Photodynamic Chemotherapy Research Articles

Doxorubicin and Zinc phthalocyanine loaded pH-responsive FA-BSP-SA/TPGS micelles for synergistic chemo-photodynamic therapy against tumors

The present study was to evaluate the chemo-photodynamic synergistic antitumor effect of FA-BSP-SA/TPGS micelles loaded with doxorubicin (Dox) and Zinc phthalocyanine (ZnPc). Multiple evaluation parameters involving quality index (particle size, zeta potential, loading capacity, and encapsulation efficiency, etc), biocompatibility, in vitro drug release, and in vitro antitumor assays were performed to explore the optimal mass ratio in FA-BSP-SA/TPGS mixed micelles. The results showed that FA-BSP-SA/TPGS25 micelles were more ideal carriers. The synergistic antitumor effect of Dox and ZnPc was also investigated and proved to be better. Moreover, the current study revealed that TPGS, Dox, and ZnPc decreased mitochondrial membrane potential and increased ROS level in breast 4T1 cancer cells. Meanwhile, in vivo antitumor assay certified that Dox@FA-BSP-SA/TPGS25+ ZnPc@FA-BSP-SA/TPGS25 micelles showed the most superior antitumor effect. In conclusion, Dox@FA-BSP-SA/TPGS25+ZnPc@FA-BSP-SA/TPGS25 micelles are promising drug-loaded nanomaterials with synergistic chemo-photodynamic effects against cancer.

Self-assembled boron dipyrromethene-based nanocarriers with encapsulated doxorubicin for chemo-photodynamic therapy

The development of water-soluble boron dipyrromethene (BODIPY) dyes is important for biomedical applications as it offers the potential to form a drug self-delivery system with superior drug utilization. Herein, the amphiphilic BODIPY dye NBDP with good water solubility and superior onsite singlet oxygen generation ability was obtained, in which the chemotherapy drug doxorubicin (DOX) was loaded for achieving a synergistic combination of chemotherapy and photodynamic therapy. The introduction of hydrophilic chains at the 3,5-position through the Knoevenagel reaction enhanced the water solubility and lengthened the conjugated structure of NBDP, resulting in a red shift of the spectrum to the near-infrared (NIR) region. The introduction of iodine atoms at the 2,6-position enhanced the intersystem crossing through the heavy atom effect and promoted singlet oxygen generation (ΦΔ = 71.1%), thereby enhancing the photodynamic therapy. Meanwhile, encapsulated DOX endowed the nanodrug with a chemotherapeutic effect, which compensated for the defects of photodynamic therapy, including the limitation of treatment depth. In vitro and in vivo experiments revealed the actualisation of NIR fluorescent imaging-guided chemo-photodynamic synergistic therapy. Hence, this multifunctional nano-system without extra carriers provides greater insight into the development of drug self-delivery systems with high drug utilization for the multi-modal diagnosis and treatment of cancer.

Sequentially Activatable Polypeptide Nanoparticles for Combinatory Photodynamic Chemotherapy of Breast Cancer.

Stimuli-activatable nanomaterials hold significant promise for tumor-specific drug delivery by recognizing the internal or external stimulus. Herein, we reported a dual-responsive and biodegradable polypeptide nanoparticle (PPTP@PTX2 NP) for combinatory chemotherapy and photodynamic therapy (PDT) of breast cancer. The NPs were engineered by encapsulating diselenide bond linked dimeric prodrug of paclitaxel (PTX2) in an intracellular acidity-activatable polypeptide micelle. Specifically, the acid-responsive polypeptide was synthesized by grafting a tetraphenyl porphyrin (TPP) photosensitizer and N,N-diisopropylethylenediamine (DPA) onto the poly(ethylene glycol)-block-poly(glutamic acid) diblock copolymer by the amidation reaction, which self-assembled into micellar NPs and was activated inside the acidic endocytic vesicles to perform PDT. The paclitaxel dimer can be stably loaded into the polypeptide NPs and be restored by PDT inside the tumor cells. The formed PPTP@PTX2 NPs remained inert during blood circulation and passively accumulated in the tumor foci, which could be activated within the endocytic vesicles via acid-triggered protonation of DPA groups to generate fluorescence signal and release PTX2 in 4T1 murine breast tumor cells. Upon 660 nm laser irradiation, the activated NPs carried out PDT via TPP and chemotherapy via PTX to induce apoptosis of 4T1 cells and thereby efficiently inhibited 4T1 tumor growth and prevented metastasis of tumor cells.

Hydrazide-manganese coordinated multifunctional nanoplatform for potentiating immunotherapy in hepatocellular carcinoma

Immune checkpoint blockade (ICB)-based immunotherapy is a revolutionary therapeutic strategy for hepatocellular carcinoma (HCC). However, tumor immune tolerance and escape severely restrict the therapeutic efficacy of ICB therapy. It is urgent to explore new strategies to potentiate ICB therapy in HCC. Herein, we developed manganese oxide-crosslinked bovine albumin/hyaluronic acid nanoparticles (BHM) by an innovative hydrazide-manganese coordination and desolvation process. Successive loading of doxorubicin (DOX) and indocyanine green (ICG) was achieved via hydrazone linkage and electrostatic interactions, respectively, obtaining DOX/ICG-coloaded BHM nanoplatform (abbreviated as BHMDI). The BHMDI nanoplatform exhibited a high drug content (>46%) and pH/reduction dual-responsive drug release behavior. The nanoplatform could efficiently alleviate tumor hypoxia by catalytic decomposition of intracellular H2O2 to O2 and significantly improve BHMDI-based photodynamic chemotherapy efficacy. The BHMDI nanoplatform downregulated the proportion of alternatively activated (M2) macrophages in tumors and simultaneously induced immunogenic death of HCC cells, thus promoting the maturation of dendritic cells and ensuing priming of CD4+ and CD8+ T cells. Importantly, programmed death-1 (PD-1) blockade in combination with BHMDI nanoplatform not only eradicated primary tumors but inhibited tumor recurrence, abscopal tumor growth and lung metastasis of HCC by triggering robust systemic antitumor immunity. This work proved the feasibility of BHMDI-based photodynamic chemotherapy for potentiating PD-1 blockade immunotherapy by reversing hypoxic and immunosuppressive tumor microenvironment.

Construction of multifunctional mesoporous silicon nano-drug delivery system and study of dual sensitization of chemo-photodynamic therapy in vitro and in vivo

This study was conducted to construct a multifunctional nanodrug delivery system (NDDS) to deplete glutathione (GSH) in tumor cells and amplify oxidative stress, enhancing the synergistic effect of chemotherapy and photodynamic therapy (PDT). l-Buthionine-sulfoximine (BSO) and chlorin e6 (Ce6) were loaded into mesoporous silicon nanoparticles (MSN), and then MSN were modified with oxidized hyaluronic acid (OHA) as a pore-blocking agent. Cisplatin (Pt(II)) was further loaded by a coordination reaction with carboxyl groups in OHA to yield a multifunctional NDDS (denoted as MSN@OHA-Ce6/BSO/Pt). The physicochemical properties and antitumor activity of the prepared nanoparticles were characterized in detail. In vitro and in vivo experiments demonstrated that OHA was shed from MSN@OHA-Ce6/BSO/Pt under acidic conditions in tumors, resulting in the release of free BSO, Ce6, and Pt(II). The released BSO could reduce intracellular GSH expression by 48.8 %, effectively enhancing the PDT effect of Ce6 and the chemotherapy effect of Pt(II). Finally, the tumor inhibitory rate (vs saline) reached 73.8 % ± 2.5 % for MSN@OHA-Ce6/BSO/Pt in A549/DDP tumor-bearing nude mice. Therefore, the multifunctional NDDS significantly enhanced the synergistic effect of PDT and chemotherapy.

Zwitterionic meso-silica/polypeptide hybrid nanoparticles for efficient azithromycin delivery and photodynamic therapy for synergistic treatment of drug-resistant bacterial infection

The treatment of drug-resistant bacterial infections attributed to the overuse of antibiotics still remains a serious challenge globally. Herein, zwitterionic charge switchable meso-silica/polypeptide hybrid nanoparticles (MSPNs) were prepared for the synergistic chemo-photodynamic therapy in the treatment of drug-resistant bacterial infections. Subsequently, azithromycin (AZT) and methylene blue (MB) were loaded in the MSPNs to form the combined chemo-photodynamic therapeutic nanoparticles (MSPNs-AZT/MB) for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Remarkably, the as-prepared MSPNs-AZT/MB exhibited a negative surface charge of −5.2 mV at physiological pH while switching into positive surface charge of 24.7 mv in an acidic environment, leading to enhanced binding with bacterial surface. The lipase-triggered AZT release up to 77.9 % was achieved, and the loaded MB demonstrated efficient singlet oxygen (1O2) generation for photodynamic therapy. The in vitro experimental results displayed an excellent antibacterial effect against MRSA in both planktonic and biofilm phenotypes. Additionally, the as-prepared MSPNs-AZT/MB exhibited synergistic and enhanced antibacterial infection effect up to 94 % comparing to monotherapy in a mice model. Considering the above advantages, the as-prepared combined chemo-photodynamic therapeutic nanoparticles showed promising biocompatibility and clinical potential for the efficient therapy of drug-resistant bacteria.

Targeted chemo-photodynamic therapy toward esophageal cancer by GSH-sensitive theranostic nanoplatform

As the sixth leading cause of cancer death, esophageal cancer is threatening the life of people worldwide. Traditional treatments, such as surgery, chemotherapy, radiotherapy, are facing always augmented challenges including invasion, multidrug resistance (MDR), off-target toxicity. Chemo & Photodynamic synergistic therapy represents one promising strategy for improved treatment efficiency. But it is still hindered by the lack of tumor targeting, deleterious side effects, and unfavorable microenvironment for photodynamic therapy (PDT). To overcome those obstacles, one theranostic nano-assambly drug, GCDs-Ce6/Pt-EGF, was designed and fabricated. Green fluorescence carbon dots (GCDs) with the excellent optical properties, modifiability and low toxicity were prepared as drug carrier. Epidermal growth factor (EGF) was conjugated to the nano-assembly to realize tumor specific targeting. Chlorin e6 (Ce6) in the presence of laser irradiation achieved PDT by generating proapoptosis reactive oxygen species (ROS). Moreover, Ce6 incorporated into GCDs endowed the nano-assambly imaging ability and facilitate image-guided therapy. Pt(IV), cisplatin prodrug, in the nano-assambly depleted the glutathione (GSH) of tumor microenvironment when it was reduced to cytotoxicity Pt(II). Compared with single treatment, GCDs-Ce6/Pt-EGF exhibited enhanced tumor cell killing capacity and better biosafety in vitro and in vivo, especially for EGFR bearing tumor. It paved ways for developing novel theranostic agent to be potentially applied in clinic.

PH-activatable oxidative stress amplifying dissolving microneedles for combined chemo-photodynamic therapy of melanoma

Photodynamic therapy (PDT)-mediated oxidation treatment is extremely attractive for skin melanoma ablation, but the strong hydrophobicity and poor tumor selectivity of photosensitizers, as well as the oxygen-consuming properties of PDT, leading to unsatisfactory therapeutic outcomes. Herein, a tumor acidic microenvironment activatable dissolving microneedle (DHA@HPFe-MN) was developed to realize controlled drug release and excellent chemo-photodynamic therapy of melanoma via oxidative stress amplification. The versatile DHA@HPFe-MN was fabricated by crosslinking a self-synthesized protoporphyrin (PpIX)-ADH-hyaluronic acid (HA) conjugate HA-ADH-PpIX with “iron reservoir” PA-Fe3+ complex in the needle tip via acylhydrazone bond formation, and dihydroartemisinin (DHA) was concurrently loaded in the hydrogel network. HA-ADH-PpIX with improved water solubility averted undesired aggregation of PpIX to ensure enhanced PDT effect. DHA@HPFe-MN with sharp needle tip, efficient drug loading and excellent mechanical strength could efficiently inserted into skin and reach the melanoma sites, where the acidic pH triggered the degradation of microneedles, enabling Fe-activated and DHA-mediated oxidation treatment, as evidenced by abundant reactive oxygen species (ROS) generation. Moreover, under light irradiation, a combined chemo-photodynamic therapeutic effect was achieved with amplified ROS generation. Importantly, the Fe-catalyzed ROS production of DHA was oxygen-independent, which work in synergy with the oxygen-dependent PDT to effectively destroy tumor cells. This versatile microneedles with excellent biosafety and biodegradability can be customized as a promising localized drug delivery system for combined chemo-photodynamic therapy of melanoma.

Correction to Cisplatin-Cross-Linked and Oxygen-Resupply Hyaluronic Acid-Based Nanocarriers for Chemo-photodynamic Therapy

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Cisplatin-Cross-Linked and Oxygen-Resupply Hyaluronic Acid-Based Nanocarriers for Chemo-photodynamic TherapyXu ChengXu ChengMore by Xu Cheng, Shuiqin ShiShuiqin ShiMore by Shuiqin Shi, Yan WuYan WuMore by Yan Wu, Liangliang ZhuLiangliang ZhuMore by Liangliang Zhu, Jiaxi XuJiaxi XuMore by Jiaxi Xu, Ting Hu*Ting HuMore by Ting Huhttps://orcid.org/0000-0003-4720-1742, Bing Wei*Bing WeiMore by Bing Wei, and Rupei Tang*Rupei TangMore by Rupei Tanghttps://orcid.org/0000-0002-2885-5049Cite this: ACS Appl. Nano Mater. 2022, 5, 8, 12045–12046Publication Date (Web):July 28, 2022Publication History Received30 June 2022Published online28 July 2022Published inissue 26 August 2022https://doi.org/10.1021/acsanm.2c02582Copyright © 2022 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views105Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (877 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Gold Nanoparticle Embedded Stimuli-Responsive Functional Glycopolymer: A Potential Material for Synergistic Chemo-Photodynamic Therapy of Cancer Cells.

Photodynamic therapy has emerged as a noninvasive treatment modality for several types of cancers. However, conventional hydrophobic photosensitizers (PS) suffer from low water solubility and poor tumor-targeting ability. Therefore, PS modified with glycopolymers can offer adequate water solubility, biocompatibility, and tumor-targeting ability due to the presence of multiple sugar units. In this study, a well-defined block copolymer poly(3-O-methacryloyl-d-glucopyranose)-b-poly(2-(4-formylbenzoyloxy)ethylmethacrylate) (PMAG-b-PFBEMA) containing pendant glucose and aldehyde units is synthesized via reversible addition-fragmentation chain transfer polymerization method. A water-soluble PS (toluidine blue O; TBO) and a potent anticancer drug, Doxorubicin (Dox) are introduced to the polymer backbone via acid-labile Schiff-base reaction (PMAG-b-PFBEMA_TBO_Dox). The PMAG-b-PFBEMA_TBO_Dox is then anchored on the surface of gold nanoparticles (AuNPs)via electrostatic interaction. This hybrid system exhibits excellent reactive oxygen species (ROS) generating ability under exposure of 630nm light-emitting diode along with triggered release of Dox under the acidic pH of tumor cells. The in vitro cytotoxicity study on human breast cancer cell line, MDA MB 231, for this hybrid system shows promising results due to the synergistic effect of ROS and Dox released. Thus, this glycopolymer-based dual (chemo-photodynamic) therapy model can work as potential material for future therapeutics.

Phenylthiol-BODIPY-based supramolecular metallacycles for synergistic tumor chemo-photodynamic therapy

The development of more effective tumor therapy remains challenging and has received widespread attention. In the past decade, there has been growing interest in synergistic tumor therapy based on supramolecular coordination complexes. Herein, we describe two triangular metallacycles (1 and 2) constructed by the formation of pyridyl boron dipyrromethene (BODIPY)-platinum coordination. Metallacycle 2 had considerable tumor penetration, as evidenced by the phenylthiol-BODIPY ligand imparting red fluorescent emission at ∼660 nm, enabling bioimaging, and transport visualization within the tumor. Based on the therapeutic efficacy of the platinum(II) acceptor and high singlet oxygen (1O2) generation ability of BODIPY, 2 was successfully incorporated into nanoparticles and applied in chemo-photodynamic tumor therapy against malignant human glioma U87 cells, showing excellent synergistic therapeutic efficacy. A half-maximal inhibitory concentration of 0.35 μM was measured for 2 against U87 cancer cells invitro. In vivo experiments indicated that 2 displayed precise tumor targeting ability and good biocompatibility, along with strong antitumor effects. This work provides a promising approach for treating solid tumors by synergistic chemo-photodynamic therapy of supramolecular coordination complexes.

(Invited) New Bioinspired Nanomaterials for Biosensing and Cancer Theranostics

Nature is an excellent source of inspiration for the widespread application of science and technology. Researchers learn from biological principles and gradually develop from the earliest direct use of biological materials to the design and development of new biomimetic materials inspired by nature. Therefore, the innovation of bioinspired nanomaterials will enable tremendous advances in biology and biochemistry with biomimetic capabilities, such as biosensing, cell imaging, and drug delivery. In this presentation, I will discuss my group’s recent work on two bioinspired nanomaterials: nano-peptoids and single-atom nanozymes.The first type of bioinspired materials is a sequence-defined peptide-like materials that can mimic the structure and function of peptides and proteins. Compared with peptides and proteins, peptoids have a high degree of thermal and chemical stability, and are resistant to proteolytic degradation. In addition, due to the lack of intramolecular and intermolecular backbone hydrogen bond donors, it is possible to precisely control the peptoid and peptoid-substrate interactions, leading to bio-inspired synthesis of nanomaterials with a layered structure. As a peptide mimic, the peptoids has biocompatibility, non-toxicity and sequence-specific heteropolymers. Nano-peptoids can be synthesized with polar and hydrophobic monomers and have the following advantages: They can be easily processed into desired shapes (e.g. dendritic, sheets, tubes and vesicles), and the size range is 2-100 nm to enhance cell targeting and uptake. The application of nano-peptoids in cell imaging and cancer theranostics will be discussed.Another type of bioinspired nanomaterials with enzyme-like properties is single-atom nanoenzymes. As a biocatalyst, natural enzymes have the ability to accelerate various reaction rates with extremely high activity and selectivity under mild conditions. However, due to the temperature and pH-related denaturation of proteins and the possibility of contamination by bacteria or other reagents, the shelf life of natural enzymes is limited or uncertain, and their purification and production costs are high. Therefore, natural enzymes must narrow the range of conditions under which they can be used, limiting their further applications in biosensing and biomedicine. R Recent research has focused on the rational design of nanomaterials with inherent enzyme-like catalytic properties (for example, oxidase, peroxidase, catalase, superoxide dismutase, and so on) and exploration of their applications in various fields. Although much progress has been made, the development of nanozymes is still hampered by several challenges. Catalytic activity and substrate selectivity are the two most important issues that need to be resolved to allow the technology to reach full maturity. Therefore, rational design and tuning of nanomaterials is highly desirable for the development of novel enzyme-mimic nanomaterials with precise catalytic sites. We have developed various Fe-N-C based single atomic site catalysts which have similar structure with active site of peroxidase. These atomically-dispersed Fe-N-C materials have enzyme-like properties, therefore they are classified as single-atom nanozymes. Together with their abundantly exposed active sites and specific structures, these single atomic nanozymes have great potential for the enhancement of biocatalytic activity and selectivity in biosensing. Jiao, H. Yan, Y. Wu, W. Gu, C. Zhu, D. Du, Y. Lin. When Nanozymes Meet Single-Atom Catalysis. Angew. Chem. Int. Ed. 2020,132, 2585-2596Zhu, S. Fu, Q. Shi, D. Du, Y. Lin. Single-Atom Electrocatalysts. Angew. Chem. Int. Ed. 2017, 56, 13944-13960.Cheng, J. Li, D. Liu, Y. Lin, D. Du. Single-Atom Nanozyme Based on Nanoengineered Fe-N-C Catalyst with Superior Peroxidase-Like Activity for Ultrasensitive Bioassays. Small, 2019, 1901485.Niu, Q. Shi, W. Zhu, D. Liu, H. Tian, S. Fu, N. Cheng, S. Li, J. N Smith, D. Du, Y. Lin. Unprecedented Peroxidase-mimicking Activity of Single-atom Nanozyme with Atomically Dispersed Fe-Nx Moieties Hosted by MOF Derived Porous Carbon. Biosensors & Bioelectronics, 2019, 142, 111495.Jiao, W. Xu, Y. Wu, H. Yan, W. Gu, D. Du, Y Lin, C. Zhu, Single-atom Catalysts Boost Signal Amplification for Biosensing. Chemical Society Reviews 2021, 50, 750-765Luo, Y. Song, M. Wang, T. Jian, S. Ding, P. Mu, Z. Liao, Q. Shi, X. Cai, H. Jin, D. Du, W. Dong, C. Chen, Y. Lin. Bioinspired Peptoid Nanotubes for Targeted Tumor Cell Imaging and Chemo-Photodynamic Therapy. Small 2019, 1902485.Song, M. Wang, S. Akkineni, W. Yang, J.J. Hettige, H. Jin, Z. Liao, P. Mu, F. Yan, M. Baer, J. De Yoreo, D. Du, Y. Lin, C. Chen. Highly Bright and Photostable Two-Dimensional Nanomaterials Assembled from Sequence-Defined Peptoids. ACS Materials Letters 2021, 3, 420-427.Cai, M. Wang, P. Mu, T. Jian, D. Liu, S. Ding, Y. Luo, D. Du, Y. Song, C. Chen, Y. Lin. Sequence-Defined Nanotubes Assembled from IR780-Conjugated Peptoids for Chemophototherapy of Malignant Glioma. Research 2021, Article ID 9861384.

Photoactivation of Chemotherapeutic Agents with Cerenkov Radiation for Chemo-Photodynamic Therapy.

Cerenkov radiation (CR) can be used as an internal light source in photodynamic therapy (PDT). Methotrexate (MTX) and paclitaxel (PTX), chemotherapeutic agents with wide clinical use, have characteristics of photosensitizers (PS). This work evaluates the possibility of photoexciting MTX and PTX with CR from 18F-FDG to produce reactive oxygen species (ROS) capable of inducing cytotoxicity. PTX did not produce ROS when excited by CR from 18F-FDG, so it is not useful for PDT. In contrast, MTX produces 1O2 (detected by ABMA) in amounts sufficient to significantly decrease the viability of the T47D cells. MTX solutions of 100 nM combined with 18F-FDG activities of 50 (1.85 MBq) and 100 μCi (3.7 MBq) produced a significant decrease in cell viability to (50.09 ± 4.95) and (47.96 ± 11.19)%, respectively, compared to MTX (66.29 ± 5.92)% and 18F-FDG (91.35 ± 7.00% for 50 μCi and 99.43 ± 11.03% for 100 μCi) alone. Using the CellRox Green reagent, the intracellular production of ROS was confirmed as the main mechanism of cytotoxicity. The results confirm the therapeutic potential of photoactivation with CR and the synergy of the combined treatment with chemotherapy + photodynamic therapy (CMT + PDT). The combination of chemotherapeutic agents with PS properties and β-emitting radiopharmaceuticals, previously approved for clinical use, will make it possible to shorten the evaluation stages of new CMT + PDT systems.

Coupling Chlorin-Based Photosensitizers and Histone Deacetylase Inhibitors for Photodynamic Chemotherapy.

Photodynamic therapy combined with chemotherapy is a promising strategy to improve the antitumor efficacy. On the basis of coupling the chlorin-based photosensitizer pyropheophorbide a (Pyro) and histone deacetylase inhibitors (HDACis) to fabricate dual-mode antitumor molecules, a series of dual-mode antitumor prodrug molecules were synthesized and assessed for antitumor activity in vitro and in vivo. The data demonstrated that compound 4, with the most favorable phototoxicity and dark toxicity, could significantly inhibit the cell migration and upregulate the expression of acetyl-H3 protein, functioning as a photosensitizer and HDACi, respectively. Furthermore, compared with talaporfin, Pyro, and SAHA, compound 4 demonstrated the best inhibitory effect on tumor growth and metastasis in tumor-bearing mice; therefore, represented by compound 4, this pharmacophore coupling strategy is much more promising and effective than the pharmacophore fusion strategy for fabricating photodynamic and chemotherapeutical dual-mode molecules.

Tumor pH-Responsive Nanocarriers With Light-Activatable Drug Release for Chemo-Photodynamic Therapy of Breast Cancer.

Developing bioresponsive nanocarriers with particular tumor cell targeting and on-demand payload release has remained a great challenge for combined chemo-photodynamic therapy (chemo-PDT). In this study, an intelligent nanocarrier (DATAT-NPCe6) responded to hierarchical endogenous tumor pH, and an exogenous red light was developed through a simple mixed micelle approach. The outside TAT ligand was masked to prevent an unexpected interaction in blood circulation. Following the accumulation of DATAT-NPCe6 in tumor tissues, tumor acidity at pH ∼6.5 recovered its targeting ability via triggering DA moiety degradation. Furthermore, the cascaded chemo-PDT was accomplished through light-stimulated nanocarrier disassembly and doxorubicin (DOX) release. Taking advantage of stability and controllability, this work provides a facile approach to designing bioresponsive nanocarriers and represents a proof-of-concept combinatorial chemo-PDT treatment.

Acid-sensitive polymeric prodrug micelles for achieving enhanced chemo-photodynamic therapy

Multimodal combination therapy is considered more effective in cancer treatment than monotherapy, because it overcomes some limitations of monotherapy. In this study, acid-sensitive polymeric prodrugs consisting of photosensitizer (Hemin) and ortho ester-terminated PEG were synthesized and loaded with doxorubicin (DOX) to obtain a dual-modal therapeutic nanoplatform (Hemin/DOX-M). This nanoplatform demonstrated good drug encapsulation and stability. In vitro experiments have confirmed that Hemin/DOX-M can be effectively internalized by HepG2 cells, trigger rapid drug release via the cleavage of ortho ester and alleviate tumor hypoxia to amplify the PDT effect under laser irradiation. In vivo experiments revealed that Hemin/DOX-M caused decreased hemolysis and selective accumulation in the tumor tissue, thereby significantly reducing the side effects. Intriguingly, In vivo antitumor evaluation revealed that Hemin/DOX-M had stronger capability at tumor growth inhibition (TGI, 79.63%) than chemo- or photodynamic therapy alone. Overall, Hemin/DOX-M is a promising candidate to increase therapeutic efficacy by achieving combination therapy against tumors.

DNA-Au Janus Nanoparticles for In Situ SERS Detection and Targeted Chemo-photodynamic Synergistic Therapy.

Cancer theranostics is of great significance in the personalized therapy. In this work, stable Janus nanoparticles (JNPs) containing PEG and two kinds of DNAs were prepared by means of "click chemistry". In response to ATP or acid condition, the prepared JNPs could form Au NP dimers, which facilitate in situ SERS detection and SERS imaging analysis of cancer cells due to the formation of "hot spots" in the nanogap between the Au NP dimers. A detection limit of 2.3 × 10-9 M was obtained for ATP. As for a pH sensor, the SERS signals increased with the decrease of pH value from 8.0 to 4.0. In situ monitoring of ATP or acid condition in cancer cells by SERS can improve the accuracy and sensitivity of diagnosis. Moreover, drugs and photosensitizers loaded on the other side of JNPs led to the chemotherapy/photodynamic therapy synergistic antitumor effect, which was verified by in vitro and in vivo experiments. Given the excellent performance in SERS detection and cancer therapy, the developed JNPs hold considerable potential in cancer theranostics.

Laser-responsive multi-functional nanoparticles for efficient combinational chemo-photodynamic therapy against breast cancer

Herein, novel laser-responsive multi-functional nanoparticles (NPs-Lip@PTX/CyA/Ce6) were fabricated with bovine serum albumins (BSA) based nanoparticles, which simultaneously carried chemotherapeutic drug paclitaxel (PTX) and P-gp inhibitor cyclosporin A (CyA), as core and photosensitizer agent Chlorin e6 (Ce6) loaded Tf-modified liposomal bilayer as shell. NPs-Lip@PTX/CyA/Ce6 exhibited apparent core-shell structure morphology with particle size of 160.9 ± 1.7 nm and zeta potential of − 26.7 ± 0.6 mV, indicating their excellent stability in aqueous solution. Besides, NPs-Lip@PTX/CyA/Ce6 possessed laser-responsive release profiles upon laser irradiation at specific wavelength, which was favor to exert efficient combinatorial chemo-photodynamic therapy and effectively reverse the multiple drug resistance (MDR). Under laser irradiation, as expected, NPs-Lip@PTX/CyA/Ce6 demonstrated superb intracellular ROS productivity and fantastic in vitro and in vivo anti-cancer therapy effect but absent of systemic toxicity. In conclusion, the nano-drug delivery system would be prospectively applied in clinic as resultful therapeutic tactic for investing compositional chemo-photodynamic therapy synergistically.

Targeted delivery and enhanced uptake of chemo-photodynamic nanomedicine for melanoma treatment

Nanoparticles (NPs) modified with targeting ligands have often shown great potential in targeted drug delivery for tumor therapy. However, the clearance of NPs by the monocyte-phagocyte system (MPS) and the relatively low cellular uptake by tumor cells have significantly limited the antitumor efficacy of a variety of nanomedicines. Tumor microenvironment-mediated multidrug resistance also reduces the antitumor efficacy of internalized nanomedicines. Herein, we developed an innovative nanomedicine for combined chemo-photodynamic therapy of melanoma through targeted drug delivery and significantly improved the cellular uptake of the nanomedicine through the charge-reversal phenomenon. An amphiphilic platinum (IV)-polyethylenimine-chlorin e6 (Pt(IV)-PEI-Ce6) polymer was designed, prepared, and self-assembled into NPs (PPC) in an aqueous solution, and these NPs were subsequently coated with hyaluronic acid (HA) to afford PPC@HA. The surface-coated HA provided PPC with a negatively charged surface potential to reduce the clearance by the MPS during systemic circulation and enhanced the targeted delivery of PPC to CD44-overexpressing melanoma cells. Upon accumulation in the tumor site, hyaluronidase overexpressed in the tumor induced HA degradation to release the positively charged PPC, resulting in an increased internalization of PPC into tumor cells. Bioactive Pt(II) was released in response to high glutathione level in the tumor cells for effective tumor chemotherapy. Under 650 nm laser irradiation, Ce6 produced reactive oxygen species (ROS), thus driving photodynamic therapy. Finally, PPC@HA exhibited combined photodynamic-chemotherapeutic antitumor efficacy against the melanoma cells in mice. Statement of significanceTumors are one of the greatest threats to human health, and chemotherapy has been one of the most common therapeutic modalities for treating tumors; however, many challenges related to chemotherapy remain, such as low delivery efficiency, side effects, and unsatisfactory therapeutic efficacy. Nanomedicines modified with targeting ligands have often shown great potential in improving targeted drug delivery for tumor therapy; however, the clearance of nanomaterials by the monocyte-phagocyte system and the relatively low cellular uptake by tumor cells have significantly limited the antitumor efficacy of a variety of nanomedicines. Herein, we developed a novel charge-reversal-based, hyaluronic acid-coated, Pt(IV) prodrug and chlorin e6-based nanomedicine to improve systemic circulation and targeted accumulation of the nanomedicine in the tumor tissue and to enhance its intracellular uptake. This nanomedicine may provide a potential new platform to improve the drug content inside tumor cells and to effectively inhibit tumor growth through combined chemotherapy and photodynamic therapy.

Novel diketopyrrolopyrrole NIR-II fluorophores and DDR inhibitors for in vivo chemo-photodynamic therapy of osteosarcoma

DNA damage response (DDR) inhibitors potentiate the therapeutic efficacy in osteosarcoma (OS) treatment. However, drug resistance, severe collateral toxicity, and poor bioavailability of DDR inhibitors in vivo are the main challenges. The NIR-II fluorescence image-guided photodynamic therapy exhibits advantageous properties and shows great potential in oncology, representing an emerging class of non-invasive treatment methods. Herein, a unique, synergistic strategy is evaluated to improve the therapeutic efficacy of a DDR inhibitor (AZD-2461) and a diketopyrrolopyrrole-based NIR-II fluorescent photosensitizer DT. The novel NIR-II photosensitizer DT is synthesized based on diacyl-substituted diketopyrrolopyrrole, and co-encapsulated with AZD-2461 using DSPE-mPEG5000-FA to form DTA dots. DTA dots significantly enhanced anti-osteosarcoma effects by increasing the generation of reactive oxygen species (ROS) and inhibiting DNA damage repair. NIR-II image-guided synergistic enhancement with high spatiotemporal resolution and strong tumor uptake is demonstrated in vivo, resulting in improved tumor control and increased apoptosis. This work reports for the first time a novel NIR-II phototheranostic nanoplatform for OS combination therapy without severe side effects, providing a practical strategy for simultaneous cancer diagnostics, therapeutics, and postoperative real-time monitoring.