Combined Chemo-photodynamic Therapy Research Articles

Phthalocyanine-Conjugated Glyconanoparticles for Chemo-photodynamic Combination Therapy.

Combination cancer therapy based on multifunctional nanomaterials has attracted great attention. The present work focuses on the preparation of the glycopolymeric nanoparticle, which contains a photosensitizer (zinc(II)phthalocyanine, ZnPc) and an anticancer drug (Doxorubicin, Dox). First, a novel mono azide-functional ZnPc-N3 with seven hydrophilic ethylene oxide chains was synthesized. Next, ZnPc alone or together with Dox bearing glycopolymers was synthesized via the RAFT polymerization method and then self-assembled into glyconanoparticles (GNPs) with narrow particle size distribution. Then the evaluation of the biological activity of GNPs (GNPs-ZnPc and GNPs-ZnPc/Dox) for dual photodynamic therapy (PDT) and chemotherapy against human breast cancer cells was investigated. The constructed GNPs were identified via general characterization methods, including dynamic light scattering (DLS) and transmission electron microscopy (TEM). The prepared GNPs-ZnPc/Dox demonstrated remarkable photophysical and photochemical properties, involving good colloidal stability in biological conditions, pH-responsive drug release, and the capacity to generate singlet oxygen under light irradiation. The outer layer of nanoparticles covered by fructose sugar moieties achieves a targeted cancer therapy owing to GLUT5 (a well-known fructose transporter) overexpression toward breast cancer cells. In vitro experiments were then performed to evaluate the chemo/phototoxicity, cellular uptake, and anticancer efficacy of GNPs-ZnPc/Dox. In comparison with free Dox, human breast cancer cells treated with GNPs-ZnPc/Dox exhibited a higher cellular internalization via GLUT5 targeting. In particular, the GNPs-ZnPc/Dox nanoplatform revealed an excellent synergistic anticancer activity in comparison with free ZnPc-N3 and free Dox, representing a novel and promising chemo-photodynamic combination therapeutic methodology to improve therapeutic efficacy.

Berberine-photodynamic therapy sensitizes melanoma cells to cisplatin-induced apoptosis through ROS-mediated P38 MAPK pathways

The clinical use of cisplatin are limited due to its drug resistance. Thus, it is urgent to find effective combination therapy that sensitizes tumor cells to this drug. The combined chemo-photodynamic therapy could increase anti-tumor efficacy while also reduce the side effects of cisplatin. Berberine is an isoquinoline alkaloid, which has been reported to show high photosensitizing activity.In this study, we have examined the effect of a combination of cisplatin and berberine-PDT in cisplatin-resistant melanoma cells. The cytotoxic effects of berberine-PDT alone or in combination with cisplatin were tested by MTT assays. We then examined the subcellular localization of berberine with confocal fluorescence microscopy. The percentage of apoptotic cells, the mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) generation assessed using flow cytometry analysis. Western blotting used in this study to determine the expression levels of MAPK signaling pathways and apoptosis-related proteins. Experimental data revealed that the mode of cell death is the caspase-dependent mitochondrial apoptotic pathways. Excessive accumulation of ROS played a key role in this process, which is confirmed by alleviation of cytotoxicity upon pretreatment with NAC. Furthermore, we found that the combined treatment activated MAPK signaling pathway. The inhibition of p38 MAPK by pretreating with SB203580 block the combined treatment-induced apoptotic cell death.In conclusion, berberine-PDT could be used as a chemo-sensitizer by promoting cell death through activation of a ROS/p38/caspase cascade.

An albumin-binding dimeric prodrug nanoparticle with long blood circulation and light-triggered drug release for chemo-photodynamic combination therapy against hypoxia-induced metastasis of lung cancer.

Photodynamic therapy (PDT) has been widely used in cancer therapy, but its therapeutic effect is reduced by the aggravating hypoxic microenvironment via upregulating hypoxia-associated proteins and promoting tumor metastasis. To mitigate these issues, we designed an albumin-binding and light-triggered core-shell dimeric prodrug nanoparticle to inhibit hypoxia-induced tumor metastasis and enhance the PDT efficacy. The prodrug nanoparticles, Ce6&DHA-S-DHA@CMN NPs (CDC NPs), were prepared using a single thioether-linked dihydroartemisinin (DHA) dimer co-encapsulated with Chlorin e6 (Ce6) and stabilized by albumin-capturing maleimide- and hypoxia-sensitive 2-nitroimidazole-modified carboxymethyl chitosan (CMCTS-MAL&NI, CMN for short). Upon laser irradiation, Ce6 could generate reactive oxygen species (ROS), which not only exerted the effect of the PDT but also broke the ROS-sensitive single thioether bridge in the dimeric prodrug DHA-S-DHA, thus accelerating the disassembly of the nanoparticles. DHA-S-DHA served as both an ROS-responsive carrier for Ce6 and a chemotherapeutic drug, synergizing with PDT and inhibiting tumor metastasis by downregulating hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF). Polyethylene glycol (PEG) modification has been widely used to stabilize hydrophobic prodrug nanoparticles and prolong the circulation time, but the PEGylated nanoparticles always suffer from accelerated blood clearance (ABC), a phenomenon which restricts their application severely. In this study, PEG was replaced by an amphipathic micelle, CMN, which could specifically capture albumin in the blood, conferring the nanoparticles long circulation and no ABC phenomenon. Under the aggravating hypoxic condition during PDT, the conversion of 2-nitroimidazole groups to 2-aminoimidazole groups in CMN could destabilize the structure of the shell and accelerate drug release. Results showed that the novel CDC NPs exhibited unique advantages in chemo-photodynamic combination therapy, such as long systemic circulation, high tumor accumulation, light-triggered drug release, HIF-1α/VEGF downregulation, and anti-metastasis efficacy, which provided a new route to overcome the ABC phenomenon of the PEGylated prodrug nanoparticles and reverse the hypoxia-induced metastasis simultaneously.

A multifunctional nanoplatform based on graphitic carbon nitride quantum dots for imaging-guided and tumor-targeted chemo-photodynamic combination therapy

Graphitic carbon nitride quantum dots (g-CNQDs) have shown great potential in imaging, drug delivery and photodynamic therapy (PDT). However, relevant research on g-CNQDs for PDT or drug delivery has been conducted separately. Herein, we develop a g-CNQDs-based nanoplatform (g-CPFD) to achieve simultaneously imaging and chemo-photodynamic combination therapy in one system. A g-CNQDs-based nanocarrier (g-CPF) is first prepared by successively introducing carboxyamino-terminated oligomeric polyethylene glycol and folic acid onto the surface of g-CNQDs via two-step amidation. The resultant g-CPF possesses good physiological stability, strong blue fluorescence, desirable biocompatibility, and visible light-stimulated reactive oxygen species generating ability. Further non-covalently loaded doxorubicin enables the system with chemotherapy function. Compared with free doxorubicin, g-CPFD expresses more efficient chemotherapy to HeLa cells due to improved folate receptor-mediated cellular uptake and intracellular pH-triggered drug release. Furthermore, g-CPFD under visible light irradiation shows enhanced inhibition on the growth of cancer cells compared to sole chemotherapy or PDT. Thus, g-CPFD exhibits exceptional anti-tumor efficiency due to folate receptor-mediated targeting ability, intracellular pH-triggered drug release and a combined treatment effect arising from PDT and chemotherapy. Moreover, this nanoplatform benefits imaging-guided drug delivery because of inherent fluorescent properties of doxorubicin and g-CPF, hence achieving the goal of imaging-guided chemo-photodynamic combination treatments.

Redox dual-responsive dendrimeric nanoparticles for mutually synergistic chemo-photodynamic therapy to overcome drug resistance

Combination therapy has exhibited crucial potential in the treatment of cancers, especially in drug-resistant cancers. In this work, a novel tumor-targeted, redox dual-responsive and paclitaxel (PTX) loaded nanoparticle based on multifunctional dendrimer and lentinan was developed for combinational chemo-photodynamic therapy of PTX-resistant cancers. The nanoparticles exhibited enhanced cellular uptake and tumor penetration based on phenylboronic acid-sialic acid interactions, and had the ability to control drug release in response to intracellular high concentration of glutathione and H2O2. Specifically, light irradiation not only triggered the photodynamic effect of the nanoparticles for prominent photodynamic cytotoxicity, but also resulted in increased internalization and accelerated release of PTX into cytoplasm through the lysosome disruption, as well as the obvious damage to microtubules and actin microfilaments, for drug resistance reversal of A549/T cells. Meanwhile, PTX treatment would arrest cells in G2/M phase, thereby prolonging the period when nuclear membrane is broken down, which further facilitated photosensitizer accumulation in nuclei and improved DNA damage response. Consequently, the combination of PTX and photodynamic treatment lead to excellent antitumor effects to drug-resistant A549/T cells in vitro and in vivo, which provides a new strategy for the design of co-delivery system to overcome drug resistance.

High payload nanoparticles composed of 7-ethyl-10-hydroxycamptothecin and chlorin e6 for synergistic chemo-photodynamic combination therapy

Combined chemo-photodynamic therapy strategy is regarded as a potential strategy for advanced cancer treatments. Herein, novel high payload 7-ethyl-10-hydroxycamptothecin (SN38)/chlorin e6 (Ce6) NPs based on the collaborative assembly of the pre-obtained SN38–Ce6 complex and biocompatible amphiphilic block polymer DSPE-PEG2000 were successfully constructed. The self-assembly mechanism of the NPs was corporately disclosed as static quenching resulted from complex formation between DSPE-PEG2000 and the pre-acquired SN38–Ce6 complex via fluorescence quenching experiment. The high payload SN38/Ce6 NPs exhibited uniform rod-like morphology with a hydrodynamic radius of about 200 nm, a zeta potential of around −25 mV, and excellent storage stability. The high payload NPs showed efficient singlet oxygen generation capacity both in tube and in murine mammary carcinoma (4T1) cells under laser irradiation. Moreover, the in vitro cytotoxicity and in vivo antitumor efficacy of the NPs (with laser) against 4T1 cell lines model were proved to be statistically significant compared to CPT-11 injection and single-drug NPs due to synergistic chemo-photodynamic therapy and high cellular uptake efficiency. Meanwhile, the systemic toxicity of the NPs was basically absent. Conclusively, the high payload dual-functional nanoparticles could be served as a promising strategy for cancer treatment in clinic.

Folic acid-modified bovine serum albumin nanoparticles with doxorubicin and chlorin e6 for effective combinational chemo-photodynamic therapy.

We herein describe a facile method to synthesize stable bovine serum albumin-based nanoparticles (BNPs) loaded with two anticancer therapeutics, doxorubicin (DOX) and a photosensitizer, chlorin e6 (Ce6), in combination with folic acid (FA) as a target cancer cell receptor for the development of an effective combined chemo and photodynamic (FA-Ce6/DOX/BNPs) therapy against cervical cancer. FA-Ce6/DOX/BNPs exhibited excellent monodispersity with an average diameter of 103.5±3.8nm, a negative zeta potential of approximately -30.44±0.35mV, and long-term stability. As a result, FA-Ce6/DOX/BNPs exhibited severe toxicity to cervical HeLa cancer cells. Also, a higher drug release rate was observed under acidic pH conditions (pH5.0). Moreover, FA-Ce6/DOX/BNPs potentiated mitochondrial reactive oxygen species (ROS) production in HeLa cells under 671-nm laser exposure, leading to activation of key regulator proteins of apoptosis such as BH3 interacting-domain death agonist (BID), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (BAX), as well as induction of the caspase cascade and mitochondrial ROS-mediated cell death. Confocal microscopy analysis further validated cellular uptake of FA-Ce6/DOX/BNPs by HeLa cells. Furthermore, results of real-time quantitative PCR (RT-qPCR) and western blot analysis further validated the anticancer effect of FA-Ce6/DOX/BNPs, as evidenced by elevated gene/protein expression levels of apoptotic biomarkers p53, BID, caspase-3, cleaved poly(ADP-ribose) polymerase 1 (PARP-1), and BAX, contrary to levels of the anti-apoptotic marker Bcl-2. Moreover, in vivo toxicity results of FA-Ce6/DOX/BNPs using laser irradiation in zebrafish larvae, as a chemo-photodynamic therapy confirmed that it does not affect the larval development without causing any adverse toxic effect in zebrafish larvae. Altogether these findings strongly support the anticancer effect of FA-Ce6/DOX/BNPs combinational chemo-photodynamic therapy, which could be a promising candidate for cervical cancer therapy.

Black phosphorus nanosheets and docetaxel micelles co-incorporated thermoreversible hydrogel for combination chemo-photodynamic therapy.

The platform of the combination chemo-photodynamic therapy has received widespread attention for enhancing anticancer efficacy and inhibiting tumor growth, which supports thermosensitive and controlled drug release. Here, an injectable thermoreversible hydrogel (BPNSs/DTX-M-hydrogel) co-encapsulating black phosphorus nanosheets (BPNSs) and docetaxel (DTX) micelles was prepared to increase drug accumulation in tumor tissue and improve anticancer efficacy. BPNSs were prepared by liquid exfoliation method with a simple and rapid preparation, and DTX micelles were prepared by the thin film dispersion method. Hydrogel was prepared with F127 as hydrogel matrix for intratumoral injection. BPNSs, DTX micelles, and BPNSs/DTX-M-hydrogel were characterized by particle size, morphology, stability and degradation, phase transition feature, and photodynamic performance. And the in vivo anticancer efficacy was evaluated in 4T1 tumor-bearing Balb/c mice. The results showed that the particle size of DTX micelles and BPNSs were about 16 and 180nm, respectively. The hydrogel with the transformation temperature at near body exhibited great photodynamic efficacy and good biodegradability. Moreover, BPNSs/DTX-M-hydrogel with the combination of chemotherapy and photodynamic therapy exhibited unique anticancer efficacy with low toxicity. In conclusion, the combination platform of chemo-photodynamic therapy based on BPNSs could be a prospective strategy in antitumor research. Graphical abstract.

Co-delivery of IR-768 and daunorubicin using mPEG-b-PLGA micelles for synergistic enhancement of combination therapy of melanoma

Malignant melanoma is an emerging problem worldwide due to the high degree of lethalness. Its aggressiveness and the ability to metastasize along with the heterogeneity at the molecular and cellular levels, limit the overall therapeutic efficacy. Despite significant advances in melanoma treatment over the last decade, there is still a need for improved therapeutic modalities. Thus, we demonstrate here a combinatorial approach that targets multiple independent therapeutic pathways, in which polymeric micelles (PMs) were used as efficacious colloidal nanocarriers loaded with both daunorubicin (DRB) as a cytotoxic drug and IR-768 as a photosensitizer. This afforded the dual drug loaded delivery system IR-768 + DRB in PMs. The fabricated mPEG-b-PLGA micelles (hydrodynamic diameters ≈ 25 nm) had a relatively narrow size distribution (PdI > ca. 0.3) with uniform spherical shapes. CLSM study showed that mPEG-b-PLGA micelles were uptaken by mitochondria, which further contributed to excellent singlet oxygen generation capacity for PDT in A375 melanoma cells. Furthermore, the PMs were efficiently internalized by tested cells through endocytosis, resulting in much higher cellular uptake comparing to the free drug. As a result of these properties, IR-768 + DRB in PMs exhibited very potent and synergistically enhanced anticancer activity against A375 cells. Additionally, this combination approach allowed to reduce drug doses and provided low side effects towards normal HaCaT. This study indicates excellent properties of mPEG-b-PLGA micelles resulting in great therapeutic potential possessed by the developed nanoscale drug delivery system for combined chemo-photodynamic therapy of melanoma.

Hyaluronic acid targeted and pH-responsive nanocarriers based on hollow mesoporous silica nanoparticles for chemo-photodynamic combination therapy

In this work, a pH-responsive and tumor targeted multifunctional drug delivery system (RB-DOX@HMSNs-N = C-HA) was designed to realize chemo-photodynamic combination therapy. Hollow mesoporous silica nanoparticles (HMSNs) was served as the host material to encapsulate doxorubicin (DOX) and photosensitizer rose bengal (RB). Hyaluronic acid (HA) was modified on the surface of HMSNs via pH-sensitive Schiff base bonds as gatekeeper as well as targeted agent. Characterization results indicated the successful preparation of HMSNs-N = C-HA with appropriate diameter of 170 nm around and the nanocarriers displayed superior drug loading capacity (15.30 % for DOX and 12.78 % for RB). Notably, the results of in vitro drug release experiments confirmed that the system possessed good pH-sensitivity, which made it possible to release cargoes in slight acid tumor micro-environments. Significantly, the in vitro cell uptake and cytotoxicity assay results fully proved that RB-DOX@HMSNs-N = C-HA could precisely target murine mammary carcinoma (4T1) cells and effectively inhibit tumor cells viability with chemo-photodynamic synergistic therapy. Overall, our work (RB-DOX@HMSNs-N = C-HA) provides an efficient approach for the development of chemo-photodynamic combination therapy.

Oxygen-producing catalase-based prodrug nanoparticles overcoming resistance in hypoxia-mediated chemo-photodynamic therapy

Extreme hypoxia inside solid tumors is the primary barrier against the advance of chemotherapy and photodynamic therapy (PDT). To address this problem, a hybrid nano-enzyme prodrug system was developed to alleviate hypoxia as well as simultaneously sensitize chemo-photodynamic therapy. Lactobionic acid (LA) and doxorubicin (DOX) precursor (cis-aconitic anhydride-linked doxorubicin, CAD) were pre-conjugated onto the side chain of catalase (CAT), then co-assembled with chlorin e6 (Ce6) to form LA-CAT-CAD@Ce6 nanoparticles (LCC@Ce6-NPs). LA as the active-targeting ligand increased cellular internalization, CAD as the pH-sensitive component triggered rapid drug release, Ce6 as the photosensitizer induced reactive oxygen species (ROS) generation, and CAT decomposed intracellular H2O2 to produce oxygen in situ. Oxygen production efficiently decreased the expression of hypoxia-inducible factor-1α (HIF-1α) and P-glycoprotein (P-gp), which enhanced chemotherapy efficiency. In addition, sufficient oxygen further amplified PDT-mediated cell-killing and apoptosis in hypoxic tumor. In vivo studies showed that combined chemo-photodynamic therapy by LCC@Ce6-NPs led to the most effective inhibition of tumor growth (TGI>90%), and even partially ablated tumor. Thus, this nano-enzyme prodrug platform can be a potentially effective treatment in clinical cancer therapy, and married to other therapeutic agents. Statement of SignificanceHypoxia in solid tumors seriously impedes the efficacy of chemotherapy or photodynamic therapy. Herein, we designed hybrid nano-enzyme prodrug particles to improve hypoxia-mediated limitations on cancer therapy. Lactobionic acid (LA) as the hydrophilic outer layer of particles increased cellular uptake by receptor-mediated endocytosis, and cis-aconitic anhydride-linked doxorubicin (CAD) as the pH sensitive component inside particles efficiently triggered DOX and Ce6 release. More importantly, catalase (CAT) as the backbone of particles was capable of greatly relieving tumor hypoxia through catalyzing the decomposition of H2O2 in situ. Oxygen re-generation not only prevented hypoxia-mediated chemo-resistance, but also amplified PDT-induced ROS cell-killing ability. As a result, the multiple combination action of this nano-system could simultaneously sensitize chemo-photodynamic therapy, thus significantly enhancing tumor therapy.

Oxygen Self-Sufficient Core-Shell Metal-Organic Framework-Based Smart Nanoplatform for Enhanced Synergistic Chemotherapy and Photodynamic Therapy.

The abnormal angiogenesis and insufficient oxygen supply in solid tumors lead to intratumoral hypoxia, which severely limits the efficacy of traditional photodynamic therapy (PDT). Here, a multifunctional nanoplatform (ZDZP@PP) based on a zeolitic imidazolate framework-67 (ZIF-67) core as a hydrogen peroxide catalyst, a zeolitic imidazolate framework-8 (ZIF-8) shell with a pH-responsive property, and a polydopamine-poly(ethylene glycol) (PDA-PEG) layer for improving the biocompatibility is fabricated for not only relieving tumor hypoxia but also enhancing the efficacy of combination chemo-photodynamic therapy. The chemotherapy drug doxorubicin (DOX) and photosensitizer protoporphyrin IX (PpIX) are encapsulated in different layers independently; thus, a unique two-stage stepwise release becomes possible. Moreover, the nanoplatform can effectively decompose hydrogen peroxide to produce oxygen and thus relieve tumor hypoxia, which further facilitates the production of cytotoxic reactive oxygen species (ROS) by PpIX under laser irradiation. Both in vitro and in vivo experimental results confirm that the combination chemo-photodynamic therapy with the ZDZP@PP nanoplatform can provide more effective cancer treatment than chemotherapy or PDT alone. Consequently, the oxygen self-sufficient multifunctional nanoplatform holds promising potential to overcome hypoxia and treat solid tumors in the future.

Delivery of MutT homolog 1 inhibitor by functionalized graphene oxide nanoparticles for enhanced chemo-photodynamic therapy triggers cell death in osteosarcoma

Photodynamic therapy (PDT) generates highly toxic reactive oxygen species (ROS) during noninvasive cancer treatment. MutT homolog 1 (MTH1) protein is a DNA oxidative damage repair protease and suppressing its function may provide a strategy to enhance PDT efficacy by improving cellular sensitivity to ROS. A nanoparticle, composed of functional graphene oxide (GO) conjugated with polyethylene glycol (PEG), folic acid (FA) and photosensitizer indocyanine green (ICG), was constructed to deliver MTH1 inhibitor (TH287) and doxorubicin. The effects of this nanoparticle on biological properties and cell death of osteosarcoma cells were investigated. We further examined the endoplasmic reticulum (ER) stress and apoptosis in osteosarcoma. A xenograft tumor model was used to validate the results in vivo. This drug-carrying PEG-GO-FA/ICG nanoparticle showed combined chemo-photodynamic therapy (Chemo-PDT) to inhibit the proliferation and migration of osteosarcoma cells. Enhanced Chemo-PDT promoted both apoptosis and autophagy by suppressing the MTH1 protein and promoting the accumulation of ROS. In this study, autophagy served as a rescue pathway against cell death, and suppressing autophagy enhanced the anti-cancer effects of Chemo-PDT. However, Chemo-PDT induced apoptosis was related to the occurrence of ER stress. ROS might contribute to ER stress and further induce apoptosis via the JNK/p53/p21 pathway. These findings provide a mechanistic understanding of nanoparticle-induced cell death in osteosarcoma. The combination of Chemo-PDT with other therapies is promising as a new strategy to treat osteosarcoma. Statement of significanceAdministration of chemotherapeutic drugs by traditional methods still has many problems. We designed a functionalized graphene oxide drug delivery system to deliver the photosensitizer indocyanine green, doxorubicin, and MTH1 inhibitor TH287. This nano delivery system showed combined chemo-photodynamic effects to inhibit osteosarcoma. Suppressing MTH1 protein might induce “phenotypic lethality” and enhance chemo-photodynamic therapy efficacy by improving cellular sensitivity to reactive oxygen species.

Development of an ultrasound triggered nanomedicine-microbubble complex for chemo-photodynamic-gene therapy

Recently, combination therapy has received much attention because of its highly therapeutic effect in various types of cancers. In particular, chemo-photodynamic combination therapy has been considered as an outstanding strategy. However, an abnormal increase in tumor angiogenesis caused by reactive oxygen species (ROS) generated during photodynamic therapy (PDT) has been reported. In this study, the complex of doxorubicin (DOX)-encapsulating anti-angiogenic small interfering RNA (siRNA) nanoparticle and chlorin e6 (Ce6)-encapsulating microbubble has been developed to suppress tumor angiogenesis. The first compartment, doxorubicin-encapsulating siRNA nanoparticle, was electrostatically coated using two biocompatible polymers to prevent the damage of genetic materials. The other part, Ce6-encapsulating microbubble, serves as an ultrasound-triggered local delivery system as well as a drug carrier. Both the in vitro and in vivo experimental results demonstrate successful inhibition of angiogenesis with a minimized damage of siRNAs caused by ROS as well as improved therapeutic effect by chemo-photodynamic-gene triple combination therapy using ultrasound-triggered local delivery.

Cyclometalated iridium(iii) complexes for mitochondria-targeted combined chemo-photodynamic therapy.

The combination of chemotherapeutic and photodynamic activities in an iridium-based molecular compound is less reported. Herein, two iridium complexes (IrC1 and IrC2) with β-carboline alkaloid ligands were designed and synthesized. Both complexes exhibited high anticancer activities with IC50 values of around 1 μM in the dark against several cell lines tested. Notably, the cytotoxicity of these two complexes against lung cancer (A549) cells increased significantly under light (425 nm) irradiation, with phototoxicity index (PI) values of 120 and 93, respectively. They were specifically enriched in the mitochondria. Cell-based assays demonstrated that IrC1 induced an increase in intracellular reactive oxygen species (ROS) levels, reduction in ATP production, mitochondrial DNA damage, an increase in lipid peroxidation levels, and proteasomal activity inhibition. Under light conditions (in some cases a two-photon laser was also applied), these effects were greatly enhanced. Overall, we have demonstrated that these iridium complexes have dual activities of chemotherapy and photodynamic therapy, which may help to design new metal-based anticancer agents for combined chemo-photodynamic therapy.

Amphiphilic block polymer-based self-assembly of high payload nanoparticles for efficient combinatorial chemo-photodynamic therapy

Combinatorial chemo-photodynamic therapy is regared as effective cancer therapy strategy, which could be realized via multiple nano-drug delivery system. Herein, novel high payload nanoparticles stabilized by amphiphilic block polymer cholesterol-b-poly(ethylene glycol) (PEG)2000 (Chol-PEG2000) were fabricated for loading chemotherapeutic drug 10-hydroxycamptothecin (HCPT) and photosensitizer chlorin e6 (Ce6). The obtained HCPT/Ce6 NPs showed uniform rod-like morphology with a hydration diameter of 178.9 ± 4.0 nm and excellent stability in aqueous solution. HCPT and Ce6 in the NPs displayed differential release profile, which was benefit for preferentially exerting the photodynamic effect and subsequently enhancing the sensitivity of the cells to HCPT. Under laser irradiation, the NPs demonstrated fantastic in vitro and in vivo anticancer efficiency due to combinational chemo-photodynamic therapy, enhanced cellular uptake effectiveness, and superb intracellular ROS productivity. Besides, the NPs were proved as absent of systemic toxicity. In summary, this nanoparticle delivery system could be hopefully utilized as effective cancer therapy strategy for synergistically exerting combined chemo-photodynamic therapy in clinic.

A supramolecular assembly mediated by host-guest interactions for improved chemo-photodynamic combination therapy.

We report a supramolecular nanomedicine (SNM-3) based on a camptothecin-tetraphenyl porphyrin conjugate, camptothecin-polyethylene glycol conjugate, and acyclic cucurbit[n]uril. The supramolecular nanomedicine is tunable by varying the composition of the three components to optimize the nanoscale morphology and therapeutic efficacy. The optimized supramolecular nanomedicine possesses great stability and enhanced intracellular singlet oxygen generation efficiency. Cytotoxicity assay demonstrates that SNM-3 improves the efficacy of chemo-photodynamic combination therapy against three cancer cell lines.

Silver-decorated, light-activatable polymeric antimicrobials for combined chemo-photodynamic therapy of drug-resistant bacterial infection.

Drug-resistant bacterial infections have stolen the spotlight in recent years as stubborn diseases intimidating public health, thus urgently requiring the development of innovative treatment strategies with high antibacterial efficiency and low bacterial resistance. Here, a polymeric antimicrobial with synergistic chemo-photodynamic therapy function is fabricated to combat drug-resistant bacterial infections. In this strategy, polymeric micelles based on amphiphilic poly(aspartic acid)-block-poly(ε-caprolactone) (PAsp-b-PCL) are used as nanocarriers to encapsulate a photosensitizer protoporphyrin IX (PpIX) in the micellar core, which then undergo silver nanoparticle decoration on the micellar shell through an in situ reduction method. Compared with mono-therapy, the combination of silver nanoparticle decoration and light-activatable PpIX enables the resulting polymeric antimicrobial to exert chemo-photodynamic activity to kill drug-resistant bacteria more potently in vitro. Furthermore, the prepared polymeric antimicrobials with synergistic antibacterial activity show robust eradication efficacy against subcutaneous infections induced by drug-resistant Staphylococcus aureus in a murine model. Therefore, our study provides a simple and potent strategy to realize combination therapy for eradicating drug-resistant bacterial infections.

Dinuclear phosphorescent rhenium(I) complexes as potential anticancer and photodynamic therapy agents.

Chemotherapeutic agents that affect lysosomal functions represent a promising strategy for selective tumor therapy and overcoming drug resistance. In this work, two dinuclear phosphorescent rhenium(i) tricarbonyl complexes (DRe1 and DRe2) containing carboline derivatives have been synthesized, characterized and explored as potential chemotherapeutic and photodynamic therapy agents. The two dinuclear rhenium(i) complexes have good intrinsic phosphorescence properties and can label the lysosomes in cancer cells. Both dinuclear rhenium(i) complexes show potent anticancer activities toward several tested cancer cells. Moreover, they also have marked inhibitory activities against cisplatin-resistant human lung carcinoma cells (A549R), with complex DRe2 displaying 16-fold higher activity than cisplatin. Mechanism studies reveal that complex DRe2 can induce cancer cells to overproduce reactive oxygen species (ROS), including superoxide anion radicals, which leads to lysosomal membrane permeabilization (LMP) and subsequent cell apoptosis. Additionally, both DRe1 and DRe2 display significant phototoxicity under light (425 nm) irradiation in A549 cells, with phototoxicity index values of 60.8 and 41.8, respectively. Therefore, these two dinuclear organometallic rhenium(i) tricarbonyl complexes are potential anticancer agents for combined chemo-photodynamic therapy.

Novel carrier-free nanoparticles composed of 7-ethyl-10-hydroxycamptothecin and chlorin e6: Self-assembly mechanism investigation and in vitro/in vivo evaluation

The combination therapy strategy based on both chemotherapy and photodynamic therapy (PDT) exhibits great potential for advanced cancer treatment. Multimodal nanodrug delivery systems based on both chemotherapeutic drug and photodynamic agent have been proven to possess excellent synergistic efficacy. In this study, 7-ethyl-10-hydroxycamptothecin (SN38) and chlorin e6 (Ce6) were co-assembled into novel carrier-free nanoparticles (SN38/Ce6 NPs) via simple antisolvent precipitation method. As expected, SN38/Ce6 NPs exhibited uniform morphology with a particle size of around 150 nm and a zeta potential of about −30 mV, good stability in aqueous solution/at lyophilized state and high cellular uptake efficiency against murine mammary carcinoma (4T1) cell lines. Besides, enhanced singlet oxygen generation capacity of the nanoparticles was both observed in test-tube and in 4T1 cell lines in contrast with Ce6 injection. Moreover, a ∼85 % inhibition rate of SN38/Ce6 NPs with laser was detected, which was significantly higher (P < 0.05) than those without laser (∼65 %) and injections (less than 20 %), verified the excellent synergistic antitumor efficacy of the nanoparticles due to combined chemo-photodynamic therapy, enhanced tumor accumulation and higher cellular internalization. Notably, chemical thermodynamic method and molecular dynamics (MD) simulations supplied solid data and visual images to estimate the driving forces for the self-assembly process of the carrier-free nanoparticles as primary hydrophobic interactions (π-π stacking) and subordinate hydrogen bonds. Conclusively, the above self-assembled carrier-free nanoparticles represented a promising synergistic anticancer strategy capable of maximal therapeutic efficacy and minimal systemic toxicity. Moreover, the application of thermodynamic method together with MD simulations in the investigation of NPs self-assembly process also provided new ideas for the assembly mechanism exploration of more complicated nanodrug delivery system.