Combined Chemo-photodynamic Therapy Research Articles

Light-triggered polymeric prodrug and nano-assembly for chemo-photodynamic therapy and potentiate immune checkpoint blockade immunotherapy for hepatocellular carcinoma

Immune checkpoint blockade (ICB) therapy has emerged as a promising approach for the treatment of hepatocellular carcinoma (HCC), especially for advanced and metastatic tumors. However, many HCC patients do not respond due to low tumor antigen exposure and the highly immunosuppressive tumor microenvironment (ITM). Chemotherapy and photodynamic therapy are considered to be effective methods for eliciting anti-tumor immune responses. Here, we developed a light-triggered nanoplatform Ce6@PMTKP for combination chemo-photodynamic therapy and the potentiation of ICB therapy. The Ce6@PMTKP micelles entrapped Ce6 for photodynamic therapy, while PMTKP contains the ROS-sensitive paclitaxel (PTX) polymeric prodrug for chemotherapy. The Ce6@PMTKP micelles showed excellent tumor accumulation and light-triggered drug release. Compared with chemotherapy or photodynamic therapy alone, the combination therapy mediated by Ce6@PMTKP was found to be more effective in the elimination of tumors, induction of immunogenic cell death, and the promotion of dendritic cell maturation and cytotoxic T lymphocytes infiltration, thus mitigating ITM immunosuppression. When combined with anti-PD-L1 immunotherapy, the Ce6@PMTKP micelles induced complete regression of primary tumors and effectively inhibited distant metastatic tumors by enhancing anti-tumor immune responses.

Co-Delivery of Paclitaxel Prodrug, Gemcitabine and Porphine by Micelles for Pancreatic Cancer Treatment via Chemo-Photodynamic Combination Therapy

Pancreatic carcinoma is an aggressive subtype of cancer with poor prognosis, known for its refractory nature. To address this challenge, we have established a stable nanoplatform that combines chemotherapy with photodynamic therapy (PDT) to achieve better curative efficacy. First, we designed and synthesized a disulfide-bonded paclitaxel (PTX)-based prodrug, which was further mixed with gemcitabine (GEM) and photosensitizer THPP in an optimized ratio. Subsequently, the mixture was added dropwise into amphiphilic polymer DSPE-PEG water solution to form micelles composed of DSPE-PEG nanoparticles (TPG NPs). The TPG NPs were around 135 nm, and showed great ability of DTT stimulated release of PTX and GEM. Moreover, the TPG NPs can be efficiently uptaken by pancreatic cancer PANC-1 cells and effectively kill them, especially when combined with 650 nm laser irradiation. Finally, the TPG NPs have shown enhanced long-term circulation ability and also exhibited efficient anti-tumor activity in combination with 650 nm laser irradiation in a pancreatic cancer mouse model. In summary, the designed TPG NPs possesses great potential for co-delivery of paclitaxel prodrug, GEM and THPP, which enables combined chemo-photodynamic therapy for cancer treatment. In addition, the stimulated release of PTX prodrug and GEM also allows for better targeting of tumor cells and the increased therapeutic effect against cancer cells. Overall, the TPG NPs can serve as a good candidate for pancreatic cancer treatment.

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.

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.

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.

A near-infrared triggered upconversion/MoS2 nanoplatform for tumour-targeted chemo-photodynamic combination therapy

The combination of photodynamic therapy and chemotherapy has shown a great potential in cancer treatment. As a promising photosensitizer, MoS2 quantum dots (QDs) have limited application due to the low tissue penetration of its light absorbing wavelength in the ultraviolet and visible regions. For the purpose of utilizing MoS2QDs in higher NIR absorption region, herein, we constructed a core/shell nano-photosensitizer upconversion@MoS2 with doxorubicin loading. This nanoplatform can convert 980 nm NIR into visible light, activating MoS2QDs to produce reactive oxygen species through fluorescence resonance energy transfer. In addition, this nanoplatform presented good biocompatibility and tumor targeting after polyethylene glycol and folic acid modification. Interestingly, with pH-responsive drug release performance, this nanoplatform presented efficient chemotherapy effects. Thus, the tumour-targeted nanoplatform can achieve up-converted luminescence imaging guided chemo-photodynamic synergistic therapy effectively.

A pH-sensitive supramolecular nanosystem with chlorin e6 and triptolide co-delivery for chemo-photodynamic combination therapy

The combination of Ce6, an acknowledged photosensitizer, and TPL, a natural anticancer agent, has been demonstrated as a useful strategy to reinforce the tumor growth suppression, as well as decrease the systemic side effects compared with their monotherapy. However, in view of the optimal chemo-photodynamic combination efficiency, there is still short of the feasible nanovehicle to steadily co-deliver Ce6 and TPL, and stimuli-responsively burst release drugs in tumor site. Herein, we described the synergistic antitumor performance of a pH-sensitive supramolecular nanosystem, mediated by the host–guest complexing between β-CD and acid pH-responsive amphiphilic co-polymer mPEG-PBAE-mPEG, showing the shell–core structural micelles with the tight β-CD layer coating. Both Ce6 and TPL were facilely co-loaded into the spherical supramolecular NPs (TPL+Ce6/NPs) by one-step nanoprecipitation method, with an ideal particle size (156.0 nm), acid pH-responsive drug release profile, and enhanced cellular internalization capacity. In view of the combination benefit of photodynamic therapy and chemotherapy, as well as co-encapsulation in the fabricated pH-sensitive supramolecular NPs, TPL+Ce6/NPs exhibited significant efficacy to suppress cellular proliferation, boost ROS level, lower MMP, and promote cellular apoptosis in vitro. Particularly, fluorescence imaging revealed that TPL+Ce6/NPs preferentially accumulated in the tumor tissue area, with higher intensity than that of free Ce6. As expected, upon 650-nm laser irradiation, TPL+Ce6/NPs exhibited a cascade of amplified synergistic chemo-photodynamic therapeutic benefits to suppress tumor progression in both hepatoma H22 tumor-bearing mice and B16 tumor-bearing mice. More importantly, lower systemic toxicity was found in the tumor-bearing mice treated with TPL+Ce6/NPs. Overall, the designed supramolecular TPL+Ce6/NPs provided a promising alternative approach for chemo-photodynamic therapy in tumor treatment.

Curcumin loaded Ag-TiO2-halloysite nanotubes platform for combined chemo-photodynamic therapy treatment of cancer cells.

The use of naturally occurring anticancer materials in combination with doped metal oxide has emerged as one of the most promising ways for improving anticancer treatment efficacy. In this study, the anticancer potential of curcumin-loaded Ag-TiO2-halloysite nanotubes (curcumin-loaded Ag-TiO2-HNTs) was examined. Ag-TiO2-HNTs with different wt% of Ag-TiO2 were synthesized and characterized using XRD, TGA, FT-IR, UV-Vis spectroscopy, and SEM-EDX. The XRD results revealed the presence of crystalline TiO2. However, the presence of Ag was detected through the SEM-EDX analysis. Cyclic voltammetry measurements suggested the enhancement of the release of ROS from TiO2 upon deposition with Ag. FT-IR and TGA analysis confirmed the successful loading of curcumin inside the nanotubes of the halloysite. In vitro drug released studies revealed the release of approximately 80-99% curcumin within 48 hours. Kinetic model studies revealed that the release of curcumin from HNT and Ag-TiO2-HNT followed the first-order and Higuchi models, respectively. The light irradiated curcumin-loaded Ag-TiO2-HNTs samples exhibited considerable anticancer potential as compared to the free curcumin, irradiated Ag-TiO2 NPs samples, and unirradiated curcumin loaded Ag-TiO2-HNTs samples. The obtained results revealed that combined chemo- and photodynamic therapy using curcumin-loaded Ag-TiO2-HNTs nanomaterial has the potential as an effective anticancer treatment method.

Microalgae-based bioactive hydrogel loaded with quorum sensing inhibitor promotes infected wound healing

Interaction between bacterial species is through quorum sensing (QS), a process that regulates and coordinates genes in virulence activities and biofilm formation. QS contributes to the slowdown of tissue repair during the wound healing process by inducing chronic inflammation of the wound. Here, we developed a multifunctional QS inhibitor based on a bioactive hydrogel system to interrupt the QS of bacteria, relieve hypoxia, and destroy biofilms, and thus accelerate the healing of infected wounds in diabetic mice. We loaded berberine (BBR, a QS inhibitor, and antibacterial agent) into a natural living microalgae Spirulina platensis (SP) to form a bioactive hydrogel (BBR@SP gel) in combination with carboxymethyl chitosan/sodium alginate. Under laser irradiation, the BBR@SP gel could constantly release BBR and produce reactive oxygen species, resulting in a synergistic QS inhibition against methicillin-resistant Staphylococcus aureus (MRSA) combined chemo-photodynamic therapy. The BBR@SP gel also suppresses and destroys biofilm formation and down-regulates the expression of virulence factors. We found that the BBR@SP gel could accelerate MRSA-infected diabetic wound healing by promoting angiogenesis, skin regeneration, and suppressing the inflammatory response. Our work presents an innovative antimicrobial strategy that eliminates drug-resistant bacteria by synergistic chemo-photodynamic killing effect, relieving biofilm hypoxia, and blocking QS simultaneously, which may open up new prospects in solving antimicrobial drug resistance and combating biofilm-related infections.

RNA Hydrogel Combined with MnO2 Nanoparticles as a Nano-Vaccine to Treat Triple Negative Breast Cancer.

Hypoxia is not only the reason of tumor metastasis but also enhances the spread of cancer cells from the original tumor site, which results in cancer recurrence. Herein, we developed a self-assembled RNA hydrogel that efficiently delivered synergistic DNA CpG and short hairpin RNA (shRNA) adjuvants, as well as MnO2 loaded-photodynamic agent chlorine e6 (MnO2@Ce6), and a chemotherapy drug doxorubicin (DOX) into MDA-MB-231cells. The RNA hydrogel consists of one tumour suppressor miRNA (miRNA-205) and one anti-metastatic miRNA (miRNA-182), both of which showed an outstanding effect in synergistically abrogating tumours. The hydrogel would be dissociated by endogenous Dicer enzyme to release loaded therapeutic molecules, and in the meantime induce decomposition of tumor endogenous H2O2 to relieve tumor hypoxia. As a result, a remarkable synergistic therapeutic effect is achieved through the combined chemo-photodynamic therapy, which simultaneously triggers a series of anti-tumor immune responses. Besides, the hydrogel as the carrier which modified aptamer to targeted MDA-MB-231 has the advantages of good biocompatibility and low cytotoxicity. This strategy could be implemented to design any other microRNA (miRNA) as the carrier, combined with other treatment methods to treat human cancer, thereby overcoming the limitations of current cancer therapies.

Biodegradable Hollow Polydopamine@manganese Dioxide as an Oxygen Self-Supplied Nanoplatform for Boosting Chemo-photodynamic Cancer Therapy.

Photodynamic therapy (PDT) has attracted extensive attention in the clinical treatment of malignant tumor. However, the acidic and hypoxic conditions of the tumor microenvironment (TME) limit the further application of PDT in the clinic. Herein, we fabricate a new nanoplatform─HPDA@MnO2@Ce6/DOX@PEG-RGD (HPMRCD)─by means of coating hollow polydopamine nanoparticles (HPDA) with manganese dioxide (MnO2), which is modified by cyclic RGD functionalized poly(ethylene glycol) (PEG) and further co-loaded with a photosensitizer, Chlorin e6 (Ce6), and a chemotherapy drug, doxorubicin (DOX). This nanoplatform could be enriched in tumor tissues, then instantly dissociated under an acidic and H2O2-rich TME. The dual-responsive release of Mn2+ ions and oxygen (O2) can relieve tumor hypoxia, which can be used as a magnetic resonance contrast agent and the latter can enhance the PDT effect. Furthermore, the degradation of HPMRCD leads to an efficient loaded therapeutic molecule release, thus yielding a potential therapy to enhance tumor suppression by adopting the combined chemo-photodynamic therapy.

Pro-oxidant drug-loaded porphyrinic zirconium metal-organic-frameworks for cancer-specific sonodynamic therapy

Sonodynamic therapy, which utilizes ultrasound (US) to produce cytotoxic reactive oxygen species (ROS), can overcome the critical drawbacks of photodynamic therapy, such as limited tissue penetration depth. However, the development of sonosensitizers having superior sonodynamic effects and desirable biocompatibility remains a major challenge. In this study, nanoscale zirconium-based porphyrinic metal organic frameworks (MOFs) (PCN-222) were developed as safe and effective nanosonosensitizers. Polyethylene glycol (PEG)-coated PCN-222 (PEG-PCN) was loaded with a pro-oxidant drug, piperlongumine (PL), to enable tumor-specific chemo-photodynamic combination therapy. Both PEG-PCN and PL-incorporated PEG-PCN (PL-PEG-PCN) showed high colloidal stability in biological media. In addition, nanoscale PL-PEG-PCN was efficiently internalized by breast cancer cells, leading to substantially increased ROS generation under US exposure. The effective intracellular delivery of PL by PEG-PCN further elevated the level of intracellular ROS in breast cancer cells owing to the pro-oxidative activity of PL. Therefore, PL-PEG-PCN revealed significantly higher sonotoxicity than free PL and PEG-PCN. Owing to the cancer-specific apoptosis triggered by PL, PL-PEG-PCN showed cancer-selective cell death in breast cancer cells compared with normal fibroblast cells. This study demonstrates that pro-oxidant drug-loaded porphyrinic MOFs are biocompatible and effective sonosensitizers for cancer-targeted chemo-sonodynamic combination therapy.

Chitosan/hyaluronan nanogels co-delivering methotrexate and 5-aminolevulinic acid: A combined chemo-photodynamic therapy for psoriasis

Psoriasis does not respond adequately to the monotherapy, tailoring combined strategies for synergistical treatment remains challenging. We fabricated chitosan/hyaluronan nanogels to co-load methotrexate (MTX) and 5-aminoleavulinic acid (ALA), i.e., MTX-ALA NGs, for a combined chemo-photodynamic therapy for psoriasis. Compared with MTX-ALA suspension, the NGs enhanced the penetration and retention of MTX and ALA through and into the skin in vitro and in vivo (p < 0.001). NGs enhanced the cellular uptake (p < 0.001), protoporphyrin IX conversion (p < 0.001), and reactive oxygen species generation (3.93-fold), subsequently exerted the synergistical anti-proliferation and apoptosis on lipopolysaccharide-irritated HaCaT cells with the apoptosis rate of 78.6%. MTX-ALA NGs efficiently ameliorated the skin manifestations and down-regulated the proinflammatory cytokines of TNF-α and IL-17A in imiquimod-induced psoriatic mice (p < 0.001). Importantly, MTX-ALA NGs reduced the toxicities of oral MTX to the liver and kidney. The results support that MTX-ALA NG is a convenient, effective, and safe combined chemo-photodynamic strategy for psoriasis treatment.

A Sequential Dual-Model Strategy Based on Photoactivatable Metallopolymer for On-Demand Release of Photosensitizers and Anticancer Drugs.

The synergistic combination of chemotherapy and photodynamic therapy has attracted considerable attention for its enhanced antitumoral effects; however, it remains challenging to successfully delivery photosensitizers and anticancer drugs while minimizing drug leakage at off‐target sites. A red‐light‐activatable metallopolymer, Poly(Ru/PTX), is synthesized for combined chemo‐photodynamic therapy. The polymer has a biodegradable backbone that contains a photosensitizer Ru complex and the anticancer drug paclitaxel (PTX) via a singlet oxygen (1O2) cleavable linker. The polymer self‐assembles into nanoparticles, which can efficiently accumulate at the tumor sites during blood circulation. The distribution of the therapeutic agents is synchronized because the Ru complex and PTX are covalently conjugate to the polymer, and off‐target toxicity during circulation is also mostly avoided. Red light irradiation at the tumor directly cleaves the Ru complex and produces 1O2 for photodynamic therapy. Sequentially, the generated 1O2 triggers the breakage of the linker to release the PTX for chemotherapy. Therefore, this novel sequential dual‐model release strategy creates a synergistic chemo‐photodynamic therapy while minimizing drug leakage. This study offers a new platform to develop smart delivery systems for the on‐demand release of therapeutic agents in vivo.

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

Tumor microenvironment (TME) is known to play a critical role in cancer progression and contributes to treatment failure or success. Herein, a versatile nanoplatform [HAFOE-Ce6/Pt-NPs(O2)] with cisplatin (Pt) cross-linking, chlorin e6 (Ce6) loading, pH sensitivity, active targeting, and oxygen resupply was developed to address this problem. This nanosystem presents as a spherical shape with a small size of 175.4 ± 2.16 nm and a negative charge of −25.32 ± 3.04 mV. Hyaluronic acid (HA) as the starting material not only improved the biocompatibility of the nanosystem but also enhanced cellular uptake by targeting the CD44 receptor. Interestingly, cisplatin could serve as both a cross-linker and anticarcinogen to increase the blood stability and therapeutic performance. Additionally, the micelles disintegration and drug release could be accelerated by the cleavage of ortho ester at low pH. More importantly, the fluorocarbon inside the particles has the ability to load oxygen and in situ release oxygen at tumor regions, which greatly reduced tumor hypoxia. In vitro and in vivo results demonstrated that HAFOE-Ce6/Pt-NPs(O2) could efficiently inhibit tumor growth by combined chemo-photodynamic therapy under 660 nm laser irradiation by way of oxygen sensitization, leading to a high mice survival rate (83.33%). Overall, this combined nanosystem could take advantage of TME while overcoming its disadvantages and was an efficient nanoplaform for cancer treatment.

Triapine/Ce6-loaded and lactose-decorated nanomicelles provide an effective chemo-photodynamic therapy for hepatocellular carcinoma through a reactive oxygen species-boosting and ferroptosis-inducing mechanism

A nanomicelles-based and lactose-decorated drug delivery system (DDS) is fabricated and loaded with a small molecule Triapine and a photosensitizer Ce6 to afford TCLMs. TCLMs is highly hepatocyte-targeted due to the specific recognition of lactose by human asialoglycoprotein receptor (ASGPR) and collapses in the acidic microenvironment of cancer cells to release cargos. The employment of Triapine and Ce6 allows a combined chemo-photodynamic therapy (CT-PDT), in which both Triapine and Ce6 act synergistically as boosters of cytotoxic reactive oxygen species (ROS) via Fenton reaction and near-infrared (NIR) light irradiation, respectively. Moreover, Triapine can evoke ferroptosis, a relatively new type of regulated cell death, and PDT is known to enhance ferroptosis mediated by singlet oxygen (1O2). In vitro, TCLMs show enhanced anticancer activity toward hepatocellular carcinoma (HCC) cells than Triapine. In vivo, the tumor-retarding ability of TCLMs outperforms Triapine not only in subcutaneous HCC-bearing mice but also in orthotopic HCC-bearing mice when assisted by an interventional therapy. Importantly, ferroptosis is demonstrated to be an essential mechanism underlying the anti-HCC activity of TCLMs. Collectively, the present work showcases nanomaterials-based DDS as a promising tool for combined CT-PDT against cancer.

Engineered macrophages as near-infrared light activated drug vectors for chemo-photodynamic therapy of primary and bone metastatic breast cancer

Patients with primary and bone metastatic breast cancer have significantly reduced survival and life quality. Due to the poor drug delivery efficiency of anti-metastasis therapy and the limited response rate of immunotherapy for breast cancer, effective treatment remains a formidable challenge. In this work, engineered macrophages (Oxa(IV)@ZnPc@M) carrying nanomedicine containing oxaliplatin prodrug and photosensitizer are designed as near-infrared (NIR) light-activated drug vectors, aiming to achieve enhanced chemo/photo/immunotherapy of primary and bone metastatic tumors. Oxa(IV)@ZnPc@M exhibits an anti-tumor M1 phenotype polarization and can efficiently home to primary and bone metastatic tumors. Additionally, therapeutics inside Oxa(IV)@ZnPc@M undergo NIR triggered release, which can kill primary tumors via combined chemo-photodynamic therapy and induce immunogenic cell death simultaneously. Oxa(IV)@ZnPc@M combined with anti-PD-L1 can eliminate primary and bone metastatic tumors, activate tumor-specific antitumor immune response, and improve overall survival with limited systemic toxicity. Therefore, this all-in-one macrophage provides a treatment platform for effective therapy of primary and bone metastatic tumors.

Lactobionic acid-modified phycocyanin nanoparticles loaded with doxorubicin for synergistic chemo-photodynamic therapy

Phycocyanin (PC) is considered to be an effective natural photosensitizer, but it has not been well utilized as its inefficient biostability and intracellular accumulation. To overcome these limitations, the nano-sized PC particles (LAPC/DOX) were developed by grafting with lactobionic acid (LA) and loading with doxorubicin (DOX). Compared to the PC solution, the storage-stability and photostability of PC particles were remarkably increased, and the formation of nanoparticles further improved its biostability. Besides, CLSM images confirmed that LA could also enhance cellular uptake, resulting in more intracellular PC and DOX accumulation. MTT assay revealed that LAPC/DOX caused the highest cytotoxicity by combined chemo-photodynamic therapy. Finally, LAPC/DOX could efficiently accumulate and spread in tumoral multicellular spheroids, resulting in the enhanced growth inhibition. Overall, the LAPC/DOX is effective in cancer treatment, which provides new insights for the usage of functional proteins in vivo.

Hyaluronic acid-based nanogels derived from multicomponent self-assembly for imaging-guided chemo-photodynamic cancer therapy

Multifunctional theranostic nanoplatforms integrated of imaging function, multi-modality therapy, stimuli-responsiveness, and targeted delivery are of highly desirable attributes in achieving precise medicine. However, preparation of multifunctional nanoplatforms often involves laborious, multiple steps and inevitably utilizes low-biocompatible or non-functional components. Herein we report a facile, one-step self-assembly strategy to fabricate hyaluronic acid (HA)-based multifunctional tumor theranostic nanoplatform by employing magnetic resonance imaging (MRI) agent Mn2+ as a reversible crosslink agent for histidine-grafted HA, along with simultaneously loading chemotherapeutic agent doxorubicin hydrochloride (DOX) and photodynamic therapy agent chlorin e6, to realize MRI-guided targeted chemo-photodynamic cancer therapy. The targeted delivery and stimuli-responsive payload release were demonstrated in vitro and in vivo. Furthermore, the combined chemo-photodynamic therapy of the nanoassembly dramatically improved the cancer therapeutic outcome, in comparison with that of free DOX and nanoplatform solely loaded DOX in a melanoma bearing mice. Our one step assemble strategy is of great potential in clinic transformation.