A Phthalocyanine–Peptide Conjugate with High In Vitro Photodynamic Activity and Enhanced In Vivo Tumor‐Retention Property

A novel zinc(II) phthalocyanine conjugated with a short peptide with a nuclear localization sequence, Gly‐Gly‐Pro‐Lys‐Lys‐Lys‐Arg‐Lys‐Val, was synthesized by click chemistry and a standard Fmoc solid‐phase peptide synthesis protocol. The conjugate was purified by HPLC and characterized with UV/Vis and high‐resolution mass spectroscopic methods. Both this compound and its non‐peptide‐conjugated analogue are essentially non‐aggregated in N,N‐dimethylformamide and can generate singlet oxygen effectively with quantum yields (Φ_Δ) of 0.84 and 0.81, respectively, relative to unsubstituted zinc(II) phthalocyanine (Φ_Δ=0.56). Conjugation of the peptide sequence, however, can enhance the cellular uptake, efficiency in generating intracellular reactive oxygen species, and photocytotoxicity of the phthalocyanine‐based photosensitizer against HT29 human colorectal carcinoma cells. The IC₅₀ value of the conjugate is as low as 0.21 μM . In addition, the conjugate shows an enhanced tumor‐retention property in tumor‐bearing nude mice. After 72 h post‐injection, the dye concentration in the tumor was significantly higher than that in other organs. The results suggest that this phthalocyanine–peptide conjugate is a highly promising photosensitizer for photodynamic therapy.     

Ag@TiO2 Nanoprisms with Highly Efficient Near‐Infrared Photothermal Conversion for Melanoma Therapy

Melanoma is a primary reason of death from skin cancer and associated with high lethality. Photothermal therapy (PTT) has been developed into a powerful cancer treatment technique in recent years. Here, we created a low‐cost and high‐performance PTT agent, Ag@TiO₂ NPs, which possesses a high photothermal conversion efficiency of ≈65 % and strong near‐infrared (NIR) absorption about 808 nm. Ag NPs were synthesized using a two‐step method and coated with TiO₂ to obtain Ag@TiO₂ NPs by a facile sol‐gel method. Because of the oxide, Ag@TiO₂ NPs exhibit remarkable high photothermal conversion efficiencies and biocompatibility in vivo and in vitro. Cytotoxicity and therapeutic efficiency of photothermal cytotoxicity of Ag@TiO₂ NPs were tested in B16‐F10 cells and C57BL/6J mice. Under light irradiation, the elevated temperature causes cell death in Ag NPs‐treated (100 μg mL^?1) cells in vitro (both p<0.01). In the case of subcutaneous melanoma tumor model, Ag@TiO₂ NPs (100 μg mL^?1) were injected into the tumor and irradiated with a 808 nm laser of 2 W cm^?2 for 1 minute. As a consequence, the tumor volume gradually decreased by NIR laser irradiation with only a single treatment. The results demonstrate that Ag@TiO₂ NPs are biocompatible and an attractive photothermal agent for cutaneous melanoma by local delivery.     

Semiconducting Polycomplex Nanoparticles for Photothermal Ferrotherapy of Cancer

This study reports the development of iron‐chelated semiconducting polycomplex nanoparticles (SPFeN) for photoacoustic (PA) imaging‐guided photothermal ferrotherapy of cancer. The hybrid polymeric nanoagent comprises a ferroptosis initiator (Fe³⁺) and an amphiphilic semiconducting polycomplex (SP_C) serving as both the photothermal nanotransducer and iron ion chelator. By virtue of poly(ethylene glycol) (PEG) grafting and its small size, SPFeN accumulates in the tumor of living mice after systemic administration, which can be monitored by PA imaging. In the acidic tumor microenvironment, SPFeN generates hydroxyl radicals, leading to ferroptosis; meanwhile, under NIR laser irradiation, it generates localized heat to not only accelerate the Fenton reaction but also implement photothermal therapy. Such a combined photothermal ferrotherapeutic effect of SPFeN leads to minimized dosage of iron compared to previous studies and effectively inhibits the tumor growth in living mice, which is not possible for the controls.     

A methyltitanocene complex of schisandrol A with high efficacy against multi‐drug resistant cervix and breast carcinoma cells

The objective of this work was to combine the ABC‐transporter inhibition characteristic of esters of the Schisandra sphenantera metabolite schisandrol A with the growth inhibitory and anti‐migratory effects typical of titanium complexes. To this end dimethyltitanocene, (h⁵‐C₅H₅)₂Ti(CH₃)₂, was reacted with the vicinal diol schisandrol A to afford the schisandroxy(methyl)titanocene ( 1 ) as a stable water‐soluble solid. In MTT assays against seven tumor cell lines it proved distinctly more cytotoxic than schisandrol A or dimethyltitanocene or combinations of these. It reached single‐digit micromolar IC₅₀(72 h) values against cells of leukemia HL‐60, melanoma 518A2 and also resistant cervix carcinoma KB‐V1/vbl and resistant breast carcinoma MCF‐7/topo. Non‐malignant fibroblasts were virtually insensitive to it [IC₅₀ (72 h) > 50 µM ]. In addition, the new complex inhibited the p‐gp drug transporters of KB‐V1/vbl cells and prevented a regrowth and closure of scratch wounds in cancer cell cultures (‘wound‐healing’ assay) when applied in concentrations < 1 µM , which is an indication of a potential anti‐migratory and anti‐invasive activity in solid tumors. Copyright © 2010 John Wiley & Sons, Ltd.     

Precisely Tuning Photothermal and Photodynamic Effects of Polymeric Nanoparticles by Controlled Copolymerization

Cancer possesses normoxic and hypoxia microenvironments with different levels of oxygen, needing different efficacies of photothermal and photodynamic therapies. It is important to precisely tune the photothermal and photodynamic effects of phototherapy nano‐agents for efficient cancer treatment. Now, a series of copolymeric nanoparticles (PPy‐Te NPs) were synthesized in situ by controlled oxidative copolymerization with different ratios of pyrrole to tellurophene by FeCl₃. The photothermal and photodynamic effects of semiconducting nano‐agents under the first near‐infrared (NIR) irradiation were precisely and systematically tuned upon simply varying the molar ratio of the pyrrole to tellurophene. The PPy‐Te NPs were used for cancer treatment in mice, exhibiting excellent biocompatibility and therapeutic effect. This work presents a simple method to tune photothermal and photodynamic therapies effect in semiconducting nano‐agents for cancer treatment.     

Photochemical Properties and Activity of Water‐Soluble Polymer/C60 Nanohybrids for Photodynamic Therapy

Water‐soluble star‐like poly(vinyl alcohol)/C₆₀ and poly{[poly(ethylene glycol) acrylate]‐co‐(vinyl acetate)}/C₆₀ nanohybrids are prepared by grafting macroradicals onto C₆₀ and are assessed as photosensitizers for photodynamic therapy. The photophysical and biological properties of both nanohybrids highlight key characteristics influencing their overall efficiency. The macromolecular structure (linear/graft) and nature (presence/absence of hydroxyl groups) of the polymeric arms respectively impact the photodynamic activity and the stealthiness of the nanohybrids. The advantages of both nanohybrids are encountered in a third one, poly[(N‐vinylpyrrolidone)‐co‐(vinyl acetate)]/C₆₀, which has linear grafts without hydroxyl groups, and shows a better photodynamic activity.

     

Pheophytin Derived Near‐Infrared‐Light Responsive Carbon Dot Assembly as a New Phototheranotic Agent for Bioimaging and Photodynamic Therapy

Carbon dots (CDs), a kind of phototheranostic agent with the capability of simultaneous bioimaging and phototherapy [i.e., photodynamic therapy (PDT) or photothermal therapy (PTT)], have received considerable attention because of their remarkable properties, including flexibility for surface modification, high biocompatibility, low toxicity and photo‐induced activity for malignant tumor cells. Among numerous carbon sources, it has been found that natural biomass are good candidates for the preparation of CD phototheranostic agents. In this study, pheophytin, a type of Mg‐free chlorophyll derivative and also a natural product with low toxicity, was used as a raw carbon source for the synthesis of CDs by using a microwave method. The obtained hydrophobic CDs exhibited a maximum near‐infrared (NIR) emission peak at approximately 680 nm, and high singlet oxygen (¹O₂) generation with a quantum yield of 0.62. The self‐assembled CDs from the as‐prepared CDs with DSPE‐mPEG2000 retained efficient ¹O₂ generation. The obtained carbon dot assembly was not only an efficient fluorescence (FL) imaging agent but also a smart PDT agent. Our studies indicated that the obtained hydrophilic CD assembly holds great potential as a new phototheranostic agent for cancer therapy. This work provides a new route for synthesis of CDs and proposes a readily available candidate for tumor treatment.     

Chemical Design of Nuclear‐Targeting Mesoporous Silica Nanoparticles for Intra‐nuclear Drug Delivery

Targeted drug delivery has been widely explored for efficient tumor therapy with desired efficacy but minimized side effects. It is widely known that large numbers of DNA‐toxins, such as doxorubicin, genes, reactive oxygen species, serving as therapeutic agents, can result in maximized therapeutic effects via the interaction directly with DNA helix. So after cellular uptake, these agents should be further delivered into cell nuclei to play their essential roles in damaging the DNA helix in cancer cells. Here, we demonstrate the first paradigm established in our laboratory in developing nuclear‐targeted drug delivery systems (DDSs) based on MSNs for enhanced therapeutic efficiency in the hope of speeding their translation into the clinics. Firstly, nuclear‐targeting DDSs based on MSNs, capable of intranuclear accumulation and drug release therein, were designed and constructed for the first time, resulting in much enhanced anticancer effects both in vitro and in vivo. Such an MSNs‐based and nuclear‐targeted drug/agent delivery strategy was further applied to overcome multidrug resistance (MDR) of malignant tumors, intra‐nuclearly deliver therapeutic genes, photosensitizers, radio‐enhancement agents and photothermal agents to realize efficient gene therapy, photodynamic therapy, radiation therapy and photothermal therapy, respectively.     

A Self‐Delivery Chimeric Peptide for Photodynamic Therapy Amplified Immunotherapy

In this paper, a self‐delivery chimeric peptide PpIX‐PEG₈‐KVPRNQDWL is designed for photodynamic therapy (PDT) amplified immunotherapy against malignant melanoma. After self‐assembly into nanoparticles (designated as PPMA), this self‐delivery system shows high drug loading rate, good dispersion, and stability as well as an excellent capability in producing reactive oxygen species (ROS). After cellular uptake, the ROS generated under light irradiation could induce the apoptosis and/or necrosis of tumor cells, which would subsequently stimulate the anti‐tumor immune response. On the other hand, the melanoma specific antigen (KVPRNQDWL) peptide could also activate the specific cytotoxic T cells for anti‐tumor immunity. Compared to immunotherapy alone, the combined photodynamic immunotherapy exhibits significantly enhanced inhibition of melanoma growth. Both in vitro and in vivo investigations confirm that PDT of PPMA has a positive effect on anti‐tumor immune response. This self‐delivery system demonstrates a great potential of this PDT amplified immunotherapy strategy for advanced or metastatic tumor treatment.     

Solubilization of C60 by micellization with a thermoresponsive block copolymer in water: Characterization,singlet oxygen generation,and DNA photocleavage

Water‐soluble diblock copolymer, poly(N‐isopropylacrylamide)‐block‐poly(N‐vinyl‐2‐pyrroridone) (PNIPAM_m‐b‐PNVP_n), was found to associate with fullerene (C₆₀), and thus C₆₀ can be solubilized in water. The 63C₆₀/PNIPAM_m‐b‐PNVP_n micelle formed a core‐shell micelle‐like aggregate comprising a C₆₀/PNVP hydrophobic core and a thermoresponsive PNIPAM shell. The C₆₀‐containing polymer micelle formation and its thermoresponsive behavior were characterized using light scattering and ¹H NMR techniques. The hydrodynamic radius (R_h) of the C₆₀‐bound polymer micelle increased with increasing temperature, which was ascribed to the hydrophobic association between dehydrated PNIPAM shells above lower critical solution temperature (LCST). ¹H NMR data suggest that the motion of the PNIPAM block is restricted above LCST due to the dehydration of the PNIPAM shell in water. The generation of singlet oxygen by photosensitization by the C₆₀‐bound polymer micelle was confirmed from photooxidation of 9,10‐anthracenedipropionic acid. Furthermore, DNA was found to be cleaved by visible light irradiation in the presence of the C₆₀‐bound polymer micelle. Therefore, there may be a hope for a pharmaceutical application of the C₆₀‐bound polymer micelle to cancer photodynamic therapy. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011.     

Photodynamic Activity of C70 Caged within Surface‐Cross‐Linked Liposomes

[70]Fullerene (C₇₀) encapsulated into a surface‐cross‐linked liposome, a so‐called cerasome, was prepared by an exchange reaction incorporating C₇₀?γ‐cyclodextrin complexes into lipid membranes. Fullerene exchange in a cerasome‐incorporated C₇₀ (CIC₇₀), as well as in a lipid‐membrane‐incorporated C₇₀ (LMIC₇₀), was completed within 1 min with stirring at 25 °C. CIC₇₀ was more resistant to lysis than LMIC₇₀ towards lysing agents such as surfactants. Furthermore, the photodynamic activity of CIC₇₀ in HeLa cells was similar to that of LMIC₇₀, indicating that C₇₀ can act as a photosensitizing drug (PS) without release from cerasome membranes. Thus, in contrast with general drug‐delivery systems (DDSs), which require the drug to be released from the interior of liposomes, carriers for PSs for use in photodynamic therapy (PDT) do not necessarily need to release the drug. These results indicate that DDSs with high morphological stability can increase the residence time in blood and achieves tumor‐selective drug delivery by the enhanced permeability and retention (EPR) effect.     

Metal–Organic Framework (MOF) Hybrid as a Tandem Catalyst for Enhanced Therapy against Hypoxic Tumor Cells

Encapsulation of active biomolecules and/or nanoparticles in metal–organic frameworks (MOFs) remains a great challenge in biomedical applications. In this work, through a stepwise in situ growth method, a black phosphorus quantum dot (BQ) and catalase were precisely encapsulated into the inner and outer layers of MOFs, respectively. The integrated MOF system as a tandem catalyst could convert H₂O₂ into O₂ in MOF‐stabilized catalase outer layer, and then O₂ was directly injected into MOF‐sensitized BQ inner, leading to high quantum yield of singlet oxygen. Upon internalization, the photodynamic therapy efficiency of the MOF system was 8.7‐fold greater than that without catalase, showing an enhanced therapeutic effect against hypoxic tumor cells. Furthermore, by coupling with photothermal therapy of BQs, photodynamic‐thermal synergistic therapy was realized both in vitro and in vivo.     

Synthesis of Poly(vinyl alcohol)/C60 and Poly(N‐vinylpyrrolidone)/C60 Nanohybrids as Potential Photodynamic Cancer Therapy Agents

Well‐defined poly(vinyl acetate) (PVAc) and poly(N‐vinylpyrrolidone)‐co‐poly(vinyl acetate) (PNVP‐co‐PVAc) chains end‐capped by Co(acac)₂ (acac=acetylacetonate) and prepared by cobalt‐mediated radical polymerization (CMRP) are grafted onto a fullerene. Homolytic Co? C bond cleavage of the polymer chain ends at 30 °C releases the polymeric radicals that add onto C₆₀, thereby leading to the corresponding PVAc/C₆₀ and PNVP‐co‐PVAc/C₆₀ nanohybrids. The [polymer–Co(acac)₂]/[C₆₀] molar ratio was varied to adjust the structure of the nanohybrids, and more particularly the number of grafted arms. Finally, the potential of the hydrosoluble PVOH/C₆₀ nanohybrids, which result from the methanolysis of the ester groups of PVAc/C₆₀, and of the PNVP‐co‐PVAc/C₆₀ nanohybrids as photosensitizers for photodynamic therapy (PDT), was approached. First, photobleaching tests demonstrated the ability of these nanohybrids to produce singlet oxygen upon irradiation, which can play a role in cell damage. Second, cell viability assays demonstrated that both types of nanohybrids are deprived of intrinsic cytotoxicity in the dark, whereas they promoted significant cell mortality when subjected to light treatment. The selective response of these materials to irradiation makes them promising compounds for PDT.     

Deep‐Level Defect Enhanced Photothermal Performance of Bismuth Sulfide–Gold Heterojunction Nanorods for Photothermal Therapy of Cancer Guided by Computed Tomography Imaging

Bismuth sulfide (Bi₂S₃) nanomaterials are emerging as a promising theranostic platform for computed tomography imaging and photothermal therapy of cancer. Herein, the photothermal properties of Bi₂S₃ nanorods (NRs) were unveiled to intensely correlate to their intrinsic deep‐level defects (DLDs) that potentially could work as electron–hole nonradiative recombination centers to promote phonon production, ultimately leading to photothermal performance. Bi₂S₃‐Au heterojunction NRs were designed to hold more significant DLD properties, exhibiting more potent photothermal performance than Bi₂S₃ NRs. Under 808 nm laser irradiation, Bi₂S₃‐Au NRs could trigger higher cellular heat shock protein 70 expression and more apoptotic cells than Bi₂S₃ NRs, and caused severe cell death and tumor growth inhibition, showing great potential for photothermal therapy of cancer guided by computed tomography imaging.     

Theranostic Nanoplatform with Hydrogen Sulfide Activatable NIR Responsiveness for Imaging‐Guided On‐Demand Drug Release

NIR light responsive nanoplatforms hold great promise for on‐demand drug release in precision cancer medicine. However, currently available systems utilize “always‐on” photothermal transducers that lack target specificity, and thus inaccurately differentiate tumors from normal tissues. Developed here is a theranostic nanoplatform featuring H₂S‐mediated in situ production of NIR photothermal agents for imaging‐guided and photocontrolled drug release. The system targets H₂S‐rich cancers. This nanoplatform shows H₂S‐activatable NIR‐II emission and NIR light controllable release of the drug Camptothecin‐11. Upon administering the system to HCT116 tumor‐bearing mice, the tumor is greatly suppressed with minimal side effects, arising from the synergy of the cancer‐specific and NIR light activated therapy. This theranostic nanoplatform thus sheds light on precision medicine with guidance through NIR‐II imaging.     

Thermohydrogel Containing Melanin for Photothermal Cancer Therapy

Melanin is an effective absorber of light and can extend to near infrared (NIR) regions. In this study, a natural melanin is presented as a photothermal therapeutic agent (PTA) because it provides a good photothermal conversion efficiency, shows biodegradability, and does not induce long‐term toxicity during retention in vivo. Poloxamer solution containing melanin (Pol–Mel) does not show any precipitation and shows sol–gel transition at body temperature. After irradiation from 808 nm NIR laser at 1.5 W cm⁻² for 3 min, the photothermal conversion efficiency of Pol–Mel is enough to kill cancer cells in vitro and in vivo. The tumor growth of mice bearing CT26 tumors treated with Pol–Mel injection and laser irradiation is suppressed completely without recurrence postirradiation. All these results indicate that Pol–Mel can become an attractive PTA for photothermal cancer therapy.

     

A Light-Responsive Injectable Hydrogel with Remodeling Tumor Microenvironment for Light-Activated Chemodynamic Therapy

Chemodynamic therapy (CDT) based on Fenton-like reaction is often limited by the tumor microenvironment (TME), which has insufficient hydrogen peroxide, and single CDT treatment is often less efficacious. To overcome these limitations, a hydrogel-based system is designed to enhance the redox stress (EOH) by loading the composite nanomaterial Cu-Hemin-Au, into the agarose hydrogels. The hydrogels can reach the tumor site upon intratumoral injection, and then coagulate and stay for extended period. Once irradiated with near-infrared light, the Cu-Hemin-Au act as a photothermal agent to convert the light energy into heat, and the EOH gradually heated up and softened, releasing the Cu-Hemin-Au residing in it to achieve photothermal therapy (PTT). Benefiting from the glucose oxidase (GOx)-like activity of the Au nanoparticles, glucose in the tumor cells is largely consumed, and hydrogen peroxide (H₂O₂) is generated in situ, and then Cu-Hemin-Au react with sufficient H₂O₂ to generate a large amount of reactive oxygen species, which promote the complete inhibition of tumor growth in mice during the treatment cycle. The hydrogel system for the synergistic enhancement of oxidative stress achieves good PTT/CDT synergy, providing a novel inspiration for the next generation of hydrogels for application in antitumor therapy.     

A C5N2 Nanoparticle Based Direct Nucleus Delivery Platform for Synergistic Cancer Therapy

Intracellular targeting has the same potential as tissue targeting to increase therapy efficacy, especially for drugs that are toxic to DNA. By adjusting intracellular traffic, we developed a novel direct‐nucleus‐delivery platform based on C₅N₂ nanoparticles (NPs). Supramolecular interactions of C₅N₂ NPs with the cell membrane enhanced cell uptake; abundant edge amino groups promoted fast and effective rupture of early endosomes; and the appropriate size of the NPs was also crucial for size‐dependent nuclear entry. As a proof of concept, the platform was not only suitable for the effective delivery of molecular drugs/dyes (doxorubicin, hydroxycamptothecine, and propidium iodide) and MnO₂ nanoparticles to the nucleus, but was also photoresponsive for nucleus‐targeting photothermal therapy (PTT) and photodynamic therapy (PDT) to further greatly increase anticancer efficacy. This strategy might open the door to a new generation of nuclear‐targeted enhanced anticancer therapy.     

Water‐soluble complex formation of fullerene and thermo‐responsive diblock copolymer

A diblock copolymer (P₉₈N₁₀₀) composed of a biocompatible water‐soluble block (PMPC) and a lower critical solution temperature (LCST) type thermo‐responsive block (PNIPAM) was prepared via controlled radical polymerization. To dissolve fullerene (C₆₀) in water, the C₆₀/P₉₈N₁₀₀ complex was prepared by mixing C₆₀ and P₉₈N₁₀₀ powders. The maximum solubilized C₆₀ concentration in water was 1.39 g/L, as estimated from UV–vis adsorption, when the polymer concentration was 5.0 g/L. The percent transmittance of the aqueous solution of the C₆₀/P₉₈N₁₀₀ complex decreased above 36 °C due to inter‐complex association above the LCST for the PNIPAM block. While the hydrodynamic radius of C₆₀/P₉₈N₁₀₀ complex was 135 nm at 20 °C, it increased to 161 nm at 50 °C. Despite the observation of ¹H NMR signals from PMPC and PNIPAM blocks for the C₆₀/P₉₈N₁₀₀ complex in D₂O at room temperature, the signals from PNIPAM disappeared above 35 °C due to restricted motion of PNIPAM. Generation of singlet oxygen (¹O₂) from the C₆₀/P₉₈N₁₀₀ complex by photo‐irradiation was confirmed using 9,10‐anthracene dipropionic acid (ADPA). The absorbance of ADPA decreased with increasing irradiation time due to oxidation of ADPA by ¹O₂. It is expected that the C₆₀/P₉₈N₁₀₀ complex can be applied as a thermo‐responsive carrier for photodynamic therapy. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 2432–2439     

Photodynamic Activity of Fullerenes and Other Molecules Incorporated into Lipid Membranes by Exchange

An effective exchange method is described whereby liposomal drug carriers of hydrophobic guest biomolecules are used to incorporate the guests into lipid membranes. The exchange method transfers the guest molecule from a cyclodextrin cavity to a liposome in water. Lipid‐membrane‐incorporated fullerenes (LMIC_x: x = 60 or 70) prepared by the exchange method have much higher liposomal stability and fullerene water solubility than those prepared by conventional methods. The LMIC₆₀ have high photodynamic activities with respect to human cancer cells under 350–500 nm excitation. Furthermore, the LMIC₆₀ bilayers, containing light‐harvesting antenna molecules in addition to the C₆₀, showed improved activities at the optimal wavelength for photodynamic therapy.