Self-Assembled Binaphthyl-Bridged Amphiphilic AABB Phthalocyanines: Nanostructures for Efficient Antimicrobial Photodynamic Therapy

Herein, the photodynamic activity of phthalocyanine (pc)-assembled nanoparticles against bacterial strains is demonstrated. The photosensitizers (PS) studied in this work are two chiral Zn^IIPcs ( PS-1 and PS-2 ), with an AABB geometry (where A and B refer to differently substituted isoindole constituents). They contain differently functionalized, chiral binaphthyloxy-linked A isoindole units, which determine the hydrophobicity of the system, and cationic methyl pyridinium moieties in the other two isoindoles to embody hydrophilicity. Both compounds have the ability to self-assemble into nanoparticles in aqueous media and have proved efficient in the photo-inactivation of Staphylococcus aureus and Escherichia coli, selected as models of Gram-positive and Gram-negative bacteria. The average size of the nanoparticles was determined by substitution at the binaphthyl core and, in turn, influences the toxicity of the PS. Thus, PS-1 , presenting a nonsubstituted binaphthyl core, forms larger nanoparticles with a larger cationic surface than the octyl-functionalized PS-2 . Although both PSs present similar structure and photophysical features, the self-assembled nanostructures of PS-1 are more effective at killing both types of strain, showing an outstanding photo-inactivation capacity with the Gram-negative E. coli.     

以上转换纳米颗粒和光动力疗法为基础的肿瘤联合治疗研究进展

光动力疗法作为一种非侵入性治疗手段已广泛应用于肿瘤的临床治疗。然而其疗效却深受紫外-可见光组织穿透深度的限制。镧系掺杂上转换纳米颗粒可以将近红外光转换为紫外-可见光,被广泛用于与传统光敏剂结合实现更为高效的光动力治疗。近年来,以上转换纳米颗粒和光动力疗法为基础的肿瘤联合治疗研究备受关注,本文重点介绍了该领域的最新研究进展,并对其未来发展方向作出了展望。     

Small Mesoporous Silica Nanoparticles as Carriers for Enhanced Photodynamic Therapy

Small mesoporous silica nanoparticles (MSNs; ca. 37 nm in diameter) have a high loading capacity for a hydrophobic photosensitizer, SiPcCl₂ (82.6 % in weight), and excellent endocytosis properties. As a result, the amount of SiPcCl₂ being delivered to cancer cells is increased by approximately two orders of magnitude compared to pure SiPcCl₂ at the same dosage, and the photodynamic therapy (PDT) efficiency is enhanced by over fourfold. Our method can be widely used to increase the dosage of hydrophobic anti‐cancer drugs in cancer cells and therefore increase the cytotoxicity of the drugs.     

Nanoparticles for Triple Drug Release for Combined Chemo- and Photodynamic Therapy

A pH-responsive drug delivery system (DDS) based on mesoporous silica nanoparticles (MSNs) has been prepared for the delivery of three anticancer drugs with different modes of action. The novelty of this system is its ability to combine synergistic chemotherapy and photodynamic therapy. A photoactive conjugate of a phthalocyanine (Pc) and a topoisomerase I inhibitor (topo-I), namely camptothecin (CPT), linked by a poly(ethylene glycol) (PEG) chain has been synthesized and then loaded into the mesopores of MSNs. Doxorubicin (DOX), which is a topoisomerase II inhibitor (topo-II), has also been covalently anchored to the outer surface of the MSNs through a dihydrazide PEG linker. In the acidic environment of tumor cells, selective release of the three drugs takes place. In vitro studies have demonstrated the endocytosis of the system into HeLa and HepG2 cells, and the subsequent release of the three drugs into the cytoplasm and nucleus. Furthermore, the cytotoxic effect of DOX, CPT and Pc has been assessed in vitro before and upon light irradiation.     

Organic Nanoparticles with Persistent Luminescence for In Vivo Afterglow Imaging-Guided Photodynamic Therapy

Optical imaging-guided photodynamic therapy (PDT), with precise localization and non-invasive treatment of tumors, is an emerging technique with great potential for cancer therapy. However, impaired by tissue auto-fluorescence that causes low signal-to-background ratio (SBR), most fluorescence imaging systems show poor sensitivity to tumors in vivo. In this study, we synthesized organic nanoparticles (ONPs) with persistent luminescence and good biocompatibility for afterglow imaging-guided PDT. The ONPs displayed near-infrared light emission with half-life time at minute level, which offered high SBR and good tissue penetration for in vivo afterglow tumor imaging. Taking advantage of their abundant singlet oxygen generation by NIR laser irradiation guided to the tumor sites, the ONPs also enabled imaging-guided PDT for efficient suppression of tumor growth in mice with minimal damage to major organs.     

Dual‐Mode Antibacterial Conjugated Polymer Nanoparticles for Photothermal and Photodynamic Therapy

In this work, dual‐mode antibacterial conjugated polymer nanoparticles (DMCPNs) combined with photothermal therapy (PTT) and photodynamic therapy (PDT) are designed and explored for efficient killing of ampicillin‐resistant Escherichia coli (Amp^r E. coli). The DMCPNs are self‐assembled into nanoparticles with a size of 50.4 ± 0.6 nm by co‐precipitation method using the photothermal agent poly(diketopyrrolopyrrole‐thienothiophene) (PDPPTT) and the photosensitizer poly[2‐methoxy‐5‐((2‐ethylhexyl)oxy)‐p‐phenylenevinylene] (MEH‐PPV) in the presence of poly(styrene‐co‐maleic anhydride) which makes nanoparticles disperse well in water via hydrophobic interactions. Thus, DMCPNs simultaneously possess photothermal effect and the ability of sensitizing oxygen in the surrounding to generate reactive oxygen species upon the illumination of light, which could easily damage resistant bacteria. Under combined irradiation of near‐infrared light (550 mW cm^?2, 5 min) and white light (65 mW cm^?2, 5 min), DMCPNs with a concentration of 9.6 × 10^?4 µm could reach a 93% inhibition rate against Amp^r E. coli, which is higher than the efficiency treated by PTT or PDT alone. The dual‐mode nanoparticles provide potential for treating pathogenic infections induced by resistant microorganisms in clinic.     

Programming DNA Nanoassembly for Enhanced Photodynamic Therapy

Photodynamic therapy (PDT) has extraordinary promise for the treatment of many cancers. However, its clinical progress is impaired by the intrinsic hypoxic tumor microenvironment that limits PDT efficacy and the safety concern associated with biological specificity of photosensitizers or vehicles. Now it is demonstrated that rationally designed DNA nanosponges can load and delivery photosensitizer effectively, target tumor precisely, and relieve hypoxia‐associated resistance remarkably to enhance the efficacy of PDT. Specifically, the approach exhibits a facile assembly process, provides programmable and versatile nanocarriers, and enables robust in vitro and in vivo anti‐cancer efficacy with excellent biosafety. These findings represent a practical and safe approach by designer DNA nanoassemblies to combat cancer effectively and suggest a powerful strategy for broad biomedical application of PDT.     

Acid-Activatable Transmorphic Peptide-Based Nanomaterials for Photodynamic Therapy

Inspired by the dynamic morphology control of molecular assemblies in biological systems, we have developed pH-responsive transformable peptide-based nanoparticles for photodynamic therapy (PDT) with prolonged tumor retention times. The self-assembled peptide–porphyrin nanoparticles transformed into nanofibers when exposed to the acidic tumor microenvironment, which was mainly driven by enhanced intermolecular hydrogen bond formation between the protonated molecules. The nanoparticle transformation into fibrils improved their singlet oxygen generation ability and enabled high accumulation and long-term retention at tumor sites. Strong fluorescent signals of these nanomaterials were detected in tumor tissue up to 7 days after administration. Moreover, the peptide assemblies exhibited excellent anti-tumor efficacy via PDT in vivo. This in situ fibrillar transformation strategy could be utilized to design effective stimuli-responsive biomaterials for long-term imaging and therapy.     

Rhodium Nanoparticles as a Novel Photosensitizing Agent in Photodynamic Therapy against Cancer

Photodynamic therapy (PDT) is a promising alternative treatment for different types of cancer due to its high selectivity, which prevents healthy tissues from being damaged. The use of nanomaterials in PDT has several advantages over classical photosensitizing agents, due to their unique properties and their capacity for functionalization. Especially interesting is the use of metallic nanoparticles, which are capable of absorbing electromagnetic radiation and either transferring this energy to oxygen molecules for the generation of reactive oxygen species (ROS) or dissipating it as heat. Although previous reports have demonstrated the capacity of Rh derivatives to serve as anti-tumor drugs, to the best of our knowledge there have been no studies on the potential use of small-sized Rh nanoparticles as photosensitizers in PDT. In this study, 5 nm Rh nanoparticles have been synthesized and their potential in PDT has been evaluated. The results show that treatment with Rh nanoparticles followed by NIR irradiation induces apoptosis in cancer cells through a p53-independent mechanism.     

Multifunctional Core–Shell Upconverting Nanoparticles for Imaging and Photodynamic Therapy of Liver Cancer Cells

Lanthanide‐doped upconversion nanoparticles (UCNPs) have attracted considerable attention for their application in biomedicine. Here, silica‐coated NaGdF₄:Yb,Er/NaGdF₄ nanoparticles with a tetrasubstituted carboxy aluminum phthalocyanine (AlC₄Pc) photosensitizer covalently incorporated inside the silica shells were prepared and applied in the photodynamic therapy (PDT) and magnetic resonance imaging (MRI) of cancer cells. These UCNP@SiO₂(AlC₄Pc) nanoparticles were uniform in size, stable against photosensitizer leaching, and highly efficient in photogenerating cytotoxic singlet oxygen under near‐infrared (NIR) light. In vitro studies indicated that these nanoparticles could effectively kill cancer cells upon NIR irradiation. Moreover, the nanoparticles also demonstrated good MR contrast, both in aqueous solution and inside cells. This is the first time that NaGdF₄:Yb,Er/NaGdF₄ upconversion‐nanocrystal‐based multifunctional nanomaterials have been synthesized and applied in PDT. Our results show that these multifunctional nanoparticles are very promising for applications in versatile imaging diagnosis and as a therapy tool in biomedical engineering.     

Molecular Design of Highly Efficient Heavy-Atom-Free Triplet BODIPY Derivatives for Photodynamic Therapy and Bioimaging

Novel BODIPY photosensitizers were developed for imaging-guided photodynamic therapy. The introduction of a strong electron donor to the BODIPY core through a phenyl linker combined with the twisted arrangement between the donor and the BODIPY acceptor is essential for reducing the energy gap between the lowest singlet excited state and the lowest triplet state (ΔE_ST), leading to a significant enhancement in the intersystem crossing (ISC) of the BODIPYs. Remarkably, the BDP-5 with the smallest ΔE_ST (ca. 0.44 eV) exhibited excellent singlet oxygen generation capabilities in both organic and aqueous solutions. BDP-5 also displayed bright emission in the far-red/near-infrared region in the condensed states. More importantly, both in vitro and in vivo studies demonstrated that BDP-5 NPs displayed a high potential for photodynamic cancer therapy and bioimaging.     

Photodynamic Therapy of Oligoethylene Glycol‐Dendronized Reduction‐Sensitive Porphyrins

Graphene oxide (GO ) and its functionalized derivatives have attracted increasing attention in medical treatment. Herein, a reduction sensitive PEI‐GO ‐SS ‐TPP was synthesized for photodynamic therapy. More than 80% porphyrin release was observed in the presence of 10 mmol•L⁻¹ DTT in one day. The confocal laser scanning microscopy confirmed that the cell uptake efficiency of PEI‐GO‐SS‐TPP was remarkably enhanced as compared to free porphyrin which was significantly dependent on incubation time. For photodynamic therapy, GSH‐OEt could effectively increase the photodynamic therapy efficiency of PEI‐GO ‐SS ‐TPP . Compared with free porphyrin, the toxicity from PEI‐GO ‐SS ‐TPP is much higher with a low IC₅₀ (2.1 µg/mL ) value. All results indicate that the PEI‐GO ‐SS ‐TPP PSs are promising for photodynamic therapy.     

Phosphorescent Polymeric Nanoparticles by Coordination Cross‐Linking as a Platform for Luminescence Imaging and Photodynamic Therapy

Water‐soluble phosphorescent polymeric nanoparticles with an average diameter of approximately 100 nm were synthesized by a coordination cross‐linking reaction. The pyridine blocks in poly(4‐vinyl pyridine‐b‐ethylene oxide) (P4VP‐b‐PEO) were cross‐linked by the iridium chloride‐bridged dimer in DMF solution. Owing to the presence of an iridium complex with different ligands in the core of the polymeric nanoparticles, NP‐1, NP‐2, and NP‐3 showed bright green, yellow, and red phosphorescence, respectively. PEG chains in the shell gave the polymeric nanoparticles solubility and biocompatibility, which was confirmed by an MTT assay using HeLa cells as a model cancer cell line. The flow cytometry and laser confocal fluorescence microscopy results revealed NP‐2, as an example, could be effectively uptaken by HeLa cells. Therefore, these polymeric nanoparticles can be used as luminescent probes for living cells. In addition, ¹O₂ could be effectively generated in the presence of NP‐2 upon irradiation with visible light (λ>400 nm, 300 mW cm^?2), which was confirmed by a clear decrease in the fluorescence intensity of 9,10‐dimethylanthracene (DMA). After incubation with NP‐2 at a concentration of 200 μg mL^?1 for 6 h, approximately 90 % of HeLa cells were effectively ablated upon irradiation with visible light for only 10 min, indicating the potential for photodynamic therapy with polymeric nanoparticles.     

Hypoxia Induced by Upconversion‐Based Photodynamic Therapy: Towards Highly Effective Synergistic Bioreductive Therapy in Tumors

Local hypoxia in tumors is an undesirable consequence of photodynamic therapy (PDT), which will lead to greatly reduced effectiveness of this therapy. Bioreductive pro‐drugs that can be activated at low‐oxygen conditions will be highly cytotoxic under hypoxia in tumors. Based on this principle, double silica‐shelled upconversion nanoparticles (UCNPs) nanostructure capable of co‐delivering photosensitizer (PS) molecules and a bioreductive pro‐drug (tirapazamine, TPZ) were designed (TPZ‐UC/PS), with which a synergetic tumor therapeutic effect has been achieved first by UC‐based (UC‐) PDT under normal oxygen environment, immediately followed by the induced cytotoxicity of activated TPZ when oxygen is depleted by UC‐PDT. Treatment with TPZ‐UC/PS plus NIR laser resulted in a remarkably suppressed tumor growth as compared to UC‐PDT alone, implying that the delivered TPZ has a profound effect on treatment outcomes for the much‐enhanced cytotoxicity of TPZ under PDT‐induced hypoxia.     

Highly Efficient,Conjugated‐Polymer‐Based Nano‐Photosensitizers for Selectively Targeted Two‐Photon Photodynamic Therapy and Imaging of Cancer Cells

Two‐photon photodynamic therapy (2P‐PDT) is a promising noninvasive treatment of cancers and other diseases with three‐dimensional selectivity and deep penetration. However, clinical applications of 2P‐PDT are limited by small two‐photon absorption (TPA) cross sections of traditional photosensitizers. The development of folate receptor targeted nano‐photosensitizers based on conjugated polymers is described. In these nano‐photosensitizers, poly{9,9‐bis[6′′‐(bromohexyl)fluorene‐2,7‐ylenevinylene]‐co‐alt‐1,4‐(2,5‐dicyanophenylene)}, which is a conjugated polymer with a large TPA cross section, acts as a two‐photon light‐harvesting material to significantly enhance the two‐photon properties of the doped photosensitizer tetraphenylporphyrin (TPP) through energy transfer. These nanoparticles displayed up to 1020‐fold enhancement in two‐photon excitation emission and about 870‐fold enhancement in the two‐photon‐induced singlet oxygen generation capability of TPP. Surface‐functionalized folic acid groups make these nanoparticles highly selective in targeting and killing KB cancer cells over NIH/3T3 normal cells. The 2P‐PDT activity of these nanoparticles was significantly improved, potentially up to about 1000 times, as implied by the enhancement factors of two‐photon excitation emission and singlet oxygen generation. These nanoparticles could act as novel two‐photon nano‐photosensitizers with combined advantages of low dark cytotoxicity, targeted 2P‐PDT with high selectivity, and simultaneous two‐photon fluorescence imaging capability; these are all required for ideal two‐photon photosensitizers.     

纳米粒子的控制生长和自组装研究进展

由于在纳米器件上潜在应用,通过化学方法控制的纳米粒子生长,以及纳米粒子自组装的一维、二维和三维点阵受到人们的广泛关注。本文介绍来近年来纳米粒子的控制生长和组装研究的现状。主要探讨了有机稳定剂对纳米粒子形状和尺寸控制的影响。含配位基团和长链烷烃的有机化合物不但可以用控制纳米粒子生长的稳定剂,而且可以用作纳米粒子自组装的模板剂。     

Smart Magnetic and Fluorogenic Photosensitizer Nanoassemblies Enable Redox-Driven Disassembly for Photodynamic Therapy

Stimuli-responsive smart photosensitizer (PS) nanoassemblies that allow enhanced delivery and controlled release of PSs are promising for imaging-guided photodynamic therapy (PDT) of tumors. However, the lack of high-sensitivity and spatial-resolution signals and fast washout of released PSs from tumor tissues have impeded PDT efficacy in vivo. Herein, we report tumor targeting, redox-responsive magnetic and fluorogenic PS nanoassemblies ( NP-RGD ) synthesized via self-assembly of a cRGD- and disulfide-containing fluorogenic and paramagnetic small molecule ( 1-RGD ) for fluorescence/magnetic resonance bimodal imaging-guided tumor PDT. NP-RGD show high r₁ relaxivity but quenched fluorescence and PDT activity; disulfide reduction by glutathione (GSH) promotes efficient disassembly into a small-molecule probe ( 2-RGD ) and an organic PS (PPa-SH), which could further bind with intracellular albumin, allowing prolonged retention and cascade activation of fluorescence and PDT to ablate tumors.     

Luminescent,Oxygen‐Supplying,Hemoglobin‐Linked Conjugated Polymer Nanoparticles for Photodynamic Therapy

Photodynamic therapy (PDT) is a promising method for cancer treatment. Two parameters that influence the efficacy of PDT are the light source and oxygen supply. Herein, we prepared a system for PDT using hemoglobin (Hb)‐linked conjugated polymer nanoparticles (CPNs), which can luminesce and supply oxygen. Hb catalyzes the activation of luminol, the conjugated polymer poly[2‐methoxy‐5‐(2‐ethylhexyloxy)‐1,4‐phenylenevinylene] (MEH–PPV) nanoparticles can absorb the chemiluminescence of luminol through chemiluminescence resonance energy transfer (CRET) and then sensitize the oxygen supplied by Hb to produce reactive oxygen species that kill cancer cells. This system could be used for the controlled release of an anticancer prodrug. The system does not need an external light source and circumvents the insufficient level molecular oxygen under hypoxia. This work provides a proof‐of‐concept to explore smart and multifunctional nanoplatforms for phototherapy.     

A Self‐Assembled Metallomacrocycle Singlet Oxygen Sensitizer for Photodynamic Therapy

Although metal‐ion‐directed self‐assembly has been widely used to construct a vast number of macrocycles and cages, it is only recently that the biological properties of these systems have begun to be explored. However, up until now, none of these studies have involved intrinsically photoexcitable self‐assembled structures. Herein we report the first metallomacrocycle that functions as an intracellular singlet oxygen sensitizer. Not only does this Ru₂Re₂ system possess potent photocytotoxicity at light fluences below those used for current medically employed systems, it offers an entirely new paradigm for the construction of sensitizers for photodynamic therapy.     

Combined Magnetic Resonance Imaging and Photodynamic Therapy Using Polyfunctionalised Nanoparticles Bearing Robust Gadolinium Surface Units

A robust dithiocarbamate tether allows novel gadolinium units based on DOTAGA (q=1) to be attached to the surface of gold nanoparticles (2.6–4.1 nm diameter) along with functional units offering biocompatibility, targeting and photodynamic therapy. A dramatic increase in relaxivity (r₁) per Gd unit from 5.01 mm ⁻¹ s⁻¹ in unbound form to 31.68 mm ⁻¹ s⁻¹ (10 MHz, 37 °C) is observed when immobilised on the surface due to restricted rotation and enhanced rigidity of the Gd complex on the nanoparticle surface. The single-step synthetic route provides a straightforward and versatile way of preparing multifunctional gold nanoparticles, including examples with conjugated zinc–tetraphenylporphyrin photosensitizers. The lack of toxicity of these materials (MTT assays) is transformed on irradiation of HeLa cells for 30 minutes (PDT), leading to 75 % cell death. In addition to passive targeting, the inclusion of units capable of actively targeting overexpressed folate receptors illustrates the potential of these assemblies as targeted theranostic agents.