Zhiguo Gao

Co-delivery of cisplatin and CJM-126 via photothermal conversion nanoparticles for enhanced synergistic antitumor efficacy

Polymeric biomaterials that can be smartly disassembled through the cleavage of the covalent bonds in a controllable way upon an environmental stimulus such as pH change, redox, special enzymes, temperature, or ultrasound, as well as light irradiation, but are otherwise stable under normal physiological conditions have attracted great attention in recent decades. The 2-(4-aminophenyl) benzothiazole molecule (CJM-126), as one of the benzothiazole derivatives, has exhibited a synergistic effect with cisplatin (CDDP) and restrains the bioactivities of a series of human breast cancer cell lines. In our study, novel NIR-responsive targeted binary-drug-loaded nanoparticles encapsulating indocyanine green (ICG) dye were prepared as a new co-delivery and combined therapeutic vehicle. The prepared drug-loaded polymeric nanoparticles (TNPs/CDDP-ICG) are stable under normal physiological conditions, while burst drugs release upon NIR laser irradiation in a mild acidic environment. The results further confirmed that the designed co-delivery platform showed higher cytotoxicity than the single free CDDP due to the synergistic treatment of CJM-126 and CDDP in vitro. Taken together, the work might provide a promising approach for effective site-specific antitumor therapy.

NIR stimulus-responsive core–shell type nanoparticles based on photothermal conversion for enhanced antitumor efficacy through chemo-photothermal therapy

A novel core-shell type nanoparticle (CSNP) was designed here to target co-delivery of doxorubicin (DOX) and photosensitizer indocyanine green (ICG) to tumor sites by the aid of NIR induced photothermal conversion effect for the purpose of synergistic chemo-photothermal cancer therapy. The electrostatically self-assembled CSNPs were prepared by amino-functionalized mesoporous silica nanoparticles (MSN-NH2) as the positive inner core and DSPE-PEG2000-COOH and DSPE-PEG2000-FA modified lecithin as the negative outer shell. The obtained CSNPs were nanospheres with a uniform size of 47 nm, which were kept stable at 4 °C in PBS (pHxa0=xa07). Research on the release of NIR stimulus (808 nm, 1.54 W cm-2, 6 min) manifested that the release property of the CSNPs was controllable under low pH conditions. In addition, specific concentration (40 μg ml-1) ICG-loaded CSNPs, achieving an appropriate temperature up to 45 °C, indicated a desired photothermal conversion efficiency. For targeting the folate receptor, the folate modified CSNPs enabled us to reach a higher cellular uptake by the mean fluorescence intensity. In vitro cell assay, the prepared CSNPs showed outstanding inhibitory efficiency (2.07% cell viability and 91.8% cell apoptosis) on MCF-7 cells for 24 h when irradiated by an 808 nm laser with a power of 1.54 W cm-2 for 6 min. Our research highlights that the prepared nanoparticles hold potential promise for cancer treatment based on photothermal conversion performance and FA-targeted delivery.

Synthesis and biological evaluation of redox/NIR dual stimulus-responsive polymeric nanoparticles for targeted delivery of cisplatin

Functional drug delivery systems enabling various favorable characteristics including specific targets, efficient cellular uptake and controllable release. At present work, a folate and cRGD dual modified nanoparticles based on NIR light and glutathione dual stimuli-responsive release system was successfully prepared and which simultaneously deliver cisplatin and ICG to tumor sites to enhance controllability. The prepared nanoparticles showed a stable uniform spherical morphology of 77.59u202fnm particle size range in PBS (pHu202f=u202f7.4, 25u202f°C) and the encapsulated cisplatin were rapidly released in acidic environment especially added glutathione (GSH) and NIR irradiation. Moreover, the prepared nanoparticles can be efficiently internalized by tumor cells through the enhanced dual targeted ligands (folate and cRGD) for ICG imaging. The cytotoxicity assays showed that the cells viability decreased to 1.95% (SGC-7901) when been exposed to NIR light, and which further decreased to 1.25% in MCF-7 cells. Thus, the prepared nanoparticles showed excellent performance for photothermal conversion therapy of tumor cells and especially on human breast tumor cells. Our research highlights the great potential of stimuli-responsive smart nanoparticles in biomaterial and nano-biomedicine.

A dual-targeting strategy for enhanced drug delivery and synergistic therapy based on thermosensitive nanoparticles

Abstract The functionalized nanoparticles have been widely studied and reported as carriers of drug transport recently. Furthermore, many groups have focused more on developing novel and efficient treatment methods, such as photodynamic therapy and photothermal therapy, since both therapies have shown inspiring potential in the application of antitumor. The mentioned treatments exhibited the superiority of cooperative manner and showed the ability to compensate for the adverse effects caused by conventional monotherapy in proposed strategies. In view of the above descriptions, we formulated a thermosensitive drug delivery system, which achieved the enhanced delivery of cisplatin and two photosensitizers (ICG and Ce6) by dual-targeting traction. Drawing on the thin film hydration method, cisplatin and photosensitizers were encapsulated inside nanoparticles. Meanwhile, the targeting peptide cRGD and targeting molecule folate can be modified on the surface of nanoparticles to realize the active identification of tumor cells. The measurements of dynamic light scattering showed that the prepared nanoparticles had an ideal dispersibility and uniform particle size of 102.6 nm. On the basis of the results observed from confocal laser scanning microscope, the modified nanoparticles were more efficient endocytosed by MCF-7 cells as a contrast to SGC-7901 cells. Photothermal conversion-triggered drug release and photo-therapies produced a significant apoptosis rate of 85.9% on MCF-7 cells. The distinguished results made it believed that the formulated delivery system had conducted great efforts and innovations for the realization of concise collaboration and provided a promising strategy for the treatment of breast cancer.

FA and cRGD dual modified lipid-polymer nanoparticles encapsulating polyaniline and cisplatin for highly effective chemo-photothermal combination therapy

Abstract A combination of chemotherapy and photothermal therapy as a promising strategy has exhibited noticeable therapeutic effect on cancer therapy. To ensure the exertion of synergistic effect on a tumor region, a multifunctional vehicle for selectively delivering therapeutic agent into tumor cells is highly desirable. Thus, folate-poly (ethylene glycol)-distearoylphosphatidylcholine (FA-PEG-DSPE), cRGD [cyclic (Arg-Gly-Asp-D-Phe-Lys)]-PEG-DSPE and lecithin were employed to develop dual modified nanoparticles (FA/cRGD-PNPs) encapsulating polyaniline and cisplatin by a film-ultrasonic dispersion method. The FA/cRGD-PNPs showed a uniform size of 102.7 nm, remarkable stability and monodispersity, and highly localized temperature respond. Compared to chemo or photothermal treatment alone, the combined treatment on cells in vitro significantly suppressed the survival rate of MDA-MB-231 cells (1.87%) and MGC-803 cells (2.37%) treated for 48 h. The results further indicated the induced cell apoptosis rate of MDA-MB-231 cells reached to 92.6% with treatment for 24 h. Hence, our research highlights the great potential in drug delivery and the combination of chemotherapy and photothermal therapy.

Cisplatin and Ce6 loaded polyaniline nanoparticles: An efficient near-infrared light mediated synergistic therapeutic agent

Lipid-polymer hybrid nanoparticle was suggested to be a new and promising drug delivery agent due to the suitable particle size and controllable release. However, the low drug loading capacity has been a critical problem in the improvement of the nano-carrier systems. At present work, we have designed and developed smart nanoparticles with cholesterol-cisplatin (IV) conjugate contained to enhance the drug loading capacity. The predesigned drug delivery system showed enhanced synergistic effect through co-delivery of cisplatin and Ce6 and the drug released in a controllable way due to the polyaniline mediated photothermal conversion. The prepared polyaniline nanoparticles showed a favorable particle size of 109.6u202fnm and spread harmoniously in aqueous solution. Moreover, the near infrared radiation (NIR) stimulus-responsive characteristic of the polyaniline nanoparticles prompts the release of cisplatin from the nanoparticles inside the cytoplasm and the αvβ3/αvβ5 integrins targeted ligands (cRGD) enhanced the cellular uptake of the polyaniline nanoparticles in receptor-overexpressing MCF-7 cells. Furthermore, the singlet oxygen generated by Ce6 further enhances the cytotoxicity and obtained the expected synergistic effect with cisplatin. Thus, the prepared cRGD-conjugated co-delivery of cisplatin and Ce6 polyaniline nanoparticles consider to be a promising nanoplatform in nano-biomedicine.

Subcellular co-delivery of two different site-oriented payloads based on multistage targeted polymeric nanoparticles for enhanced cancer therapy

The co-delivery of two or more anti-tumor agents using nanocarriers has shown great promise in cancer therapy, but more work is needed to selectively target drugs to specific subcellular organelles. To this end, our research has reported on smart polymeric nanoparticles that can encapsulate two different site-oriented pro-drug molecules, allowing them to reach their targeted subcellular organelles based on NIR-mediated controlled release, allowing for targeted modifications in the nucleus or the mitochondria. Specially, an all-trans retinoic acid (RA) conjugated cisplatin derivative (RA-Pt) can be delivered with high affinity to the nucleus of target cells, facilitating the binding of cisplatin to double-stranded DNA. Similarly, a synthesized derivative generated by conjugation of triphenylphosphine (TPP) and celastrol (TPP-Cet) may facilitate mitochondrial targeted drug delivery in tumor cells, inducing ROS accumulation and thereby leading to apoptosis. Relative to nanoparticles loaded with a single therapeutic agent, dual antitumor agent-loaded nanocarriers showed promising synergy, exhibiting significant tumor inhibition in vivo (81.5%), and less systemic toxicity than the free therapeutic agents alone or the drug-loaded nanoparticles without targeted ligands. These results indicated that site-oriented payloads can effectively enhance antitumor therapeutic efficiency and these studies offer a novel multistage targeted-delivery strategy in synergistic therapy for cancer treatment.

Enhanced highly toxic reactive oxygen species levels from iron oxide core–shell mesoporous silica nanocarrier-mediated Fenton reactions for cancer therapy

In this study, iron oxide core-shell mesoporous silica nanoparticles (Fe3O4@MSN) were prepared via the hydrolysis of tetraethyl orthosilicate on the surfaces of Fe3O4 nanoparticles, and these were further conjugated with folate (PEG-FA) and mitochondrial targeting triphenylphosphonium (TPP) to form Fe3O4@MSN-TPP/PEG-FA. A reactive oxygen species (ROS) promoting synergistic combined chemotherapy platform was designed through Fe3O4@MSN-TPP/PEG-FA encapsulating doxorubicin (DOX) and 3-amino-1,2,4-triazole (AT) for cancer therapy. DOX could stimulate the activation of nicotinamide adenine dinucleotide phosphate oxidases (NOXs), which change oxygen into superoxide radicals, which could be further triggered to produce hydrogen peroxide (H2O2) using the superoxide dismutase (SOD) enzyme. AT, as a catalase inhibitor, was employed to inhibit catalase activity to protect the production of H2O2. Thereafter, H2O2 was catalyzed with the help of Fe2+/Fe3+ to form highly toxic free hydroxyl radicals through Fenton reactions, which could induce cell death via synergistic DOX therapy. From in vitro assays, the prepared DOX/AT-loaded Fe3O4@MSN-TPP/PEG-FA showed remarkable inhibition efficiency (3.23% cell viability and 88.1% cell apoptosis) towards MGC-803 cells. This work has created a novel approach to gradually promote the production of ROS and combine this with chemotherapy to enhance anticancer efficacy.

1,3-dimethyl-6-nitroacridine derivatives induce apoptosis in human breast cancer cells by targeting DNA

Abstract The acridine derivatives can interact with the double-stranded DNA, which is regarded as the biological target of the anticancer drugs in cancer treatment. We designed and synthesized a new series of 1,3-dimethyl-6-nitroacridine derivatives as potential DNA-targeted anticancer agents. These compounds could partially intercalate into the calf thymus DNA, differing from the parent acridine. The results showed that the substitutions of the acridine ring had great effect on DNA binding affinity. The binding constants determined by UV-vis spectroscopy were found to be 105u2009M−1 grade. Anticancer activity of these compounds was screened using MTT assay. Most compounds inhibited 50% cancer cell growth at concentration below 30u2009μM, the results were consistent with the DNA binding ability. Compounds 1 and 6 were found to have more effective cytotoxicity, especially in human breast cancer cell lines. To investigate the action mechanism, we studied cell apoptosis, morphological changes, and cell cycle distribution in MCF-7 and MDA-MB-231 cells. Compounds 1 and 6 caused MCF-7 and MDA-MB-231 cells death due to apoptosis, and induced cell apoptosis in a dose-dependent manner. They also had significant effect on cell cycle progression and arrested cell cycle at G2/M phase. The results demonstrated that compounds 1 and 6 are promising candidates for cancer treatment.

Decoration of Cisplatin on 2D Metal–Organic Frameworks for Enhanced Anticancer Effects through Highly Increased Reactive Oxygen Species Generation

Herein, a biocompatible 2D metal-organic frameworks (Cu-TCPP(Fe)) based on TCPP(M) (TCPP = tetrakis (4-carboxyphenyl) porphyrin, M = Fe) and copper ion were synthesized as a novel drug carrier. Sequentially, the cisplatin was loaded on the merge of carboxyl-rich Cu-TCPP(Fe) through forming favorable carboxyl-drug interactions. The prepared Pt/Cu-TCPP(Fe) showed highly enhanced cytotoxicity than that of free cisplatin in human pulmonary carcinoma A549 cells, whereas inverse inhibitory effects were observed in human normal BEAS-2B cells. Further, the mechanism of action about the desirable results was also elaborated. Our study highlighted the potential synergies between the nanocarrier and the anticancer drugs.