Combined Chemo-photodynamic Therapy Research Articles

Targeted Chemo-Photodynamic Combination Platform Based on the DOX Prodrug Nanoparticles for Enhanced Cancer Therapy.

Chemo-photodynamic combination therapy has been received widespread attention in cancer treatment due to its excellent characteristics, such as reducing the adverse side effects of chemo-drugs and improving the therapeutic effects for various cancers. In this study, RGD and DOX was conjugated to PEG by thiol-ene addition and Schiff's base reaction, respectively, to prepare the targeted and pH-sensitive antitumor prodrug nanoparticles (RGD-PEG-DOX NPs, RGD-NPs). Subsequently, the photosensitizer chlorin e6 (Ce6) was encapsulated into RGD-NPs, thus obtaining a simple and efficient chemo-photodynamic combination platform (RGD-PEG-DOX/Ce6 NPs, RGD-NPs/Ce6). This nanoparticle possessed high drug loading property of both the chemo-drug and photosensitizer and could simultaneously release them under the mild acidic microenvironment of cancer cells, which was expected to realize the synchronization therapy of chemotherapy and photodynamic therapy (PDT). Compared with free DOX and Ce6, RGD-NPs/Ce6 could significantly improve the cellular uptake capacities of DOX and Ce6, resulting in the increased contents of ROS in cancer cells and effective cytotoxicity for tumor cells (MDA-MB-231 cells and MCF-7 cells) upon a laser radiation. The in vivo experiment showed that RGD-NPs/Ce6 displayed superior tumor targeting, accumulation, and retention ability than the other groups (free DOX, free Ce6 and NPs/Ce6), and thus significantly enhancing the antitumor effect in vivo with a laser radiation. In addition, the cardiotoxicity induced by DOX was thoroughly wiped out after being loaded and delivered by the nanoparticles according to the pathological analysis. Therefore, the targeted chemo-photodynamic combination therapeutic platform may be a promising candidate for enhanced cancer therapy.

Core-interlayer-shell Fe3O4@mSiO2@lipid-PEG-methotrexate nanoparticle for multimodal imaging and multistage targeted chemo-photodynamic therapy

Multimodal imaging-guided multistage targeted synergistic combination therapy possesses many advantages including increased tumoricidal effect, reduced toxicity, and retarded drug resistance. Herein, we have elaborately developed a core-interlayer-shell structure Fe3O4@mSiO2@lipid-PEG-methotrexatenanoparticle(FMLM), in which the Fe3O4 core could be used for magnet-stimulate-response drug release, magnetic resonance imaging, and early-phase magnet targeting ability; the mSiO2 layer could encapsulate anticancer drug doxorubicin (Dox) for chemotherapy; and the protective shell of lipid-PEG and lipid-PEG-methotrexate offered later-phase specific cellular targeting ability, good water dispersibility, and loading of photosensitizer zinc phthalocyanine (ZnPc) for simultaneous near-infrared fluorescence imaging and photodynamic therapy. Both in vitro and in vivo studies indicated that the both Dox and ZnPc-loaded FMLM (Dox/ZnPc-FMLM) exhibited the enhanced tumor accumulation, increased cellular uptake, improved anticancer activity, and weaked side effects compared with Dox/ZnPc-Fe3O4@mSiO2@lipid-PEG nanoparticle (Dox/ZnPc-FML) and free drug. For the first time, magnet targeting cooperative with methotrexate macromolecular prodrug targeting is successfully exploited to develop a promising versatile theranostic nanoplatform for dual-modal fluorescence and magnetic resonance imaging-guided combined chemo-photodynamic cancer therapy.

Self-assembled DNA nanowires as quantitative dual-drug nanocarriers for antitumor chemophotodynamic combination therapy.

To combine cocktail chemotherapy and photodynamic therapy into one biocompatible and biodegradable nanocarrier, self-assembled DNA nanowires were fabricated and co-loaded with a photosensitizer chlorin e6 (Ce6) and a chemotherapeutic drug doxorubicin (DOX) for antitumor chemophotodynamic combination therapy. Two short DNA chains served as building blocks for the self-assembly of DNA nanowires in a supersandwich hybridization reaction that led to the successful formation of linear DNA nanowires of 500 bases, equal to a length of 167 nm. Ce6 and DOX were loaded onto the nanowires through covalent or noncovalent intercalation interactions, respectively. The DNA nanowires were taken up into cells, and the released Ce6 and DOX were ultimately distributed in different cellular compartments. The photosensitizer-loaded nanowires demonstrated increased generation of photodynamic reactive oxygen species (ROS) compared to that of free Ce6. In comparison with chemo- or photodynamic therapy alone, the combined treatment provided by DNA nanowires loaded with dual-drug significantly increased the incidence of HepG-2 cell death and produced a clear synergistic effect in the treatment of cancer cells. The DNA nanowire nanocarrier provided a flexible and quantitative drug-loading module that allowed for dose control of both drugs. More importantly, the DNA nanowires demonstrate a strong synergistic effect in antitumor chemophotodynamic combination therapy, likely because of increased photodynamic ROS generation and the distribution of Ce6 and DOX in different intracellular compartments. This work suggests that DNA nanowires may be useful as multifunctional and effective therapeutic nanocarriers for chemophotodynamic modalities in cancer therapy.

Carrier-free, self-assembled pure drug nanorods composed of 10-hydroxycamptothecin and chlorin e6 for combinatorial chemo-photodynamic antitumor therapy in vivo.

Carrier-free nanodrugs formulated from the supramolecular self-assembly of pure drug molecules have emerged as an innovative and promising strategy for tumor therapy. We report herein a new and simple method to directly assemble a small hydrophobic anticancer drug, 10-hydroxycamptothecin (HCPT), with a photosensitizer chlorin e6 (Ce6) to form stable, discrete nanorods (NRs), which not only circumvent the extreme hydrophobicity of HCPT but also incorporate two different modalities into one delivery system for combination therapy. Different ratios of HCPT to Ce6 were evaluated to afford the optimal nanoformulation. The as-prepared HCPT/Ce6 NRs were fully characterized, indicating a relatively uniform size of about 360 nm in length and 135 nm in width, and a surface charge of about -33 mV. Efficient internalization of the NRs by cancer cells was observed by using a confocal microscope and the generation of singlet oxygen species arising from the NRs under 655 nm laser irradiation was detected by DCFH-DA. As a result, very potent in vitro efficacy against several kinds of cancer cell lines was achieved through chemo-photodynamic dual therapy. The in vivo tumor suppression effect of HCPT/Ce6 NRs was verified on a subcutaneous xenograft mouse model, achieving almost complete inhibition of the tumor growth, which may benefit from the superiority of nanomedicine and combination therapy. The rationale of this facile and green strategy for carrier-free nanodrug formulation via the self-assembly approach might provide new opportunities for the development of combinatorial therapeutics for tumors.

Synthesis, photophysical properties and in vitro evaluation of a chlorambucil conjugated ruthenium(ii) complex for combined chemo-photodynamic therapy against HeLa cells.

The combination of chemotherapy with photodynamic therapy can lead to improved therapeutic efficiencies and reduced side effects compared to conventional chemotherapy. Chlorambucil (CHL) is a DNA alkylating agent, but problems like drug instability, "off-target" binding and in situ monitoring after administration often limit its clinical application. In this regard, we designed a new heteroleptic Ru(ii) complex CHL-RuL, bearing a CHL conjugated pendant, which is desired to serve as an image-guided chemo-photodynamic combined theranostic agent. CHL-RuL shows considerable promise as a photosensitizer for two-photon excitation photodynamic therapy: strong and wide UV-Vis absorption bands centered around 400 nm, strong red emission (∼702 nm) with a long lifetime at the microsecond level, moderate singlet oxygen quantum yield, and significant two-photon absorption cross-section (118 GM). More interestingly, this chemical modification affords CHL-RuL greater cellular uptake and remarkable mitochondria accumulation in HeLa cells. Furthermore, CHL-RuL shows a slight selective cytotoxicity toward carcinoma HeLa cells over normal MRC-5 cells. MTT assay results and two-photon scanning cell imaging demonstrate that CHL-RuL exhibits obvious chemo-photodynamic dual action against HeLa cells.

A reactive oxygen species (ROS)-responsive low molecular weight gel co-loaded with doxorubicin and Zn(ii) phthalocyanine tetrasulfonic acid for combined chemo-photodynamic therapy.

Low molecular weight gels (LMWGs) have significant advantages in drug delivery such as high drug loading capacity, in situ delivery of drug to the lesion site, sustaining drug release with excellent bioavailability, and minimized side effects. Here, we synthesized a reactive oxygen species (ROS)-responsive gelator to prepare an injectable gel. An anticancer drug, doxorubicin hydrochloride (DOX), and a photosensitizer, Zn(ii) phthalocyanine tetrasulfonic acid (ZnPCS4), were loaded into the gel for combined chemo-photodynamic therapy. The ROS-responsive gelator was characterized by proton nuclear magnetic resonance (1H NMR) and the morphology of gels was investigated by scanning electron microscopy (SEM). The rheological properties and destruction-recovery capability of both blank and drug-loaded gels were studied. The cytotoxicity of LMWGs against 3T3 fibroblasts and 4T1 breast cancer cells was tested. The in vitro drug release of both drugs was studied and the in vivo anticancer activities of DOX-ZnPCS4-coloaded LMWGs were investigated in tumor-bearing mice. The results revealed that the injectable ROS-responsive DOX-ZnPCS4-coloaded LMWGs exhibited excellent anti-tumor efficacy by a synergistic therapy.

Tumor-Homing and Penetrating Peptide-Functionalized Photosensitizer-Conjugated PEG-PLA Nanoparticles for Chemo-Photodynamic Combination Therapy of Drug-Resistant Cancer.

The combination of photodynamic therapy (PDT) and chemotherapy holds great potential in combating drug-resistant cancers. However, the major challenge that lies ahead is how to achieve high coloading capacity for both photosensitizer and chemo-drugs and how to gain efficient delivery of drugs to the drug-resistant tumors. In this study, we prepared a nanovehicle for codelivery of photosensitizer (pyropheophorbide-a, PPa) and chemo-drugs (paclitaxel, PTX) based on the synthesis of PPa-conjugated amphiphilic copolymer PPa-PLA-PEG-PLA-PPa. The obtained nanoparticles (PP NP) exhibited a satisfactory high drug-loading capacity for both drugs. To achieve effective tumor-targeting therapy, the surface of PP NP was decorated with a tumor-homing and penetrating peptide F3. In vitro cellular experiments showed that F3-functionalized PP NP (F3-PP NP) exhibited higher cellular association than PP NP and resulted in the strongest antiproliferation effect. In addition, compared with the unmodified nanoparticles, F3-PP NP exhibited a more preferential enrichment at the tumor site. Pharmacodynamics evaluation in vivo demonstrated that a longer survival time was achieved by the tumor-bearing mice treated with PP NP (+laser) than those treated with chemotherapy only or PDT only. Such antitumor efficacy of combination therapy was further improved following the F3 peptide functionalization. Collectively, these results suggested that targeted combination therapy may pave a promising way for the therapy of drug-resistant tumor.

Co-Delivery of Cisplatin Prodrug and Chlorin e6 by Mesoporous Silica Nanoparticles for Chemo-Photodynamic Combination Therapy to Combat Drug Resistance.

Combination therapy shows great promise in circumventing cisplatin resistance. We report herein the development of a novel nanoscale drug delivery system (nDDS) based nanotherapeutic that combines chemotherapy and photodynamic therapy (PDT) into one single platform to achieve synergistic anticancer capacity to conquer cisplatin resistance. Mesoporous silica nanoparticle (MSNs) was used as the drug delivery vector to conjugate cisplatin prodrug and to load photosensitizer chlorin e6 (Ce6) to afford the dual drug loaded delivery system MSNs/Ce6/Pt. The hybrid nanoparticles have an average diameter of about 100 nm and slightly positive surface charge of about 18.2 mV. The MSNs/Ce6/Pt nanoparticles can be efficiently internalized by cells through endocytosis, thereby achieving much higher cellular Pt uptake than cisplatin in cisplatin-resistant A549R lung cancer cells. After 660 nm light irradiation (10 mW/cm(2)), the cellular reactive oxygen species (ROS) level in MSNs/Ce6/Pt treated cells was elevated dramatically. As a result of these properties, MSNs/Ce6/Pt exhibited very potent anticancer activity against A549R cells, giving a half-maximal inhibitory concentration (IC50) value for the combination therapy of 0.53 μM, much lower than that of cisplatin (25.1 μM). This study suggests the great potential of nDDS-based nanotherapeutic for combined chemo-photodynamic therapy to circumvent cisplatin resistance.

PH-Sensitive self-assembling nanoparticles for tumor near-infrared fluorescence imaging and chemo-photodynamic combination therapy.

The development of visual tumor theranostic nanoparticles has become a great challenge. In this study, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was conjugated to acid-sensitive cis-aconitic anhydride-modified doxorubicin (CAD) to obtain pH-sensitive anti-tumor prodrug nanoparticles (TCAD NPs) via self-assembling. Subsequently, the photosensitizer chlorin e6 (Ce6) was loaded into the resulting prodrug nanoparticles to prepare a novel tumor near-infrared fluorescence imaging and chemo-photodynamic combination therapy system (TCAD@Ce6 NPs). An accelerated release of doxorubicin (DOX) and chlorin e6 (Ce6) from the TCAD@Ce6 NPs could be achieved due to the hydrolysis of the acid-sensitive amide linker under mild acidic conditions (pH = 5.5). An in vitro experiment showed that A549 lung cancer cells exhibited a significantly higher uptake of DOX and Ce6 by using our delivery system than the free form of DOX and Ce6. An in vivo experiment showed that TCAD@Ce6 NPs displayed better tumor targeting gathering through the enhanced permeability and retention (EPR) effect than free Ce6, thus improving fluorescence imaging. Moreover, the chemo-photodynamic combination therapy of TCAD@Ce6 NPs combined with near-infrared laser irradiation was confirmed to be capable of inducing high apoptosis and necrosis of tumor cells (A549) in vitro and to display a significantly higher tumor growth suppression in the A549 lung cancer-bearing mice model. Furthermore, compared with exclusive chemotreatment (DOX) or photodynamic treatment (Ce6), our system showed enhanced therapeutic effects both in vitro and in vivo. In conclusion, the high performance TCAD@Ce6 NPs can be used as a promising NIR fluorescence imaging and highly effective chemo-photodynamic system for theranostics of lung cancer, etc. in the near future.

Actively targeting D-α-tocopheryl polyethylene glycol 1000 succinate-poly(lactic acid) nanoparticles as vesicles for chemo-photodynamic combination therapy of doxorubicin-resistant breast cancer.

Drug resistance is the major reason for therapeutic failure during cancer treatment. Chemo-photodynamic combination therapy has potential to improve the treatment efficiency in drug-resistant cancers, but is limited by the incompatible physical properties of the photosensitizer with a chemo-drug and poor accumulation of both drugs into the inner areas of the tumor. Herein, a novel drug delivery system was designed by incorporating the photosensitizer, chlorine 6, chemically in the shell and the chemo-drug, doxorubicin, physically in the core of D-α-tocopheryl polyethylene glycol 1000 succinate-poly(lactic acid) (TPGS-PLA) nanoparticles with a targeting ligand, tLyp-1 peptide, decorated over the surface (tLyp-1-NP). This nanoparticle with a high drug loading capacity of both the photosensitizer and chemo-drug is expected to realize chemo-photodynamic combination therapy of drug-resistant cancer and simultaneously achieve the specific deep penetration and accumulation of drugs into the inner areas of tumor. tLyp-1-NP was prepared via a nanoprecipitation method and it exhibited a uniformly spherical morphology with a size of approximately 130 nm. After appropriate irradiation, tLyp-1-NP showed high cellular uptake and strong cytotoxicity in both human umbilical vein endothelial cells (HUVEC cells) and doxorubicin-resistant human breast adenocarcinoma cells (MCF-7/ADR cells) in vitro. After intravenous administration, compared with the unmodified NPs, tLyp-1-NP was found to have superior tumor targeting ability and more potent reversion of doxorubicin-resistant cancer. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and the hematoxylin and eosin staining of the treated tumors further demonstrated the anti-tumor efficacy of tLyp-1-NP in the presence of a laser. These observations collectively suggest the potential of tLyp-1-NP for the actively targeting chemo-photodynamic combination therapy of drug-resistant cancer.

Clinical efficacy of photodynamic therapy.

ObjectiveThe management of cervical intraepithelial neoplasia (CIN) and early invasive cancer of the uterine cervix is very difficult to approach, especially in case of young woman who wants to preserve her fertility. Conization of the cervix may have various kinds of disadvantage. The objective of this clinical retrospective study is to investigate the therapeutic effects and clinical efficacy of photodynamic therapy (PDT) including combined chemo-photodynamic therapy in patients with pre-malignant CIN and malignant invasive cervical cancer.MethodsTotal number of PDT trial case was 50 cases and total number of patient was 22 patients who registered to PDT clinic. We used photogem sensitizer and 632 nm diode laser in early two cases. After then we performed PDT using photofrin sensitizer and 630 nm diode laser in other cases. We used flat-cut, microlens, cylindrical diffuser, and interstitial type optic fibers in order to irradiate the lesions. 240 J/cm2 energy was irradiated to the lesions.ResultsCIN 2 were 4 cases (18.2%) and CIN 3 were 15 (68.2%) and invasive cervical cancer were 3 (13.6%). Complete remission (CR) was found in 20 patients (91%). One case of 19 patients with CIN lesion recurred at 18 months after PDT treatment. CR was found in 18 cases in the patients with CIN lesions (95%). CR was found in 2 cases in the patients with invasive cervical cancer (67%).ConclusionOur data showed that CR rate was fantastic in CIN group (95%). This study suggests that PDT can be recommended as new optimistic management modality on the patients with pre-malignant CIN lesions including carcinoma in situ and relatively early invasive cancer of the uterine cervix. Combined chemo-photodynamic therapy is essential in case of invasive cervical cancer. For the young age group who desperately want to preserve their fertility and have a healthy baby, PDT can be a beacon of hope.

A Stimulated Mixed Micelle System for In Vitro Study on Chemo-Photodynamic Therapy.

A mixed micelle system with pH-responsive and photoactive zinc tetra(progaryloxy-phenyl) porphyrin (ZnTPP) core is constructed for encapsulation of doxorubicin (DOX) to facilitate combined chemo-photodynamic therapy in one delivery system. The mixed micelles show low critical micelle concentration, good storage stability, a pH dependent behavior, and better singlet oxygen generation efficiency compared to the star-shaped PEG-ZnTPP micelles, where the aggregation of ZnTPP within the core, resulting in less photoactive effect. The cell viability treated with DOX-loaded mixed micelles shows higher cytotoxicity than single drug loaded micelles under light irradiation. The improved therapeutic efficiency indicates the combined effect of DOX and ZnTPP and this mixed micelle system has potential as dual-modality for cancer treatment.

An efficient gold nanocarrier for combined chemo-photodynamic therapy on tumour cells

A multimodal Au@mSiO2 nanocarrier in which AuNPs act as PDT-assistor cores and mesoporous silica shells as supporters to load two drugs.

Biodegradable core-shell nanoassemblies for the delivery of docetaxel and Zn(II)-phthalocyanine inspired by combination therapy for cancer

Combination therapies for cancer aim to exploit either additive or synergistic effects arising from the action of two species with the final goal to maximize the therapeutic efficacy. In this work, we develop multifunctional nanoparticles (NPs) for co-delivery of the conventional anticancer drug docetaxel (DTX) and the second generation photosensitizer zinc-phthalocyanine (ZnPc) as potential dual carrier system for the combination of chemotherapy and photodynamic therapy (PDT). Biodegradable and amphiphilic block copolymers based on poly(ε-caprolactone) (PCL=B) and poly(ethylene oxide) (PEO=A), with AB and ABA architectures, were assembled in “core-shell” NPs and loaded with both DTX and ZnPc employing the melting/sonication method. Hydrodynamic diameters within the range 60–100nm and low polydispersity indexes were obtained. Zeta potential was negative for all the formulations and unaffected by drug encapsulation. Concerning drug loading ability of NPs, the entrapment efficiency was related to initial ZnPc/DTX ratio. Steady-stationary and time-resolved emission fluorescence measurements pointed out the embedding of monomeric ZnPc in the NPs, excluding the presence of ZnPc self-supramolecular oligomers. The release of DTX was biphasic whereas ZnPc remained mainly associated with NPs. Singlet oxygen generation was observed when ZnPc-loaded NPs were irradiated at 610nm within a 45min time range, despite that ZnPc was not released in the medium. Stability of NPs in the presence of serum proteins and plasma was excellent and no toxicity toward red blood cells was found. NPs cytotoxicity was evaluated in HeLa cells irradiated for 30min with a halogen lamp. After 72h, viability of cells treated with ZnPc/DTX-loaded NPs strongly decreased as compared to NPs loaded only with DTX, thus showing a combined effect of both DTX and ZnPc. Superior antitumor activity of ZnPc/DTX-loaded NPs as compared to DTX-loaded NPs was confirmed in an animal model of orthotopic amelanotic melanoma, thus pointing to the application of PEO–PCL NPs in the combined chemo-photodynamic therapy of cancer.