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Perfluorocarbon-based O2 nanocarrier for efficient photodynamic therapy

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Abstract

Tumor hypoxia has been considered as one of the major factors that limits the efficiency of photodynamic therapy (PDT), in which oxygen is needed to generate singlet oxygen for cell destruction. Inspired by the excellent O2 carrying ability of perfluorocarbon molecules in artificial blood, we perpared a series of polymer micelles with perfluorocarbon core to carry both photo-sensitizer and O2 to the tumor site, aiming to improve PDT efficiency. We found that the accelerated generation of 1O2 correleted with the increased perfluorocarbon amount. In vitro cell study further showed that the new perfluorocarbon formulation not only improved the production of 1O2, thereby enhancing the photodynamic therapy efficiency, but also significantly reduced cell toxicity when compared with the one without these perfluoro units. This work provides a new option for improving PDT efficiency with the new perfluorocarbon-incorporated nanoplatform.

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... In blood, oxygen extraction from PFC emulsions can reach 90% of oxygen content [28]. However, oxygen release can also be controlled by external stimuli, such as irradiation for photodynamic therapy (PDT) [29]. Niu and colleagues used PFC-containing N-isopropylacrylamide-based hydrogels to enhance cell survival by preventing occurrence of anoxia in hydrogels [30]. ...
... The hydrogels had higher oxygen levels and promoted the survival and proliferation of mesenchymal stem cells (MSCs). Yet, the duration of oxygen release remained relatively short and the control over the oxygen release was poor [29]. ...
Article
Oxygen is essential for the survival, function, and fate of mammalian cells. Oxygen tension controls cellular behaviour via metabolic programming, which in turn controls tissue regeneration, stem cell differentiation, drug metabolism, and numerous pathologies. Thus, oxygen-releasing biomaterials represent a novel and unique strategy to gain control over a variety of in vivo processes. Consequently, numerous oxygen-generating or carrying materials have been developed in recent years, which offer innovative solutions in the field of drug efficiency, regenerative medicine, and engineered living systems. In this review, we discuss the latest trends, highlight current challenges and solutions, and provide a future perspective on the field of oxygen-releasing materials.
... As shown in Figure 7A, all of them could be classified into four categories. We could find that current research directions for CPDT mainly focus on studies on nanomaterial technology (Eisenbrey et al., 2018;Hu et al., 2019;Xavierselvan et al., 2021), clinical applications (Leroy et al., 2021;Yano et al., 2021), mechanism (Juarranz et al., 2008;Robertson et al., 2009), and photosensitizers (Zhang, et al., 2018). Besides that, in the overlay visualization map of keywords co-occurrence analysis, VOSviewer could impart keywords with different colors according to their AAY. ...
... In recent years, with spectacular advances in the development of nanomaterials and nanotechnology for targeted drug delivery, various oxygen-carrying nanoparticles and oxygen-generating nanomaterials have been developed for oxygen delivery inside the tumor. Among them, the oxygencarrying nanosystems include oxygen-carrying nanobubbles and nanodroplets (Eisenbrey et al., 2018;Xavierselvan et al., 2021), perfluorocarbon-based O 2 nanocarrier (Cheng et al., 2015;Hu et al., 2019), and hemoglobin-polymer conjugate as nanocarrier , and so on. Whereas the oxygen-generating nanosystems include MnO 2 nanoparticles (Lin et al., 2018), nonfluorinated chitosan-chlorin e6/catalase nanoparticles (Chen et al., 2015;Sahu et al., 2020), biomimetic nanothylakoids (Ouyang et al., 2018), etc. ...
Article
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A growing body of research has illuminated that photodynamic therapy (PDT) serves as an important therapeutic strategy in oncology and has become a hot topic in recent years. Although numerous papers related to cancer PDT (CPDT) have been published, no bibliometric studies have been conducted to summarize the research landscape, and highlight the research trends and hotspots in this field. This study collected 5,804 records on CPDT published between 2000 and 2021 from Web of Science Core Collection. Bibliometric analysis and visualization were conducted using VOSviewer, CiteSpace, and one online platform. The annual publication and citation results revealed significant increasing trends over the past 22 years. China and the United States, contributing 56.24% of the total publications, were the main driving force in this field. Chinese Academy of Sciences was the most prolific institution. Photodiagnosis and Photodynamic Therapy and Photochemistry and Photobiology were the most productive and most co-cited journals, respectively. All keywords were categorized into four clusters including studies on nanomaterial technology, clinical applications, mechanism, and photosensitizers. “nanotech-based PDT” and “enhanced PDT” were current research hotspots. In addition to several nano-related topics such as “nanosphere,” “nanoparticle,” “nanomaterial,” “nanoplatform,” “nanomedicine” and “gold nanoparticle,” the following topics including “photothermal therapy,” “metal organic framework,” “checkpoint blockade,” “tumor microenvironment,” “prodrug” also deserve further attention in the near future.
... Other photosensitizers proposed for image-guided PDT are ICG [78], TCPP [101] and pheophorbide a-conjugated poly(N-(2-hydroxypropyl)methacrylamide) when irradiated at 680 nm [92]. Besides, the chelating properties of porphyrins towards ions such as Mn 2+ [101] or Gd 3+ [80] or 64 Cu [99] can be used for magnetic resonant imaging (MRI). ...
... Efforts have been made in order to increase the solubility of fluorinated polymers by using charged poly(ethylene imine) stars (around 2 mg·mL −1 in [60]), for example. Another approach is to use random copolymers allowing for higher polymer concentrations (3 mg·mL −1 and up to 10 mg·mL −1 in [97] and [64] (Figure 6b), respectively). ...
Article
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Photodynamic therapy is a technique already used in ophthalmology or oncology. It is based on the local production of reactive oxygen species through an energy transfer from an excited photosensitizer to oxygen present in the biological tissue. This review first presents an update, mainly covering the last five years, regarding the block copolymers used as nanovectors for the delivery of the photosensitizer. In particular, we describe the chemical nature and structure of the block copolymers showing a very large range of existing systems, spanning from natural polymers such as proteins or polysaccharides to synthetic ones such as polyesters or polyacrylates. A second part focuses on important parameters for their design and the improvement of their efficiency. Finally, particular attention has been paid to the question of nanocarrier internalization and interaction with membranes (both biomimetic and cellular), and the importance of intracellular targeting has been addressed.
... Increased delivery of oxygen by the inhalation of pure oxygen at high pressure during PDT is also employed to increase oxygen supply and overcome tumor hypoxia. Direct delivery of O 2 into tumors using an appropriate O 2 carrier, such as hemoglobin (Hb) and PS co-delivery, e.g., with ZnPc [99], or ICG [100]), or perfluorocarbons [101][102][103], is one of the most common approaches developed to overcome tumor hypoxia during PDT procedure. ...
... Perfluorocarbon-containing photosensitizers are characterized by high oxygen capacity that is valuable to enrich oxygen during PDT [101][102][103]. Perfluorocarbons (PFCs) consist of carbon chains with complete fluorination of the carbon skeleton, where the high electronegativity of fluorine endows PFCs with excellent oxygen affinity [101]. ...
Article
The selectivity of photodynamic therapy (PDT) derived from the tailored accumulation of photosensitizing drug (photosensitizer; PS) in the tumor microenvironment (TME), and from local irradiation, turns it into a “magic bullet” for the treatment of resistant tumors without sparing the healthy tissue and possible adverse effects. However, locally-induced hypoxia is one of the undesirable consequences of PDT, which may contribute to the emergence of resistance and significantly reduce therapeutic outcomes. Therefore, the development of strategies using new approaches in nanotechnology and molecular biology can offer an increased opportunity to eliminate the disadvantages of hypoxia. Emerging evidence indicates that wisely designed phototherapeutic procedures, including: (i) ROS-tunable photosensitizers, (ii) organelle targeting, (iii) nano-based photoactive drugs and/or PS delivery nanosystems, as well as (iv) combining with other strategies (i.e. PTT, chemotherapy, theranostics or the design of dual anticancer drug and photosensitizers) can significantly improve the PDT efficacy and overcome the resistance. This mini-review addresses the role of hypoxia and hypoxia-related molecular mechanisms of the HIF-1α pathway in the regulation of PDT efficacy. It also discusses the most recent achievements as well as future perspectives and potential challenges of PDT application against hypoxic tumors.
... Perfluorocarbon (PFC) consists of a carbon skeleton and high electronegative fluorine and exhibits an excellent oxygen affinity, representing a suitable material for oxygen transport [69][70][71]. A case using pH-sensitive PFC-modified nanoparticles to load oxygen and a PS, IR780, has been reported by Ma et al. [69]. ...
... A case using pH-sensitive PFC-modified nanoparticles to load oxygen and a PS, IR780, has been reported by Ma et al. [69]. An amphiphilic/fluorous random copolymer was used to construct micelles showing good O2 carrying ability, thereby revealing satisfactory photocytotoxicity [70]. Likewise, Hu et al. indicated that PFC and oxygen co-loaded hyaluronic acid (HA) vesicles grafted with chlorin e6 (Ce6) by reducible disulfide bonds revealed excellent performance in carrying oxygen. ...
Article
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Photodynamic therapy (PDT) works through photoactivation of a specific photosensitizer (PS) in a tumor in the presence of oxygen. PDT is widely applied in oncology to treat various cancers as it has a minimally invasive procedure and high selectivity, does not interfere with other treatments, and can be repeated as needed. A large amount of reactive oxygen species (ROS) and singlet oxygen is generated in a cancer cell during PDT, which destroys the tumor effectively. However, the efficacy of PDT in treating a deep-seated tumor is limited due to three main reasons: Limited light penetration depth, low oxygen concentration in the hypoxic core, and poor PS accumulation inside a tumor. Thus, PDT treatments are only approved for superficial and thin tumors. With the advancement of nanotechnology, PDT to treat deep-seated or thick tumors is becoming a reachable goal. In this review, we provide an update on the strategies for improving PDT with nanomedicine using different sophisticated-design nanoparticles, including two-photon excitation, X-ray activation, targeting tumor cells with surface modification, alteration of tumor cell metabolism pathways, release of therapeutic gases, improvement of tumor hypoxia, and stimulation of host immunity. We focus on the difficult-to-treat pancreatic cancer as a model to demonstrate the influence of advanced nanomedicine in PDT. A bright future of PDT application in the treatment of deep-seated tumors is expected.
... Besides, reversible addition-fragmentation chain transfer (RAFT) polymerization technique was used, so plenty of amphiphilic/fluorine random copolymers with different contents of perfluorocarbon (perfluorooctyl) were prepared. 228 The higher PFC content in the copolymers can produce ROS more effectively, thus improving PDT efficiency in vitro. They found that an increase in PFC amount can carry more oxygen and therefore produce more ROS. ...
Article
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Cancer is a leading cause of death worldwide, accounting for an estimated 10 million deaths by 2020. Over the decades, various strategies for tumor therapy have been developed and evaluated. Photodynamic therapy (PDT) has attracted increasing attention due to its unique characteristics, including low systemic toxicity and minimally invasive nature. Despite the excellent clinical promise of PDT, hypoxia is still the Achilles' heel associated with its oxygen-dependent nature related to increased tumor proliferation, angiogenesis, and distant metastases. Moreover, PDT-mediated oxygen consumption further exacerbates the hypoxia condition, which will eventually lead to the poor effect of drug treatment and resistance and irreversible tumor metastasis, even limiting its effective application in the treatment of hypoxic tumors. Hypoxia, with increased oxygen consumption, may occur in acute and chronic hypoxia conditions in developing tumors. Tumor cells farther away from the capillaries have much lower oxygen levels than cells in adjacent areas. However, it is difficult to change the tumor's deep hypoxia state through different ways to reduce the tumor tissue's oxygen consumption. Therefore, it will become more difficult to cure malignant tumors completely. In recent years, numerous investigations have focused on improving PDT therapy's efficacy by providing molecular oxygen directly or indirectly to tumor tissues. In this review, different molecular oxygen supplementation methods are summarized to alleviate tumor hypoxia from the innovative perspective of using supplemental oxygen. Besides, the existing problems, future prospects and potential challenges of this strategy are also discussed.
... Hu et al. [64] synthesized different amphiphilic fluorous random copolymers with different amount of perfluorocarbon, that embed Hypocrellin B (HB) as PS, assembled themself into micelles in water (diameter 200 nm). The O2 carrying ability of the conjugate was related to the PFC content. 1 O2 production of HB after light irradiation (630 nm, 6 J/well) of the conjugate measured with SOSG was equivalent as for HB in water. ...
Article
Full-text available
Photodynamic therapy (PDT) has drawn great interest in recent years mainly due to its low side effects and few drug resistances. Nevertheless, one of the issues of PDT is the need for oxygen to induce a photodynamic effect. Tumours often have low oxygen concentrations, related to the abnormal structure of the microvessels leading to an ineffective blood distribution. Moreover, PDT consumes O2. In order to improve the oxygenation of tumour or decrease hypoxia, different strategies are developed and are described in this review: 1) The use of O2 vehicle; 2) the modification of the tumour microenvironment (TME); 3) combining other therapies with PDT; 4) hypoxia-independent PDT; 5) hypoxia-dependent PDT and 6) fractional PDT.
... Compared with the above methods, perfluorocarbons (PFCs) as a carrier has excellent oxygen affinity including much higher oxygen solubility and diffusivity (Castro & Briceno, 2010;Chen et al., 2017;Cheng et al., 2015;Dang, He, Chen, & Yin, 2017;Jalani, Jeyachandran, Bertram Church, & Cerruti, 2017;Sheng et al., 2018;Tang et al., 2018;Que et al., 2016). Progress has been made in the covalent modification of PFCs (Niu, Gao, & Wu, 2014;Wijekoon, Fountas-Davis, & Leipzig, 2013) and PDT based on the PFC modification (Hu et al., 2019;Zhu et al., 2016). However, to our knowledge, the PDT based on the PFCs which is covalently immobilized to biomaterials has not been widely reported. ...
Article
Photodynamic therapy (PDT) is a method for killing cancer cells by employing reactive singlet oxygen (¹O2). However, the inherent hypoxia and oxygen consumption in tumors during PDT lead to a deficient oxygen supply, which in turn hinder the photodynamic efficacy. To overcome this issue, fluorinated-functionalized polysaccharide-based nanocomplexes were prepared by anchoring perfluorocarbons (PFCs) and pyropheophorbide a (Ppa) onto the polymer chains of hyaluronic acid (HA) to deliver O2 in hypoxia area. These amphiphilic conjugates can self-assemble into micelles and its application in PDT is evaluated. Due to the high oxygen affinity of perfluorocarbon segments, and the tumor-targeting nature of HA, the photodynamic effect of the oxygen self-carrying micelles is remarkably enhanced, which is confirmed by increased generation of ¹O2 and elevated phototoxicity in vitro and in vivo. These results emphasize the promising potential of polysaccharide-based nanocomplexes for enhanced PDT of Ocular Choroidal Melanoma.
... Encapsulating PSs in NPs can improve the solubility and stability of PSs, avoid self-quenching, and thereby increase 1 O 2 yield [23][24][25]. In addition, NPs can also be designed to deliver oxygen or generate oxygen in situ, thereby relieving tumor hypoxia, which is detrimental for efficient PDT [26][27][28]. The NPs can inherently target to tumors through the enhanced permeability and retention (EPR) effect, a unique phenomenon of solid tumors including PCa related to their anatomical and pathophysiological differences from normal tissues [29]. ...
Article
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Patients with pancreatic cancer (PCa) have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy (PDT) is a minimally invasive treatment modality whose efficacy and safety in treating unresectable localized PCa have been corroborated in clinic. Yet, it suffers from certain limitations during clinical exploitation, including insufficient photosensitizers (PSs) delivery, tumor-oxygenation dependency, and treatment escape of aggressive tumors. To overcome these obstacles, an increasing number of researchers are currently on a quest to develop photosensitizer nanoparticles (NPs) by the use of a variety of nanocarrier systems to improve cellular uptake and biodistribution of photosensitizers. Encapsulation of PSs with NPs endows them significantly higher accumulation within PCa tumors due to the increased solubility and stability in blood circulation. A number of approaches have been explored to produce NPs co-delivering multi-agents affording PDT-based synergistic therapies for improved response rates and durability of response after treatment. This review provides an overview of available data regarding the design, methodology, and oncological outcome of the innovative NPs-based PDT of PCa.
... These interventions are often combined with oxygen or carbogen breathing in order to potentiate anti-cancer therapy (Krafft, 2020). It has been described that these approaches with an increase blood oxygen-carrying capacity may lead to an increase in response to radiation therapy (Teicher et al., 1991;Koch et al., 2002;Song et al., 2017;Zhou et al., 2018), photodynamic therapy (Fingar et al., 1988;Cheng et al., 2015;Tang et al., 2017;Song et al., 2018;Wang et al., 2018;Hu et al., 2019;Kv et al., 2020;Fang et al., 2021), sonodynamic therapy (Zeng et al., 2020;Guo et al., 2021), chemotherapy (Teicher et al., 1987;Teic her et al., 1990;Teicher, 1994;Song et al., 2019;Wu et al., 2020), and immunotherapy (Jiang et al., 2021;Yang et al., 2021). ...
Article
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Hypoxia is a common feature of solid tumors that contributes to angiogenesis, invasiveness, metastasis, altered metabolism and genomic instability. As hypoxia is a major actor in tumor progression and resistance to radiotherapy, chemotherapy and immunotherapy, multiple approaches have emerged to target tumor hypoxia. It includes among others pharmacological interventions designed to alleviate tumor hypoxia at the time of radiation therapy, prodrugs that are selectively activated in hypoxic cells or inhibitors of molecular targets involved in hypoxic cell survival (i.e., hypoxia inducible factors HIFs, PI3K/AKT/mTOR pathway, unfolded protein response). While numerous strategies were successful in pre-clinical models, their translation in the clinical practice has been disappointing so far. This therapeutic failure often results from the absence of appropriate stratification of patients that could benefit from targeted interventions. Companion diagnostics may help at different levels of the research and development, and in matching a patient to a specific intervention targeting hypoxia. In this review, we discuss the relative merits of the existing hypoxia biomarkers, their current status and the challenges for their future validation as companion diagnostics adapted to the nature of the intervention.
... Hemoglobin was loaded into liposomal vesicles or embedded into red blood cell membranes for delivering O 2 in the TME [72][73][74]. As an alternative, perfluorocarbons (PFC) and O 2 have been co-loaded with PSs in liposomes or other nanocarriers with the aim of improving tumor oxygenation [75][76][77][78]. Other approaches exploit the unique features of the TME, such as high H 2 O 2 concentration. ...
Article
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The widespread diffusion of photodynamic therapy (PDT) as a clinical treatment for solid tumors is mainly limited by the patient’s adverse reaction (skin photosensivity), insufficient light penetration in deeply seated neoplastic lesions, unfavorable photosensitizers (PSs) biodistribution, and photokilling efficiency due to PS aggregation in biological environments. Despite this, recent preclinical studies reported on successful combinatorial regimes of PSs with chemotherapeutics obtained through the drugs encapsulation in multifunctional nanometric delivery systems. The aim of the present review deals with the punctual description of several nanosystems designed not only with the objective of co-transporting a PS and a chemodrug for combination therapy, but also with the goal of improving the therapeutic efficacy by facing the main critical issues of both therapies (side effects, scarce tumor oxygenation and light penetration, premature drug clearance, unspecific biodistribution, etc.). Therefore, particular attention is paid to the description of bio-responsive drugs and nanoparticles (NPs), targeted nanosystems, biomimetic approaches, and upconverting NPs, including analyzing the therapeutic efficacy of the proposed photo-chemotherapeutic regimens in in vitro and in vivo cancer models.
... Additionally, reports have shown that the lifetime of singlet oxygen ( 1 O 2 ) in PFC is longer than in the cellular environment or in water [30]. Therefore, the advantage of using PFC nanodroplets for oxygen and PS delivery is that they both will be in the same vicinity for photodynamic action to occur, resulting in improved treatment outcomes [38,39]. ...
Article
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Photodynamic therapy (PDT) is a well-known cancer therapy that utilizes light to excite a photosensitizer and generate cytotoxic reactive oxygen species (ROS). The efficacy of PDT primarily depends on the photosensitizer and oxygen concentration in the tumor. Hypoxia in solid tumors promotes treatment resistance, resulting in poor PDT outcomes. Hence, there is a need to combat hypoxia while delivering sufficient photosensitizer to the tumor for ROS generation. Here we showcase our unique theranostic perfluorocarbon nanodroplets as a triple agent carrier for oxygen, photosensitizer, and indocyanine green that enables light triggered spatiotemporal delivery of oxygen to the tumors. We evaluated the characteristics of the nanodroplets and validated their ability to deliver oxygen via photoacoustic monitoring of blood oxygen saturation and subsequent PDT efficacy in a murine subcutaneous tumor model. The imaging results were validated with an oxygen sensing probe, which showed a 9.1 fold increase in oxygen content inside the tumor, following systemic injection of the nanodroplets. These results were also confirmed with immunofluorescence. In vivo studies showed that nanodroplets held higher rates of treatment efficacy than a clinically available benzoporphyrin derivative formulation. Histological analysis showed higher necrotic area within the tumor with perfluoropentane nanodroplets. Overall, the photoacoustic nanodroplets can significantly enhance image-guided PDT and has demonstrated substantial potential as a valid theranostic option for patient-specific photodynamic therapy-based treatments.
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Fe³⁺ ions can promote the self‐assembly of Fmoc‐protected amino acids to form nanovesicles and catalyze the transformation of H2O2 enriched in cancer cells to oxygen, thereby ameliorating the hypoxic condition and promoting the photosensitizing activity of the encapsulated photosensitizer (ZnPc) in the nanovesicles. By entrapping an additional therapeutic agent (ACF), the nanovesicles can exhibit a synergistic effect for eradication of hypoxic cancer cells and tumors.Tumor Therapy Abstract A facile approach to assemble catalase‐like photosensitizing nanozymes with a self‐oxygen‐supplying ability was developed. The process involved Fe³⁺‐driven self‐assembly of fluorenylmethyloxycarbonyl (Fmoc)‐protected amino acids. By adding a zinc(II) phthalocyanine‐based photosensitizer (ZnPc) and the hypoxia‐inducible factor 1 (HIF‐1) inhibitor acriflavine (ACF) during the Fe³⁺‐promoted self‐assembly of Fmoc‐protected cysteine (Fmoc‐Cys), the nanovesicles Fmoc‐Cys/Fe@Pc and Fmoc‐Cys/Fe@Pc/ACF were prepared, which could be disassembled intracellularly. The released Fe³⁺ could catalyze the transformation of H2O2 enriched in cancer cells to oxygen efficiently, thereby ameliorating the hypoxic condition and promoting the photosensitizing activity of the released ZnPc. With an additional therapeutic component, Fmoc‐Cys/Fe@Pc/ACF exhibited higher in vitro and in vivo photodynamic activities than Fmoc‐Cys/Fe@Pc, demonstrating the synergistic effect of ZnPc and ACF.
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Phototherapy, such as photodynamic therapy (PDT) and photothermal therapy (PTT), possesses unique characteristics of non-invasiveness and minimal side effects in cancer treatment, compared with conventional therapies. However, the ubiquitous tumor hypoxia microenvironments could severely reduce the efficacy of oxygen-consuming phototherapies. Perfluorocarbon (PFC) nanomaterials have shown great practical value in carrying and transporting oxygen, which makes them promising agents to overcome tumor hypoxia and extend reactive oxygen species (ROS) lifetime to improve the efficacy of phototherapy. In this review, we summarize the latest advances in PFC-based PDT and PTT, and combined multimodal imaging technologies in various cancer types, aiming to facilitate their application-oriented clinical translation in the future.
Article
A facile approach to assemble catalase‐like photosensitizing nanozymes with a self‐oxygen‐supplying ability was developed. The process involved Fe 3+ ‐driven self‐assembly of fluorenylmethyloxycarbonyl (Fmoc)‐protected amino acids. By adding a zinc(II) phthalocyanine‐based photosensitizer (ZnPc) and the hypoxia‐inducible factor 1 (HIF‐1) inhibitor acriflavine (ACF) during the Fe 3+ ‐promoted self‐assembly of Fmoc‐protected cysteine (Fmoc‐Cys), the nanovesicles Fmoc‐Cys/Fe@Pc and Fmoc‐Cys/Fe@Pc/ACF were prepared, which could be disassembled intracellularly. The released Fe 3+ could catalyze the transformation of H 2 O 2 enriched in cancer cells to oxygen efficiently, thereby ameliorating the hypoxic condition and promoting the photosensitizing activity of the released ZnPc. With an additional therapeutic component, Fmoc‐Cys/Fe@Pc/ACF exhibited higher in vitro and in vivo photodynamic activities than Fmoc‐Cys/Fe@Pc, demonstrating the synergistic effect of ZnPc and ACF.
Article
Photodynamic therapy (PDT) is a non-invasive treatment for various cancers and non-malignant diseases. Despite its clinical promise, one of the major drawbacks of some PDT agents is their oxygen-dependent nature. This limits their efficiency in hypoxic solid tumors. Recent advances in nanotechnology and nanomedicine have led to the development of oxygen self-sufficient materials as PDT agents to overcome this problem. The key factors in this area are discussed in this review. This includes why tumors tend to be hypoxic, the relationship between PDT and oxygen, and the challenges and opportunities of PDT in hypoxia. In particular, recent advances in the design of oxygen self-sufficient nanomaterials to overcome hypoxia and achieve effective PDT in solid tumors are highlighted.
Article
Photodynamic therapy (PDT) has garnered an increasing interest by both researchers and clinicians as a non-invasive therapy that allows a selective treatment towards tumors temporally and spatially, which is a relatively safe strategy without obvious systemic side effects and drug resistance. However, the lack of O2 content in solid tumors is one of the most important factors limiting the effectiveness of PDT, as the hypoxic tumor regions not only induce tumor development and metastasis but also reduce the responsiveness of tumor tissues to PDT along with other treatments like chemotherapy and radiotherapy. Therefore, dealing with hypoxia is desirable and has become a hot research topic for both academic and clinical fields. This review summarizes the latest strategies and applications of reconstructing the tumor microenvironment and developing novel anti-hypoxia photosensitizers (PSs). It also summarizes the synergistic strategies that combine PDT with other treatment approaches to achieve complementary effects, significantly improving the treatment accuracy and efficacy. By evaluating several examples, this review concludes that the innovation of “theranostics” PS is the core impetus for the efficacy of PDT. In addition, it highlights that the structural designing of PS can effectively regulate the energy release process of the excited state and achieve imaging and PDT simultaneously.
Article
A critical issue of photodynamic therapy (PDT) is the hypoxia feature in tumor microenvironment and the PDT-caused continuous oxygen consumption, which suppresses the effect of tumor treatment. Though the perfluorocarbon-based microbubbles with high oxygen affinity have been utilized to supply endogenous oxygen to improve PDT, some risks are wished to be addressed including oxygen leakage and storage issues. Herein, perfluorohexane (PFH) and Fe3O4 nanoparticles were encapsulated in biocompatible polyphosphazenes (PPZ) and polydopamine (PDA) shells were further grown to prevent the leakage of PFH. After loading chlorine e6 (Ce6) and modifying with polyethylene glycol (PEG), a multimodal nanotheranostic (PFH–Fe3O4@[email protected]) were successfully constructed for ultrasonic (US), magnetic resonance (MR) and fluorescence imaging guided photothermal therapy (PTT) and enhanced PDT. PFH can not only bind and delivery oxygen but also be used as contrast agent for US imaging. While PDA is a frequently used PTT agent and Ce6 is PDT agent as well as fluorescent agent. The yolk-shell nanoplatform showed good biocompatibility, biostability and well cellular uptake. Importantly, strengthened PDT efficiency has also been greatly improved due to high oxygen-rich PFH. Furthermore, the nanoplatform efficiently generated hyperthermia to kill tumor upon 808 nm illumination. Remarkably, the PTT/enhanced PDT combination therapy can be realized under the guidance of US/MR/fluorescence imaging. This nanoplatform could dramatically inhibit tumor growth by PTT and improved PDT, demonstrating great promising for multimodal imaging guided phototherapy.
Article
Photodynamic therapy (PDT) has been a preferred clinical technology for treating superficial tumors due to its advantages of high selectivity, non-invasiveness and negligible drug resistance. However, the hypoxic tumor microenvironment weakens the efficiency of O2-dependent PDT. Moreover, the PDT process consumes a large amount of O2 and destroys the tumor blood vessels and further blocks the O2 supply to tumor sites. Therefore, developing more advanced materials and methods for PDT of the hypoxic tumor is an essential scientific significance. This tutorial review summarizes the strategies for improving the efficacy of PDT in hypoxic tumor therapy, which is categorized into three sections: (I) enhancing O2 concentration in the tumor; (II) disregarding hypoxia; and (III) exploiting hypoxia. The advantages of combining PDT with other therapeutics, such as chemotherapy, chemo-dynamic therapy, gas therapy, immunotherapy and gene therapy, are also demonstrated. Finally, the existing challenges and future perspectives on clinical PDT for hypoxic tumors are discussed.
Article
It is desirable for a sustainable society that the production and utilization of renewable materials are net‐zero in terms of carbon emissions. Carbon materials with emerging applications in CO2 utilization, renewable energy storage and conversion, and biomedicine have attracted much attention both academically and industrially. However, the preparation process of some new carbon materials suffers from energy consumption and environmental pollution issues. Therefore, the development of low‐cost, scalable, industrially and economically attractive, sustainable carbon material preparation methods are required. In this regard, the use of biomass and its derivatives as a precursor of carbon materials is a major feature of sustainability. Recent advances in the synthetic strategy of sustainable carbon materials and their emerging applications are summarized in this short review. Emphasis is made on the discussion of the original intentions and various sustainable strategies for producing sustainable carbon materials. This review provides basic insights and significant guidelines for the further design of sustainable carbon materials and their emerging applications in catalysis and the biomedical field. Nanostructured carbon materials afford unparalleled potential in catalytic and biomedical applications due to their versatile features. It is critical to sustainably fabricate next generation nanostructured carbon materials for tackling current challenges toward a carbon‐neutral society. In this review, recent developments in the sustainable synthetic strategy of nanostructured carbon materials and their emerging applications in catalysis and biomedical are summarized.
Article
Photodynamic therapy (PDT) is a treatment modality in which a photosensitizer is irradiated with light, producing reactive oxygen species, often via energy transfer with oxygen. As it is common for tumors to be hypoxic, methods to deliver photosensitizer and oxygen are desirable. One such approach is the use of perfluorocarbons, molecules in which all C—H bonds are replaced with C—F bonds, to co-deliver oxygen due to the high solubility of gases in perfluorocarbons. This review highlights the benefits and limitations of several fluorinated nanomaterial architectures for use in PDT.
Article
An amphiphilic polymer (CmPOX) based on poly(2-methyl-2-oxazoline) linked to a hydrophobic part composed of an aliphatic chain ended by a photo-active coumarin group has been synthesized. It exhibits the ability of forming small polymeric self-assemblies, typically of ca. 10 nm in size which were characterized by TEM, cryo-TEM and DLS. The nanocarriers were further formulated to yield photo-crosslinked systems by dimerization of coumarin units of a coumarin-functionalized poly(methyl methacrylate) (CmPMMA) and CmPOX. The formed vectors were used to encapsulate Pheophorbide a, a known photosensitizer for PhotoDynamic Therapy. Cytotoxicity as well as photooxicity experiments led in vitro on human tumor cells revealed the great potential of these nanovectors for photodynamic therapy.
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Photodynamic therapy (PDT) kills cancer cells by converting tumour oxygen into reactive singlet oxygen (1 O 2) using a photosensitizer. However, pre-existing hypoxia in tumours and oxygen consumption during PDT can result in an inadequate oxygen supply, which in turn hampers photodynamic efficacy. Here to overcome this problem, we create oxygen self-enriching photodynamic therapy (Oxy-PDT) by loading a photosensitizer into perfluorocarbon nanodroplets. Because of the higher oxygen capacity and longer 1 O 2 lifetime of perfluorocarbon, the photodynamic effect of the loaded photosensitizer is significantly enhanced, as demonstrated by the accelerated generation of 1 O 2 and elevated cytotoxicity. Following direct injection into tumours, in vivo studies reveal tumour growth inhibition in the Oxy-PDT-treated mice. In addition, a single-dose intravenous injection of Oxy-PDT into tumour-bearing mice significantly inhibits tumour growth, whereas traditional PDT has no effect. Oxy-PDT may enable the enhancement of existing clinical PDT and future PDT design.
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The purpose of this study is to investigate the feasibility for quantitative measurement of singlet oxygen ((1)O(2)) generation by using a newly developed (1)O(2)-specific fluorescence probe Singlet Oxygen Sensor Green reagent (SOSG). (1)O(2) generation from photoirradiation of a model photosensitizer Rose Bengal (RB), in initially air-statured phosphate buffered saline (PBS) was indirectly monitored with SOSG. In the presence of (1)O(2), SOSG can react with (1)O(2) to produce SOSG endoperoxides (SOSG-EP) that emit strong green fluorescence with the maximum at 531 nm. The green fluorescence of SOSG-EP is mainly dependent on the initial concentrations of RB and SOSG, and the photoirradiation time for (1)O(2) generation. Furthermore, kinetic analysis of the RB-sensitized photooxidation of SOSG is performed that, for the first time, allows quantitative measurement of (1)O(2) generation directly from the determination of reaction rate. In addition, the obtained (1)O(2) quantum yield of porphyrin-based photosensitizer hematoporphyrin monomethyl ether (HMME) in PBS by using SOSG is in good agreement with the value that independently determined by using direct measurement of (1)O(2) luminescence. The results of this study clearly demonstrate that the quantitative measurement of (1)O(2) generation using SOSG can be achieved by determining the reaction rate with an appropriate measurement protocol.
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Advancement of gas sensor technology over the past few decades has led to significant progress in pollution control and thereby, to environmental protection. An excellent example is the control of automobile exhaust emissions, made possible by the use of oxygen gas sensors. Since early 1970''s there have been sustained studies on oxygen sensors and has led to development of sensors for various applications with varying performance characteristics. Solid electrolyte based potentiometric, amperometric and metal oxide based semiconducting resistive type sensors are used for high temperature applications. For solution-based pollution monitoring, dissolved oxygen sensors based on Clark electrodes have played a major role. More recently, for biological and medical applications, optical oxygen sensors are beginning to have an impact. In this review, we focus on both high temperature as well as dissolved oxygen sensors and compare the different methods of oxygen sensing, discuss underlying principles, and outline the designs and specific applications.
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Opportunistic fungal pathogens may cause superficial or serious invasive infections, especially in immunocompromised and debilitated patients. Invasive mycoses represent an exponentially growing threat for human health due to a combination of slow diagnosis and the existence of relatively few classes of available and effective antifungal drugs. Therefore systemic fungal infections result in high attributable mortality. There is an urgent need to pursue and deploy novel and effective alternative antifungal countermeasures. Photodynamic therapy (PDT) was established as a successful modality for malignancies and age-related macular degeneration but photodynamic inactivation has only recently been intensively investigated as an alternative antimicrobial discovery and development platform. The concept of photodynamic inactivation requires microbial exposure to either exogenous or endogenous photosensitizer molecules, followed by visible light energy, typically wavelengths in the red/near infrared region that cause the excitation of the photosensitizers resulting in the production of singlet oxygen and other reactive oxygen species that react with intracellular components, and consequently produce cell inactivation and death. Antifungal PDT is an area of increasing interest, as research is advancing (i) to identify the photochemical and photophysical mechanisms involved in photoinactivation; (ii) to develop potent and clinically compatible photosensitizers; (iii) to understand how photoinactivation is affected by key microbial phenotypic elements multidrug resistance and efflux, virulence and pathogenesis determinants, and formation of biofilms; (iv) to explore novel photosensitizer delivery platforms; and (v) to identify photoinactivation applications beyond the clinical setting such as environmental disinfectants.
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Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment.
Article
Hypoxia, defined as an oxygen-deficient condition, is known to be a characteristic feature for most solid tumors that not only facilitates tumor metastasis but also jeopardizes the efficacy of therapies, especially photodynamic therapy (PDT) in which oxygen is essential in the treatment process. To overcome this problem, novel oxygen self-carrying nanoparticles (PMT NPs) have been developed for highly efficient and selective cancer treatment. Substituted diphenyl anthracene is designed as a more suitable ¹O2 donor compared to diphenyl anthracene. Photooxidation in situ of diphenyl anthracene is achieved by introducing tetraphenyl porphyrin (TPP) into the polymer architecture. Micelles are obtained by a nanoprecipitation method and IR780 is encapsulated into the core of the micelles as a photosensitizer. Once the PMT NPs are ingested by HepG2 cells, they can induce the release of reactive oxygen species (ROS) to kill cancer cells with 808 nm laser irradiation. The micelles are about 60 nm in diameter with a narrow distribution, and are quite suitable for passive targeting to tumors via the enhanced permeability and retention (EPR) effect. In the presence of an 808 nm laser, the PMT NPs can release ROS and in turn significantly enhance the PDT effect. This innovative nanoplatform has exhibited excellent antitumor efficiency, was clearly verified by in vitro and in vivo assays, and may serve as a versatile theranostic platform for clinical tumor therapy.
Article
Self-assembly of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic dodecyl-graft amphiphilic copolymers in water was investigated in detail, especially focused on the effects of monomer sequence and chain flexibility on the size controllability, mobility, and thermoresponse of micelles. For this, we designed and synthesized PEG/dodecyl graft copolymers with different sequence distribution, backbone, composition, and chain length via controlled or free radical copolymerization: acrylate random, methacrylate/acrylate gradient and bidirectional gradient, and methacrylate random block. Acrylate-based amphiphilic random copolymers produced uniform micelles in water, whose size was just determined by composition. The flexible acrylate-based micelles had higher mobility of graft PEG and in-core dodecyl units than methacrylate counterparts yet effectively maintained uniform and compact size (~10 nm) up to high concentration. Additionally, sequence distribution critically affected size controllability of micelles. Gradient or random block copolymers with highly biased and/or locally accumulated hydrophobic monomer segments provided micelles with different size and/or broad size distribution. Thus, it was revealed that random, statistical, and non-biased sequence distribution of hydrophilic and hydrophobic monomers is a key factor to efficiently induce composition-dependent precision self-assembly of PEG/dodecyl-graft copolymers into uniform size micelles in water.
Article
Saturated fluorocarbons, their derivatives and emulsions are capable of dissolving anomalously high amounts of oxygen and other gases. The mechanistic aspects of this remarkable effect remain to be explored experimentally. Here, the synthesis of a library of amphiphilic fluorous block-copolymers incorporating different fluorinated monomers is described, and the capacity of these copolymers for oxygen transport in water is systematically investigated. The structure of the fluorous monomer employed was found to have a profound effect on both the oxygen-carrying capacity and the gas release kinetics of the polymer emulsions. Furthermore, the release of O2 from the polymer dispersions could be triggered by changing the pH of the solution. This is the first example of a polymer-based system for controlled release of a non-polar, non-covalently entrapped respiratory gas.
Article
Photodynamic therapy (PDT) is an adjuvant, non-invasive cancer treatment that is often limited by the photosensitizer solubility and the availability of oxygen in the tumor environment during treatment. This study describes the use of a water-dispersible fluorous polymer to deliver a small molecule photosensitizer with the goal of overcoming these limitations. Covalent conjugation of the photosensitizer to a fluorous polymer demonstrated enhanced singlet oxygen production, showing the potential to improve the PDT efficacy in hypoxic tumor environments. Cellular uptake and efficiency were evaluated using models for squamous cell carcinoma and melanoma. The high fluorine content of the photosensitizer-conjugated polymer drove self-assembly into micellar nanoparticles that showed uptake into both cancer cell lines, inducing cell death when exposed to broad based white light, but was non-toxic otherwise. Taken together these results demonstrate that the fluorous polymer platform serves as an effective delivery system for small molecule photosensitizers while increasing the generation of toxic reactive oxygen species.
Article
Tumor hypoxia is known to be one of critical reasons that limit the efficacy of cancer therapies, particularly photodynamic therapy (PDT) and radiotherapy (RT) in which oxygen is needed in the process of cancer cell destruction. Herein, taking advantages of the great biocompatibility and high oxygen dissolving ability of perfluorocarbon (PFC), we develop an innovative strategy to modulate the tumor hypoxic microenvironment using nano-PFC as an oxygen shuttle for ultrasound triggered tumor-specific delivery of oxygen. In our experiment, nanodroplets of PFC stabilized by albumin are intravenously injected into tumor-bearing mice under hyperoxic breathing. With a low-power clinically adapted ultrasound transducer applied on their tumor, PFC nanodroplets that adsorb oxygen in the lung would rapidly release oxygen in the tumor under ultrasound stimulation, and then circulate back into the lung for reoxygenation. Such repeated cycles would result in dramatically enhanced tumor oxygenation and thus remarkably improved therapeutic outcomes in both PDT and RT treatment of tumors. Importantly, our strategy may be applied for different types of tumor models. Hence, this work presents a simple strategy to promote tumor oxygenation with great efficiency using agents and instruments readily available in the clinic, so as to overcome the hypoxia-associated resistance in cancer treatment.
Article
Photodynamic therapy (PDT) is a noninvasive therapeutic modality with fast healing process and little or no scarring. The production of reactive oxygen species is highly dependent on oxygen concentration, and thus, the therapeutic efficacy of PDT would be retarded by inefficient oxygen supply in hypoxic tumor cell and the oxygen self-consuming mechanism of PDT. It is well-known that perfluorocarbons are endowed with properties of enhanced oxygen solubility and transfer capacity. Herein, we prepared a series of nanoplatforms of spherical micelles with different ratios of pentafluorophenyl to porphyrin in the core and utilized these micelles as models to examine the influence of content of fluorinated segments on the PDT effect of porphyrins. It was found for the first time, as far as we are aware, that the production efficacy of singlet oxygen increased with the rising in the ratio of pentafluorophenyl to porphyrin. Thus, this work presents a new avenue to improve PDT efficacy by enhancing oxygen solubility and diffusivity of nanoplatforms with the incorporation of perfluorocarbon segments.
Article
Intelligent 2D theranostic nanomaterials are successfully designed based on the pH-/H2 O2 -responsive MnO2 nanosheets anchored with upconversion nanoprobes. They react with acidic H2 O2 to generate sufficient oxygen for enhancing the synergetic radio/photodynamic therapy efficacy upon NIR light/X-ray irradiation and recover/enhance the upconversion luminescence for monitoring the therapeutic process. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Article
The low selectivity of the currently available photosensitizers, which causes the treatment-related toxicity and side effects on adjacent normal tissues, is a major limitation for clinical photodynamic therapy (PDT) against cancer. Moreover, since PDT process is strongly oxygen dependent, its therapeutic effect is seriously hindered in hypoxic tumor cells. To overcome these problems, a cell-specific, H2O2-activatable and O2-evolving PDT nanoparticle (HAOP NP) is developed for highly selective and efficient cancer treatment. The nanoparticle is composed of photosensitizer and catalase in the aqueous core, Black Hole Quencher in the polymeric shell, and functionalized with a tumor targeting ligand c(RGDfK). Once the HAOP NP is selectively taken up by αvβ3 integrin-rich tumor cells, the intracellular H2O2 penetrates the nanoparticle and is catalyzed by catalase to generate O2, leading to the shell rupture and release of photosensitizer. Under irradiation, the released photosensitizer induces the formation of cytotoxic singlet oxygen (1O2) in the presence of O2 to kill cancer cells. The cell-specific and H2O2-activatable generation of 1O2 selectively destroys cancer cells and prevents the damage to normal cells. More significantly, the HAOP NP could continuously generate O2 in PDT process, which greatly improves the PDT efficacy in hypoxic tumor. Therefore, this work presents a new paradigm for H2O2-triggered PDT against cancer cells and provides a new avenue for overcoming hypoxic conditions to achieve effective treatment of solid tumors.
Article
Herein, amphiphilic/fluorous random copolymers bearing poly(ethylene glycol) (PEG) chains and perfluorinated alkane pendants were developed as novel non-cytotoxic polymers for protein conjugation. Three kinds of random copolymers with different initiating terminals (carboxylic acid, pyridyl disulfide, N-hydroxysuccinimide ester) were prepared by reversible addition-fragmentation chain transfer (RAFT) copolymerization of a PEG methyl ether methacrylate and a perfluorinated alkane methacrylate with corresponding functional chain transfer agents. All of the polymers were soluble in water to form nanostructures with perfluorinated compartments via fluorous interaction: large aggregates from the intermolecular multi-chain association and compact unimer micelles from the intramolecular single-chain folding. Such a PEGylated and perfluorinated random copolymer was non-cytotoxic to NIH 3T3 mouse embryonic fibroblast cells and human umbilical vein endothelial cells (HUVECs). Additionally, a random copolymer with a pyridyl disulfide terminal was also successfully conjugated with a thiolated lysozyme.
Article
In the study presented here, we developed a bioreducible biarmed methoxy poly(ethylene glycol)-(pheophorbide a)2 (mPEG-(ss-PhA)2) conjugate for cancer-cell-specific photodynamic therapy (PDT). PhA molecules were chemically conjugated with biarmed linkages at one end of the mPEG molecule via disulfide bonds. Under aqueous conditions, the amphiphilic mPEG-(ss-PhA)2 conjugate self-assembled to form core-shell-structured nanoparticles (NPs) with good colloidal stability. The mPEG-(ss-PhA)2 NPs exhibited intramolecular and intermolecular self-quenching effects that enabled the NPs to remain photo-inactive in a physiological buffer. However, the dissociation of the NP structure was effectively induced by the cleavage of the disulfide bonds in response to intracellular reductive conditions, triggering the rapid release of PhA molecules in a photoactive form. In cell-culture systems, in addition to significant phototoxicity and intracellular uptake, we observed that the dequenching processes of PhA in the mPEG-(ss-PhA)2 NPs highly depended on the expression of intracellular thiols and that supplementation with glutathione monoethylester facilitated more rapid PhA release and enhanced the PhA phototoxicity. These findings suggest that the bioreducible activation mechanism of mPEG-(ss-PhA)2 NPs in cancer cells can maximize the cytosolic dose of active photosensitizers to achieve high cytotoxicity, thereby enhancing the treatment efficacy of photodynamic cancer.
Article
Insufficient oxygenation (hypoxia), acidic pH (acidosis), and elevated levels of reactive oxygen species (ROS), such as H2O2, are characteristic abnormalities of the tumor microenvironment (TME). These abnormalities promote tumor aggressiveness, metastasis, and resistance to therapies. To date, there is no treatment available for comprehensive modulation of the TME. Approaches so far have been limited to regulating hypoxia, acidosis, or ROS individually, without accounting for their interdependent effects on tumor progression and response to treatments. Hence we have engineered multifunctional and colloidally stable bioinorganic nanoparticles composed of polyelectrolyte-albumin complex and MnO2 nanoparticles (A-MnO2 NPs) and utilized the reactivity of MnO2 toward peroxides for regulation of the TME with simultaneous oxygen generation and pH increase. In vitro studies showed that these NPs can generate oxygen by reacting with H2O2 produced by cancer cells under hypoxic conditions. A-MnO2 NPs simultaneously increased tumor oxygenation by 45% while increasing tumor pH from pH 6.7 to pH 7.2 by reacting with endogenous H2O2 produced within the tumor in a murine breast tumor model. Intratumoral treatment with NPs also led to the downregulation of two major regulators in tumor progression and aggressiveness, that is, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor in the tumor. Combination treatment of the tumors with NPs and ionizing radiation significantly inhibited breast tumor growth, increased DNA double strand breaks and cancer cell death as compared to radiation therapy alone. These results suggest great potential of A-MnO2 NPs for modulation of the TME and enhancement of radiation response in the treatment of cancer.
Article
We describe the preparation of well-defined multicompartment micelles from polybutadiene-block-poly(1-methyl-2-vinyl pyridinium methyl sulfate)-block-poly(methacrylic acid) (BVqMAA) triblock terpolymers and their use as advanced drug delivery systems for photodynamic therapy (PDT). A porphyrazine derivative was incorporated into the hydrophobic core during self-assembly and served as a model drug and fluorescent probe at the same time. The initial micellar corona is formed by negatively charged PMAA and could be gradually changed to poly(ethylene glycol) (PEG) in a controlled fashion through interpolyelectrolyte complex formation of PMAA with positively charged poly(ethylene glycol)-block-poly(L-lysine) (PLL-b-PEG) diblock copolymers. At high degrees of PEGylation, a compartmentalized micellar corona was observed, with a stable bottlebrush-on-sphere morphology as demonstrated by cryo-TEM measurements. By in vitro cellular experiments, we confirmed that the porphyrazine-loaded micelles were PDT-active against A549 cells. The corona composition strongly influenced their in vitro PDT activity, which decreased with increasing PEGylation, correlating with the cellular uptake of the micelles. Also, a PEGylation-dependent influence on the in vivo blood circulation and tumor accumulation was found. Fully PEGylated micelles were detected for up to 24 h in the bloodstream and accumulated in solid subcutaneous A549 tumors, while non- or only partially PEGylated micelles were rapidly cleared and did not accumulate in tumor tissue. Efficient tumor growth suppression was shown for fully PEGylated micelles up to 20 days, demonstrating PDT efficacy in vivo.
Article
We report aqueous, room temperature RAFT polymerization of N-isopropylacrylamide (NIPAM) and, subsequently, its block copolymerization utilizing a poly(N,N-dimethylacrylamide) macro-CTA. A series of thermally responsive AB diblock and ABA triblock copolymers have been prepared. These polymers contain hydrophilic N,N-dimethylacrylamide (DMA) A blocks of fixed molecular weight and temperature-responsive NIPAM B blocks of varied chain length. Using a combination of 1H NMR spectroscopy, T2 relaxation measurements, dynamic light scattering (DLS), and static light scattering (SLS), we demonstrate that these block copolymers are indeed capable of reversibly forming micelles in response to changes in solution temperature and that the micellar size and transition temperature are dependent on both the NIPAM block length and the polymer architecture (diblock vs triblock).
Article
Abstract— Hypocrellins are perylenequinone pigments with substantial absorption in the red spectral region and high singlet oxygen yield. They are available in pure monomelic form and may be derivatized to optimize properties of red light absorption, tissue biodistribution and toxicity. In vitro screening of synthetic derivatives of the naturally occurring compound, hypocrellin B (HB), for optimal properties of cyto-(dark) toxicity and phototoxicity resulted in selection of three compounds for preclinical evaluation: HBEA-R1 (ethanolaminated HB), HBBA-R2 (butylaminated HB) and HBDP-R1 [2-(N,N-dimethylami-no)-propylamine-HB]. Extinction coefficients at 630 nm (φ630) are 6230, 6190 and 4800, respectively; and 1O2 quantum yields, φ, 0.60, 0.32 and 0.42. Intracellular uptake is essentially complete within 2 h (HBEA-R1, HBBA-R2) and 20 h (HBDP-R1). Greatest uptake is associated with lysosomes and Golgi. The HBEA-R1 and HBBA-R2 elicit phototoxicity in vitro primarily via the type II mechanism, with some type I activity under stringently hypoxic conditions. Transcutaneous phototherapy with HBEA-R1 permanently ablates EMToVEd tumors growing in the flanks of Balb/c mice, with minimal cutaneous effects. The HBBA-R2 does not elicit mutagenic activity in strains TA98 and TA100 of Salmonella typhi-murium. Further development of selected hypocrellin derivatives as photosensitizers for photodynamic therapy is warranted.
Article
This overview covers recent literature on fluorinated amphiphiles and self-assemblies of biomedical interest. It includes 1) “standard” perfluoroalkylated surfactants, 2) (perfluoroalkyl)alkyl diblock amphiphiles, 3) amphiphilic biomimetics bearing multiple CF3 groups, and 4) the environmental issues raised by perfluorooctanoic acid, perfluorooctane sulfonate and related compounds.
Article
Perfluorocarbons (PFCs) are fluorinated compounds that have been used for many years in clinics mainly as gas/oxygen carriers and for liquid ventilation. Besides this main application, PFCs have also been tested as contrast agents for ultrasonography and magnetic resonance imaging since the end of the 1970s. However, most of the PFCs applied as contrast agents for imaging were gaseous. This class of PFCs has been recently substituted by liquid PFCs as ultrasound contrast agents. Additionally, liquid PFCs are being tested as contrast agents for (19)F magnetic resonance imaging (MRI), to yield dual contrast agents for both ultrasonography and (19)F MRI. This review focuses on the development and applications of the different contrast agents containing liquid perfluorocarbons for ultrasonography and/or MRI: large and small size emulsions (i.e. nanoemulsions) and nanocapsules.
Article
A novel series of perfluorocarbon (PFC) emulsions, based on perfluorodecalin (C10F18) and stabilised with up to 2.5% (w/v) of lecithin have been produced for evaluation as injectable, temporary respiratory gas-carrying blood substitutes. Some formulations contained 1.0% (w/v) of perfluorodimorpholinopropane (C11F22N2O2) to retard droplet growth through molecular diffusion (Ostwald Ripening). Other emulsions contained novel, amphiphilic fluorinated surfactants, such as, for example, the monocarbamate, C8F17C2H4NHC(O)(CH2CH2O)2Me (designated compound P6), at 0.1% (w/v) to enhance stability. Emulsions were prepared by homogenisation, were steam sterilisable and were stable for > 300 days (25 degrees C). Injection of rats (7.5 ml kg-1 b.w.) with emulsions produced significant (P < 0.05), transient increases in liver and spleen weights. One emulsion inhibited phorbol 12-myristate 13-acetate (PMA)-stimulated, Luminol-enhanced, chemiluminescence of human polymorphonuclear leucocytes (PMNL) in vitro, suggesting possible applications in ischaemic tissues for suppressing PMNL-mediated inflammation. The P6 fluoro-surfactant inhibited spontaneous platelet aggregation in hirudin-anticoagulated human blood in vitro, suggesting possible applications as an anti-thrombotic agent.
Article
Artificial oxygen carriers aim at improving oxygen transport and oxygen unloading to the tissues. Artificial oxygen carriers may thus be used as an alternative to allogeneic blood transfusions but also to improve tissue oxygenation and the function of organs with marginal oxygen supply. Such substances are not ‘artificial blood’ as they are designed exclusively to carry oxygen and carbon dioxide (CO2) and are devoid of other properties of blood such as coagulation and anti-infectious qualities. The aim of the present chapter is to describe the currently evaluated artificial oxygen carriers, to summarize their efficacy, and to discuss potential side effects.
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Perfluorocarbon emulsions are being clinically evaluated as artificial oxygen carriers to reduce allogeneic blood transfusions or to improve tissue oxygenation. Perfluorocarbon emulsions are efficacious in animal experiments, and in humans they are well tolerated and at least as successful to reverse physiologic transfusion triggers than autologous blood. Perfluorocarbon emulsions may be used in the future in the concept of augmented acute normovolaemic haemodilution. In this concept relatively low preoperative haemoglobin levels are targeted during preoperative normovolaemic haemodilution and a perfluorocarbon emulsion is given to augment oxygen delivery during surgery when low endogenous haemoglobin levels are expected. The autologous blood is subsequently retransfused in the postoperative period when the patient's oxygenation is provided primarily by the endogenous haemoglobin. Additional uses of perfluorocarbon emulsions will include treatments of diseases with compromised tissue oxygenation such as cerebral or myocardial ischaemia, air embolism and emergency or trauma surgery as long as no allogeneic blood is available.
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Molecular binding of hypocrellins to human serum albumin (HSA) needs to be further clarified considering the phototherapeutic potentials of hypocrellins to vascular diseases. In the current work, it was estimated that the binding constant of hypocrellin B (HB) to HSA was 2.28 x 10(4) M(-1). Furthermore, based on the fluorescence responses for both HB and the tryptophan of HSA, it was suggested that the binding of HB to HSA should be more specific rather than distributed randomly on the surface of HSA, which was also confirmed by photobleaching of the tryptophan via photosensitization of HB. Besides, it was found that both of the photo-bleaching of the tryptophan and the photo-oxidation of HB were principally oxygen-dependent, suggesting reactive oxygen species generated via the photosensitization of HB, instead of the free radicals of the photosensitizer (HB*-), play the most important role in photodynamic processes.
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The unique behavior of perfluorocarbons (PFCs), including their high oxygen dissolving capacity, hydrophobic and lipophobic character, and extreme inertness, derive directly, in a predictable manner, from the electronic structure and spatial requirements of the fluorine atom. Their low water solubility is key to the prolonged in vivo persistence of the now commercially available injectable microbubbles that serve as contrast agents for diagnostic ultrasound imaging. Oxygent, a stable, small-sized emulsion of a slightly lipophilic, rapidly excreted PFC, perfluorooctyl bromide (perflubron), has been engineered. Significant oxygen delivery has been established in animal models and through Phase II and III human clinical trials. However, an inappropriate testing protocol and the lack of funding led to temporary suspension of the trials.
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Block copolymer micelles are generally formed by the self-assembly of either amphiphilic or oppositely charged copolymers in aqueous medium. The hydrophilic and hydrophobic blocks form the corona and the core of the micelles, respectively. The presence of a nonionic water-soluble shell as well as the scale (10-100 nm) of polymeric micelles are expected to restrict their uptake by the mononuclear phagocyte system and allow for passive targeting of cancerous or inflamed tissues through the enhanced permeation and retention effect. Research in the field has been increasingly focused on achieving enhanced stability of the micellar assembly, prolonged circulation times and controlled release of the drug for optimal targeting. With that in mind, our group has developed a range of block copolymers for various applications, including amphiphilic micelles for passive targeting of chemotherapeutic agents and environment-sensitive micelles for the oral delivery of poorly bioavailable compounds. Here, we propose to review the innovations in block copolymer synthesis, polymeric micelle preparation and characterization, as well as the relevance of these developments to the field of biomedical research.