can be considered as pharmaceutical ingredients and make porphyrin-based amphiphiles possibly reach 100% DLE. Meanwhile, the porphyrin molecules may cooperate with some fluorescent drugs and present unique optical behaviors. The drug release of small molecules nanomedicine could be expedited by the porphyrin molecules, as the photo-induced hyperthermia can boost the molecular movements. With these ideas in mind, our group developed a full active pharmaceutical ingredients nanoparticle (FAPIN) which consists of porphyrin-drug amphiphiles and contained 100% pharmaceutical agents (Fig. 13).101 This FAPIN contained a hydrophobic porphyrin derivative (pheophorbide a, Pa) conjugated with a fluorescent, hydrophilic drug Irinotecan (Ir) to form an amphiphilic molecule (PaIr, Fig. 13a). The PaIr amphiphile assembled into pomegranate-liked nanostructure (PaIr NPs, Fig. 13b) with a diameter of ~80 nm (Fig. 13c). Since Pa and Ir are both


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fluorescent, a unique energy transfer relay happened in PaIr NPs, which quenches the fluorescence of both Pa and Ir. The fluorescence of Pa can be recovered upon the collapse of the nanostructure, while the fluorescence of Ir is restored when the Ir was released. The energy transfer relay imparted PaIr NPs with a self-indicating feature which can monitor the nanostructure status and drug release pattern in a real-time manner. The PaIr NPs experienced continuous nanostructure loss within the cells as Ir was gradually released with time elapse (Fig. 13c and 13d). The photo-induced hyperthermia contributed by Pa expedited the structure collapse and drug release, which can promote the efficacy of the chemotherapy. The PaIr NPs were also able to indicate their biodistributions in mice models because of the powerful imaging capacities of porphyrin. Preferential accumulation of the PaIr NPs at tumor sites was also observed and laser treatment of the tumor resulted in an increased fluorescence due to the expedited loss of the nanostructure (Fig. 13e). By chelation of Mn2+ to PaIr NPs, the tumor ablation effect of PaIr NPs could be monitored in real time manner by MRI (Fig. 13f). The PaIr NPs lead to excellent PTT and PDT effects (Fig. 13g and 13h) which extensively slow down or ablate the patient-derived brain tumor xenograft due to the synergistic effect of phototherapies and chemotherapy (Fig. 13i). With only two doses of PaIr NPs, 3 out of 6 mice were completely cured. The FAPIN was simple yet highly functional, with only two simple molecules conjugated together, and we seamlessly integrated PDT, PTT, chemotherapy, NIRFI and MRI in one single nanoparticle, and achieved promising anti-tumor effect.



Figure 13. The porphyrin-based FAPIN offered a promising theranostic platform with enhanced anti-tumor effects. a) Synthesis of the porphyrin-drug amphiphile. b) TEM micrograph of FAPIN. Scale bar is 100 nm. c) In vitro dissociation of the FAPIN was indicated by fluorescence recovery of porphyrin (Pa). d) In vitro drug releasing process was indicated by fluorescence of drug (Ir). e) NIRFI capacity of FAPIN. f) The PTT-induced tumor regression was indicated by time-dependent MRI. In e) and f), the red lightning symbols denote laser treatments. g) PTT and h) PDT effect of FAPIN. i) Anti-tumor effect of FAPIN and the controls. The high laser dose (H) is 0.8 w/cm2 for 3 min, and low dose (L) is 0.4 w/cm2 for 3 min. *p < 0.05; **p < 0.01; ***p < 0.001. Reprinted with permission from Ref. 101. Copyright 2018 Elsevier B.V.

In spite of those excellent characters, small-molecule nanomedicines like FAPIN still face some shortcomings. The driving forces of the self-assembly are mainly contributed by hydrophobic force or/and “π-π” stacking, which may not be stable enough during systemic circulation. Meanwhile, the bare drug surface on the nanomedicine generally yields poor pharmacokinetics due to its vulnerability to


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opsonization.102, 103 To tackle these problems, our group developed a Trojan-Horse nanotheranostic with size/charge dual transformability, multimodal therapeutics and imaging capacities, and extremely high efficacy (Fig. 14).104 Inspired by FAPIN, we conjugated Pa with DOX by a hydrazone bond to form a porphyrin-drug amphiphile (PhD, Fig. 14a) that can be assembled into FAPIN-like structure (PhD NP). To make the FAPIN-like nanostructure more stable, a dual-aldehyde functionalized PEG was introduced to cross-link the whole assembly and form a PEG surface with Schiff bases (Fig. 14b). With the PEGylation, the surface amine groups on PhD NPs were shielded and the PhD NPs thus showed lower surface charge (Fig. 14c), which reduced opsonization during circulation and improve the pharmacokinetics of the nanoparticles. When PhD NPs encountered the tumor microenvironment (TME), the slightly-lowered pH (6.8) enabled detachment of the PEG by cleaving the Schiff base. Once PEG was peeled off, the nanoparticles surface charge was elevated due to the exposure of the amine groups (Fig. 14c), while the small nanoparticles in the Trojan Horse can also be released and begin a size transformation (Fig. 14d). The photo-mediated therapy was highly controllable, the PhD NPs only ablated a specific area that light-directed (Fig. 14e). After the transformation, the small size and strong positive charge of the nanoparticles allowed the nanoparticles to penetrate deeper in tumor tissue and get internalized into cancer cells more effectively in comparison to their non-transformable counterparts (Fig. 14f). Furthermore, the PhD NPs showed excellent NIRFI, MRI, PDT and PTT diagnostic and therapeutic capacities similar to those observed with FAPIN. NIRFI and MRI were able to visualize the biodistributions and tumor accumulations of nanoparticles, while the PDT and PTT effects synergistically worked with the chemotherapeutic effects of DOX. With three doses of PhD NPs, a 100% complete cure rate was achieved an oral cancer mouse model with laser treatment (Fig. 14g). Even without the phototherapeutic effect with light treatment, the PhD NPs showed similar anti-tumor efficacy to a commercial DOX nanoformulation (Doxil), due to their deeper penetration in tumor and elevated uptake in cancer cells.



Figure 14. The porphyrin-based “Trojan Horse” nanotheranostics. a) The building blocks and their corresponding functionalities. b) Self-assembly of the nanoparticle. c) TEM microphages captured the size transformation. The scale bar of 0 h is 10 nm; 1 h and 12 h are 30 nm. d) The charge transformation evaluated by dynamic light scattering. e) Laser-directed phototherapeutic effect on OSC-3 oral cancer cells, the yellow lightnings indicate the laser-treated areas. The live cells were indicated by DIC6(3), the dead cells stained with propidium iodide (PI). f) The microscopic distribution of transformable nanoparticles (pPhD NPs) in tumor tissue in comparison with the non-transformable pPhD NPs (NT-pPhD NPs) to prove the superior tumor penetrations. The scale bar is 50 μm. g) The tumor volume changes on tumor-bearing mice model. The black arrows denote the intravenous administration, and red ones point out the tumor treated by laser. *p < 0.05; **p < 0.01; ***p < 0.001. Adapted with permission from Ref. 104. Copyright 2018 Nature Publishing Group.


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In the design of porphyrin-based small molecules nanomedicine, Yan and the coworkers developed a carrier-free, chemophotodynamic dual nanodrug (Ce6-DOX NP) by simply co-assembling porphyrin and chemotherapeutic drugs without any chemical reaction.105 They smartly “conjugated” Ce6 with DOX via electrostatic interaction between the carboxyl groups (on Ce6) and amine groups (on DOX), then assembled them into nanodrug through hydrophobic force and “π-π” stacking among Ce6 and DOX molecules (Fig. 15a). The resulting Ce6-DOX NPs not only showed uniform particle size, robust stability, and bright in vitro and imaging capacities, but also exhibited synergistic chemo-photodynamic therapy which could effectively ablate the tumor (Fig. 15b and 15c). This porphyrin-based nanodrug offers a safe and green method for nanomedicine preparation, which avoids the use of organic chemicals that may concomitantly bring out biological toxicity.

Figure 15. The porphyrin-based, carrier-free, chemophotodynamic dual nanodrug (Ce6-DOX NP). a) The self-assembly of the Ce6-DOX NP. b) Anti-tumor efficacy of the Ce6-DOX NPs. The arrows indicate the laser treatment (150 mW/cm2 for 10 min). c) Optical images of the Ce6-DOX NPs treated tumors that excised from the mice on day 14. Red circles indicate the complete-cured tumor. Adapted with permission from Ref. 105. Copyright 2016 American Chemical Society.

In the design of porphyrin-based small molecule nanomedicines, the porphyrins showed promising therapeutic and diagnostic capabilities in cancer treatment. Moreover, porphyrins could establish an energy transfer system with drugs to visualize the subcellular behaviors of the small molecule nanomedicines and the PTT effect of porphyrins also enables a photo-expedited drug release process. In addition, porphyrins provided the hydrophobic driving force for the self-assembly of the nanoparticle



while also fluorescently indicating the breakdown of the nanomedicine and release of the therapeutic agent. Perspective and conclusions This review highlights the recent studies which have investigated porphyrin-based, multifunctional nanomedicines and their therapeutic and diagnostic activities. There are many types of porphyrin-based nanomedicines and this review has focused on liposomes, micelles, polymeric nanoparticles, porphyrinpeptide nanoparticles and small-molecules nano-assemblies. The building blocks of these nanomedicines are mainly conjugates of porphyrin and other molecules. Besides these conjugate-based nanomedicines, porphyrin molecules have been extensively loaded or doped into nanostructures and have conferred nanomedicines with myriads of theranostic merits.106-111 Porphyrin derivatives largely extend the functionalities of nanomedicine by i) displaying intrinsic NIRF for optical imaging; ii) converting light into cytotoxic ROS for PDT; iii) releasing the light energy to generate photo-induced hyperthermia for PTT; iv) PAI due to thermoelastic expansion; v) chelating Mn2+ for MRI and other metal isotopes for PET or SPECT; vi) providing driven force for self-assembly with their rigid, planar, hydrophobic chemical structure, either by hydrophobic forces or “π-π” stacking between the porphyrin molecules. Although extensive studies have been conducted on the use of porphyrin derivatives for the creation of nanomedicines with copious theranostic functionalities, porphyrin-based nanomedicines still have some imperfections. Since the therapeutic effects of porphyrins, including PDT and PTT, rely on incident light energy, limited light penetration can hinder the applications of porphyrin-based nanomedicines. These porphyrin-based nanomedicines may only be applicable to light-accessible tumors, like those developed on skin, oral cavity, bladder or those reached by light catheter112-114. The optical imaging properties also face the same hurdle because light can’t reach deep-seated tumor to invoke NIRF. To tackle the light penetration problem, one possible strategy is introducing an energy transfer system in the nanomedicine. Either a bioluminescent or chemiluminescent molecule may be conjugated with porphyrins and once their luminescence is triggered by a substrate, their emissive energy can be transferred to the adjacent porphyrins to elicit the photo-related therapeutic and diagnostic functionalities. In addition, X-ray has the superb ability to penetrate tissue and some inorganic materials can absorb energy from X-rays and release fluorescence.115-118 If we incorporate these materials with porphyrins in an energy transfer system, porphyrin-based nanomedicines can then be superpowered by X-rays and realize unlimited penetrations in human body, theoretically, which will largely broaden their therapeutic and diagnostic applications in cancers. The balance between particle stability and payload release is also important because the porphyrin-based nanomedicine should be stable enough to bear the shearing force during the systemic


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circulation but needs to be fragile in the tumor site. A stimuli-responsive cross-linkage may be a good solution as the nanomedicine can be bundled with responsive chemical bonds to guarantee the stability of the nanostructure during the circulation in blood stream.72, 119 Once accumulating in the tumor site, the responsive cross-linkage can be readily broken down by the factors that only exist in tumor microenvironment, and release the payloads for cancer treatment. Since porphyrins dissipate the light energy into pathways with different therapeutic and diagnostic functions (PTT, PDT, NIRFI), a precise balance is needed because these processes are not always mutually synergistic. For example, PDT and NIRFI can be blunted if PTT dominates the photo-induced effect. The task of balancing these photorelated effects to achieve the ideal theranostic effect is also a challenge needs to be continually addressed. The phototherapies are highly controllable because they ablate tumor only within a confined area. Therefore, porphyrin-based nanomedicines currently have limited applications on the treatment of cancer metastases. To circumvent this limitation, porphyrin-based nanomedicines may be combined with immunotherapy, as phototherapy is reportedly able to stimulate anti-tumor immunity including the “abscopal effect” to improve systemic cancer treatment.120-124 Porphyrin-based nanomedicines have shown powerful phototherapeutic effects which have been extensively employed for cancer ablation and already reached considerable efficacy in the light-accessible tumor models. In the future, researchers may pay more attention to systemic effect of porphyrin-based nanomedicines, either by combining them with other therapeutic modalities or extending the porphyrins themselves to venture out of the “confined area”.



Acknowledgment We thank the financial support from NIH/NCI (R01CA199668), NIH/NICHD (R01HD086195) and UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the National Cancer Institute (NCI P30CA093373).


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Porphyrin-Based Nanomedicines for Cancer Treatment - Bioconjugate

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