Synergistic Chemo-photodynamic Therapy Research Articles

Acid-triggered synergistic chemo-photodynamic therapy systems based on metal-coordinated supramolecular interaction.

To enhance anticancer efficacy and decrease side effects, the synergistic multi-agent therapy has now increasingly gotten great attention. Herein, the flexible polycaprolactone had been modified by histidine and formed assembles with PEGylated metallo-porphyrin via metal-coordinated supramolecular interaction. This supramolecular assembles showed excellent acid sensitivity. At neutral environment, the hydrophobic anticancer drug could be effectively co-encapsulated with photosensitizer Fe-TPP to improve the water solubility. While at the intracellular microenvironment, the changed acid environment would trigger the drug and Fe-TPP release due to the reduction of metal-coordinated interaction between histidine and metallo-porphyrin leading to the disintegration of assembles. The in vivo anticancer experiments toward HeLa and MCF-7 cells disclosed that this co-delivery system of anticancer drug and photosensitizer showed enhanced anticancer efficacy, implying that the synergistic chemo-photodynamic therapy could improve cellular proliferation inhibition. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2955-2962, 2018.

Ultrasound Triggered Conversion of Porphyrin/Camptothecin-Fluoroxyuridine Triad Microbubbles into Nanoparticles Overcomes Multidrug Resistance in Colorectal Cancer.

Multidrug resistance remains one of the main obstacles to efficient chemotherapy of colorectal cancer. Herein, an efficient combination therapeutic strategy is proposed based on porphyrin/camptothecin-floxuridine triad microbubbles (PCF-MBs) with high drug loading contents, which own highly stable co-delivery drug combinations and no premature release. The triad PCF-MBs can act not only as a contrast agent for ultrasound (US)/fluorescence bimodal imaging but also a multimodal therapeutic agent for synergistic chemo-photodynamic combination therapy. Upon local ultrasound exposure under the guidance of ultrasound imaging, in situ conversion of PCF-MBs into porphyrin/camptothecin-floxuridine nanoparticles (PCF-NPs) leads to high accumulation of chemo-drugs and photosensitizer in tumors due to the induced high permeability of the capillary wall and cell membrane temporarily via sonoporation effect, greatly reducing the risk of systemic exposure. Most importantly, it was found that the PCF-MB-mediated photodynamic therapy could significantly reduce the expression of adenosine-triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2), which is responsible for the drug resistance in chemotherapy, resulting in a prominent intracellular camptothecin increase. In vivo experiments revealed that the PCF-MBs in combination with ultrasound and laser irradiation could achieve a 90% tumor inhibition rate of HT-29 cancer with no recurrence. Therefore, such triad PCF-MB-based combination therapeutic strategy shows great promise for overcoming drug resistance of colorectal cancer and other cancers.

An Ultra-Robust and Crystalline Redeemable Hydrogen-Bonded Organic Framework for Synergistic Chemo-Photodynamic Therapy.

The low structural stability of hydrogen-bonded organic frameworks (HOFs) is a thorny issue retarding the development of HOFs. A rational design approach is now proposed for construction of a stable HOF. The resultant HOF (PFC-1) exhibits high surface area of 2122 m2 g-1 and excellent chemical stability (intact in concentrated HCl for at least 117 days). A new method of acid-assisted crystalline redemption is used to readily cure the thermal damage to PFC-1. With periodic integration of photoactive pyrene in the robust framework, PFC-1 can efficiently encapsulate Doxorubicin (Doxo) for synergistic chemo-photodynamic therapy, showing comparable therapeutic efficacy with the commercial Doxo yet considerably lower cytotoxicity. This work demonstrates the notorious stability issue of HOFs can be properly addressed through rational design, paving a way to develop robust HOFs and offering promising application perspectives.

A tumor-targeted Ganetespib-zinc phthalocyanine conjugate for synergistic chemo-photodynamic therapy

Therapeutic effects of photodynamic therapy (PDT) are limited by the selectivity of photosensitizer (PS). Herein, a novel tumor-targeted drug-PS conjugate (Gan-ZnPc) which integrated with zinc phthalocyanine (ZnPc) and Ganetespib has been developed. ZnPc is a promising PS with remarkable photosensitization ability. Ganetespib is a heat shock protein 90 (Hsp90) inhibitor with preferential tumor selectivity and conjugated to ZnPc as a tumor-targeted ligand. The multifunctional small molecule conjugate, Gan-ZnPc, could be bound to extracellular Hsp90 and then selectively internalized into the tumor cells, followed by the generation of abundant intracellular reactive oxygen species (ROS) upon irradiation. Besides, Gan-ZnPc can arrest cell proliferation and induce apoptosis by the inhibition of Hsp90. Herein, with combination of the inhibition of Hsp90 and the generation of cytotoxic ROS, Gan-ZnPc implements tumor selectivity, concentrated PDT and chemotherapy in a synergistic manner, which results in highly effective anti-tumor activity in vitro and in vivo.

Light-activatable dual-source ROS-responsive prodrug nanoplatform for synergistic chemo-photodynamic therapy.

In the context of prodrug nanomedicines for cancer therapy, one of the great challenges is the slow and variable release of the parent drug in tumors. Recently, many smart redox-sensitive nanocarriers have been developed to address this problem. However, due to significant tumor heterogeneity, some redox-sensitive nanomedicines still show poor selectivity in drug release. Herein, we report the design and synthesis of a ROS-triggered prodrug nanoplatform fabricated with oxidation-responsive cabazitaxel (CTX) prodrugs for synergistic chemo-photodynamic therapy, thioether-/selenoether-linked conjugates of CTX and oleic acid (OA). These prodrugs can be readily self-assembled into nanoparticles, with pyropheophorbide a (PPa) co-encapsulated into the prodrug-nanosystem for combination therapy. The dual-source ROS-responsive prodrug nanosystems selectively and rapidly release CTX not only in response to endogenous ROS overproduced in tumor cells, but also to exogenous PPa-generated ROS under laser irradiation. Moreover, the selenium-containing linkage demonstrates significant advantages over a sulfur-containing linkage in terms of ROS-triggered drug release and cytotoxicity. The prepared prodrug-nanosystems significantly prolong the systemic circulation and tumor distribution of both CTX and PPa, thereby demonstrating synergistic chemo-photodynamic therapy in vivo. All these drug delivery advantages render the nanosystem extremely promising for cancer treatment.

Self-assembly of porphyrin-grafted lipid into nanoparticles encapsulating doxorubicin for synergistic chemo-photodynamic therapy and fluorescence imaging.

The limited clinical efficacy of monotherapies in the clinic has urged the development of novel combination platforms. Taking advantage of light-triggered photodynamic treatment combined together with the controlled release of nanomedicine, it has been possible to treat cancer without eliciting any adverse effects. However, the challenges imposed by limited drug loading capacity and complex synthesis process of organic nanoparticles (NPs) have seriously impeded advances in chemo-photodynamic combination therapy. In this experiment, we utilize our previously synthesized porphyrin-grafted lipid (PGL) NPs to load highly effective chemotherapeutic drug, doxorubicin (DOX) for synergistic chemo-photodynamic therapy.Methods: A relatively simple and inexpensive rapid injection method was used to prepare porphyrin-grafted lipid (PGL) NPs. The self-assembled PGL NPs were used further to encapsulate DOX via a pH-gradient loading protocol. The self-assembled liposome-like PGL NPs having a hydrophilic core were optimized to load DOX at an encapsulation efficiency (EE) of ~99%. The resultant PGL-DOX NPs were intact, highly stable and importantly these NPs successfully escaped from the endo-lysosomal compartment after laser irradiation to release DOX in the cytosol. The therapeutic efficacy of the aforementioned formulation was validated both in vitro and in vivo.Results: PGL-DOX NPs demonstrated excellent cellular uptake, chemo-photodynamic response, and fluorescence imaging ability in different cell lines. Under laser irradiation, cells treated with a low molar concentration of PGL-DOX NPs reduced cell viability significantly. Moreover, in vivo experiments conducted in a xenograft mouse model further demonstrated the excellent tumor accumulation capability of PGL-DOX NPs driven by the enhanced permeability and retention (EPR) effect. Through fluorescence imaging, the biodistribution of PGL-DOX NPs in tumor and major organs was also easily monitored in real time in vivo. The inherent ability of porphyrin to generate ROS under laser irradiation combined with the cytotoxic effect of the anticancer drug DOX significantly suppressed tumor growth in vivo.Conclusion: In summary, the PGL-DOX NPs combined chemo-photodynamic nanoplatform may serve as a potential candidate for cancer theranostics.

Synergistic chemo-photodynamic therapy by “big & small combo nanoparticles” sequential release system

Chemo-photodynamic combination has been manifested great potential for synergistic cancer therapy. Moreover, the synergistic efficacy could be significantly enhanced by well-designed sequential release manner of photosensitizers (PSs). Here we propose a “big & small combo nanoparticles (NPbig&small)” system for double loading PSs methylene blue (MB) and single absorbing chemotherapeutics drug Gemcitabine hydrochloride (GM·HCl). The “grown-in” MB from NPbig&small show two-peak sequential release profile, significantly improve the absorbed chemotherapeutic efficacy of GM·HCl. The corresponding two-peak sequential release profile can be illustrated by related mathematics function. The sequential release property was clearly observed through morphological evolution of NPs both in water and cells by TEM. Furthermore, NPbig&small demonstrate well EPR effect and improved synergistic efficacy from in vitro and in vivo results. Thus, NPbig&small chemo-photodynamic system and the programmable sequential release mechanism provide a promising platform that ensures an enhanced synergistic chemo-photodynamic effect in cancer treatment.

Ternary cocktail nanoparticles for sequential chemo-photodynamic therapy

BackgroundPrevious clinical trials have already demonstrated that combinations of two or more drugs were more effective in the cancer treatment, especially sequential photodynamic design combing with sequential chemotherapy. In our study, we propose a ternary cocktail NP delivery system based on self-decomposable NPs, which could realize synergistic chemo-photodynamic therapy through double loading chemo-drugs and multi-level programmable PDT treatment.MethodsPS drug methylene blue (MB) was encapsulated into the center of the NPsmall, NPbig&thin, and NPbig&thick carriers through “grown-in” loading mechanism, which was released based on the drug concentration difference of the drug release environment. NPsmall, NPbig&thin, and NPbig&thick carriers have three different drug release profiles, which could realize multi-level programmable PDT treatment. At the same time, antitumor drug gemcitabine hydrochloride (GM) and Docetaxel (DTX), were chosen as the double loading chemo-drugs that absorbed onto the NPbig&thin and NPbig&thick surface, respectively. In specific, various particle configurations were used for modulating the inner MB sequential release with three pulse Tmax. Also, by adjusting the NPbig&thin and NPbig&thick configuration, the release interval lag time between absorbed GM and DTX can be successfully modulated to achieve maximized chemotherapeutic efficacy.ResultsIn vitro and in vivo results demonstrated that these three pulses Tmax and the sustained release of MB could maximize the multi-level programmable PDT treatment. And the absorbed GM and DTX also have a release time lag of 12 h, which has been proved as the most effectiveness synergistic interval lag time in the cancer treatment.ConclusionSuch a precise sequential release manner ternary cocktail NPs provided a promising platform for efficient and safe chemo-photodynamic therapy, which serves as a promising drug delivery system to cure cancer in the future.

Synergistic chemo-photodynamic therapy by “Big & small combo NPs” sequential release system

Synergistic chemo-photodynamic therapy by “Big & small combo NPs” sequential release system

Acid-responsive metallo-supramolecular micelles for synergistic chemo-photodynamic therapy

Due to the molecular complexity of many diseases, combination therapy is becoming increasingly important for a better long-term prognosis and to decrease side effects. In this presented work, a kind of AB2 Y-shape supramolecular micelles based on the metal-coordinated interaction between histidine and iron-tetraphenylporphyrins (Fe-TPP) had been successfully prepared which exhibited excellent acid-responsivity in acidic aqueous solution (pH < 6, similar to tumor micro-environment). To verify the application for drug delivery, doxorubicin was loaded at neutral. Then the anticancer efficiency was evaluated in vivo towards HeLa and MCF-7 cells. The obtained date indicated that the loaded drug released at tumor acid condition because the micelles disassembled. Importantly, the existence of Fe-TPP being as photosensitizer obviously improved the anticancer efficiency, confirming that synergistic chemo-photodynamic therapy could effectively enhance cellular proliferation inhibition.

A tumor-targeted activatable phthalocyanine-tetrapeptide-doxorubicin conjugate for synergistic chemo-photodynamic therapy

Chemo-photodynamic therapy is a promising strategy for cancer treatments. However, it remains a challenge to develop a chemo-photodynamic therapeutic agent with little side effect, high tumor-targeting, and efficient synergistic effect simultaneously. Herein, we report a zinc(II) phthalocyanine (ZnPc)-doxorubicin (DOX) prodrug linked with a fibroblast activation protein (FAP)-responsive short peptide with the sequence of Thr-Ser-Gly-Pro for chemo-photodynamic therapy. In the conjugate, both photosensitizing activity of ZnPc and cytotoxicity of DOX are inhibited obviously. However, FAP-triggered separation of the photosensitizer and DOX can enhance fluorescence emission, singlet oxygen generation, dark- and photo-cytotoxicity significantly, and lead to a synergistic anticancer efficacy against HepG2 cells. The prodrug can also be specifically and efficiently activated in tumor tissue of mice. Thus, this prodrug shows great potential for clinical application in chemo-photodynamic therapy.

PH-responsive metallo-supramolecular nanogel for synergistic chemo-photodynamic therapy

Benefited from the high orientation of coordinated interaction, metallo-supramolecular materials have attracted enormous interest in many fields. Herein, a novel metallo-supramolecular nanogel (SNG)-based drug delivery system for synergistic chemo-photodynamic therapy is explored to enhance anticancer efficacy. It is fabricated by the metallo-supramolecular-coordinated interaction between tetraphenylporphyrin zinc (Zn-Por) and histidine. It can respond to tumor acid microenvironment to release the co-delivered anticancer drug and photosensitizer to kill the lesion cells. Zn-Por moieties in SNG keep the photosensitivity in the range of visible wavelength and possess the ability of generating active oxygen species for photodynamic therapy. The drug-loaded SNG provides a di-functional platform for chemotherapy and photodynamic therapy. Compared with the single chemotherapy of free doxorubicine (DOX) or photodynamic therapy of Zn-Por in SNG, DOX-loaded SNG with irradiation shows higher in vitro cytotoxicity and in vivo anticancer therapeutic activity, endowing the SNG with great potential in cancer treatments. The statement of significanceA combination of multiple non-cross-resistant anticancer agents has been widely applied clinically. Applying multiple drugs with different molecular targets can raise the genetic barriers and delay the cancer adaption process. Multiple drugs targeting different cellular pathways can function synergistically, giving higher therapeutic efficacy and target selectivity. Overall, developing a combination therapeutic approach might even be the key to enhance anticancer efficacy and overcome chemo-resistance. Herein, a novel metallo-supramolecular nanogel (SNG) is fabricated by the metallo-supramolecular-coordinated interaction between tetraphenylporphyrin zinc (Zn-Por) and histidine. The DOX-loaded SNG provides a di-functional platform for chemotherapy and photodynamic therapy because it can respond to tumor acid microenvironment to release the co-delivered anticancer drug and photosensitizer to kill the lesion cells.

Dual pH-responsive mesoporous silica nanoparticles for efficient combination of chemotherapy and photodynamic therapy.

A kind of dual pH-responsive mesoporous silica nanoparticle (MSN)-based drug delivery system, which can respond to the cancer extracellular and intercellular pH stimuli, has been fabricated for synergistic chemo-photodynamic therapy. By grafting histidine onto the silica surface, the acid sensitive PEGylated tetraphenylporphyrin zinc (Zn-Por-CA-PEG) can be used as a gatekeeper to block the nanopores of MSNs by the metallo-supramolecular-coordinated interaction between Zn-Por and histidine. This gatekeeper is stable enough to prevent the loaded drug from leaching out in healthy tissue. However, at cancer extracellular pH (∼6.8) the conjugated acid sensitive cis-aconitic anhydride (CA) between Zn-Por and PEG will cleave and the surface of Zn-Por will be amino positively charged to facilitate cell internalization. Furthermore, the metallo-supramolecular-coordination will disassemble in intracellular acidic microenvironments (∼5.3) to release the carried drug and Zn-Por due to the removal of the gatekeeper. The photosensitivity of Zn-Por further makes it possible to combine chemotherapy and photodynamic therapy. This dual pH-sensitive MSN-based drug delivery system showed higher in vitro cytotoxicity than the single chemotherapy of free DOX or photodynamic therapy of Zn-Por, presenting its great potential for cancer treatment to overcome the challenges in efficient delivery in the site and ideal anti-cancer efficacy.

A facile strategy to generate polymeric nanoparticles for synergistic chemo-photodynamic therapy.

Synergistic therapy is a promising strategy for cancer treatment. A nanoparticle with chemo-photodynamic properties was fabricated via π-π stacking interactions between the drug and photosensitizer. It exhibited efficient anticancer activity both in vitro and in vivo.