Smart photo-enabled micelles for cancer therapy: Mechanisms, challenges, and innovations.

Nanotechnology has made an important contribution to oncology in recent years, especially for drug delivery. While many different nano-delivery systems have been suggested for cancer therapy, selenium nanoparticles (SeNPs) are particularly promising anticancer drug carriers as their core material offers interesting synergistic effects to cancer cells. Se compounds can exert cytotoxic effects by acting as pro-oxidants that alter cellular redox homeostasis, eventually leading to apoptosis induction in many kinds of cancer cells. Herein, we report on the design and synthesis of novel layer-by-layer Se-based nanocomplexes (LBL-Se-NCs) as carriers of small interfering RNA (siRNA) for combined gene silencing and apoptosis induction in cancer cells. The LBL-Se-NCs were prepared using a straightforward electrostatic assembly of siRNA and chitosan (CS) on the solid core of the SeNP. In this study, we started by investigating the colloidal stability and protection of the complexed siRNA. The results show that CS not only functioned as an anchoring layer for siRNA, but also provided colloidal stability for at least 20 days in different media when CS was applied as a third layer. The release study revealed that siRNA remained better associated with LBL-Se-NCs, with only a release of 35% after 7 days, as compared to CS-NCs with a siRNA release of 100% after 48 h, making the LBL nanocarrier an excellent candidate as an off-the-shelf formulation. When applied to H1299 cells, it was found that they can selectively induce around 32% apoptosis, while significantly less apoptosis (5.6%) was induced in NIH/3T3 normal cells. At the same time, they were capable of efficiently inducing siRNA downregulation (35%) without loss of activity 7 days post-synthesis. We conclude that LBL-Se-NCs are promising siRNA carriers with enhanced stability and with a dual mode of action against cancer cells.

The purpose of this study was to explore the photodynamic and photothermal effects of the supramolecular material Purp@COP and to test the anti-cancer effect on HepG2 cells in vitro.Materials and methodsPurp@COP is a covalent organic polymer (COP) with robust tailoring heteroatom incorporation, plentiful pore structure, and multiple functions similar to the metal–organic framework (MOF). Hepatocellular carcinoma cell line HepG2 was cultured with Purp@COP for 24 h and treated with near-infrared 808-nm laser 1 W/cm2 for 10 min. Cell Counting Kit-8 (CCK-8) assay, colony formation assay, live–dead cell fluorescence staining, and Annexin V/propidium iodide (PI) staining flow cytometry were performed to detect the viability, proliferation, and apoptosis of the HepG2 cells.ResultsThe supramolecular material Purp@COP exhibited significant photothermal performance under near-infrared 808-nm laser irradiation in vitro. With the treatment of Purp@COP and near-infrared 808-nm laser irradiation on HepG2 cells, cell viability and colony formation capacity were decreased, and the number and proportion of apoptotic cells were increased.ConclusionsThe supramolecular material Purp@COP has both photothermal and photodynamic effects and can significantly induce cancer cell death and inhibit the proliferation of cancer cells in vitro.

In combining the photothermal and photodynamic effects for killing cancer cells through the localized surface plasmon resonance (LSP) of photosensitizer-linked Au nanorings (NRIs), which are up-taken by the cells, the cells can be killed via different processes, including necrosis and apoptosis. In particular, the dominating effect, either photothermal or photodynamic effect, for cancer cell killing leading to either necrosis or apoptosis process is an important issue to be understood for improving the therapy efficiency. In this paper, we demonstrate the study results in differentiating the necrosis and apoptosis processes of cell death under different laser illumination conditions. With the LSP resonance wavelength of the Au NRIs around 1064 nm, the illumination of a 1064-nm cw laser can mainly produce the photothermal effect. The illumination of a 1064-nm fs laser can lead to LSP resonance-assisted two-photon absorption of the photosensitizer (AlPcS) for generating singlet oxygen and hence the photodynamic effect, besides the photothermal effect. Also, the illumination of a 660-nm cw laser can result in single-photon absorption of the photosensitizer for generating singlet oxygen and the photodynamic effect. By comparing the necrosis and apoptosis distributions in dead cells between the cases of different laser illumination conditions, we can differentiate the cancer cell killing processes between the photothermal effect, photodynamic effect, and the mixed effect.

Small interfering RNA (siRNA), is a class of double-stranded RNA at first non-coding RNA molecules, operating within the RNA interference (RNAi) pathway. It interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation. siRNAs have been widely used to study gene function and extensively exploited for their potential therapeutic applications. siRNAs have gained attention as a potential therapeutic reagent due to their ability to inhibit specific genes in cancer cells. Increased resistance to apoptosis is a challenging issue for treatment of many cancers, including breast cancer. It has been recently reported that siRNAs and RNAi technology can be used to increase the apoptotic susceptibility of cancer cells. It has been shown that apoptosis is induced in cancer cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene. Association of siRNA with apoptosis via mitochondrial depolarization and caspase-3 activation has been highlighted in cancer cells. Although many aspects of siRNA actions in cancer cells have been revealed through in vivo and in vitro studies, the biological mechanisms underlying siRNA mediated knockdown of gene expression and apoptosis induction in cancer cells are not yet fully understood. The main aim of this review is to investigate the effects of siRNAs on apoptosis induction in breast cancer cells.

Recent studies indicated that the leucine zipper domain protein Par-4 induces apoptosis in certain cancer cells by activation of the Fas prodeath pathway and coparallel inhibition of NF-kappaB transcriptional activity. However, the intracellular localization or functional domains of Par-4 involved in apoptosis remained unknown. In the present study, structure-function analysis indicated that inhibition of NF-kappaB activity and apoptosis is dependent on Par-4 translocation to the nucleus via a bipartite nuclear localization sequence, NLS2. Cancer cells that were resistant to Par-4-induced apoptosis retained Par-4 in the cytoplasm. Interestingly, a 59-amino-acid core that included NLS2 but not the C-terminal leucine zipper domain was necessary and sufficient to induce Fas pathway activation, inhibition of NF-kappaB activity, and apoptosis. Most important, this core domain had an expanded target range for induction of apoptosis, extending to previously resistant cancer cells but not to normal cells. These findings have identified a unique death-inducing domain selective for apoptosis induction in cancer cells (SAC domain) which holds promise for identifying key differences between cancer and normal cells and for molecular therapy of cancer.

Graphene-based nanomaterials are of great interest in a wide range of applications in electronics, the environment, and energy as well as in biomedical and bioengineering. Their unique properties make them generally applicable as prognostic, diagnostic, and therapeutic agents in cancer. In this work, we focused on photodynamic and photothermal therapeutic properties of our previously synthesized carboxylated photoluminescent graphene nanodots (cGdots). The cGdots are ∼5 nm in diameter and excited at 655 nm. Our findings reveal that, upon laser irradiation by near-infrared (wavelength 670 nm) sensitizer, electrons of the cGdots starts to vibrate and form electron clouds, thereby generating sufficient heat (>50 °C) to kill the cancer cells by thermal ablation. The generation of singlet oxygen also occurs due to irradiation, thus acting similarly to pheophorbide-A, a well-known photodynamic therapeutic agent. The cGdots kills MDA-MB231 cancer cells (more than 70%) through both photodynamic and photothermal effects. The cGdots were equally effective in the in vivo model of MDA-MB231 xenografted tumor-bearing mice also as observed for 21 days. The cGdot was intravenously injected, and the tumor was irradiated by laser, resulting in final volume of tumor was ∼70% smaller than that of saline-treated tumor. It indicates that the growth rate of cGdot-treated tumor was slower compared to saline-treated tumor. The synthesized cGdots could enable visualization of tumor tissue in mice, thereby illustrating their use as optical imaging agents for detecting cancer noninvasively in deep tissue/organ. Collectively, our findings reveal that multimodal cGdots can be used for phototherapy, through photothermal or photodynamic effects, and for noninvasive optical imaging of deep tissues and tumors simultaneously.

Signals from the tumor microenvironment trigger cancer cells to adopt an invasive phenotype through epithelial-mesenchymal transition (EMT). Relatively little is known regarding key signal transduction pathways that serve as cytosolic bridges between cell surface receptors and nuclear transcription factors to induce EMT. A better understanding of these early EMT events may identify potential targets for the control of metastasis. One rapid intracellular signaling pathway that has not yet been explored during EMT induction is calcium. Here we show that stimuli used to induce EMT produce a transient increase in cytosolic calcium levels in human breast cancer cells. Attenuation of the calcium signal by intracellular calcium chelation significantly reduced epidermal growth factor (EGF)- and hypoxia-induced EMT. Intracellular calcium chelation also inhibited EGF-induced activation of signal transducer and activator of transcription 3 (STAT3), while preserving other signal transduction pathways such as Akt and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation. To identify calcium-permeable channels that may regulate EMT induction in breast cancer cells, we performed a targeted siRNA-based screen. We found that transient receptor potential-melastatin-like 7 (TRPM7) channel expression regulated EGF-induced STAT3 phosphorylation and expression of the EMT marker vimentin. While intracellular calcium chelation almost completely blocked the induction of many EMT markers, including vimentin, Twist and N-cadherin, the effect of TRPM7 silencing was specific for vimentin protein expression and STAT3 phosphorylation. These results indicate that TRPM7 is a partial regulator of EMT in breast cancer cells, and that other calcium-permeable ion channels are also involved in calcium-dependent EMT induction. In summary, this work establishes an important role for the intracellular calcium signal in the induction of EMT in human breast cancer cells. Manipulation of calcium signaling pathways controlling EMT induction in cancer cells may therefore be an important therapeutic strategy for preventing metastases.

Fucoidan-functionalized molybdenum carbide nanospheres for combined therapy: Photothermal, photodynamic, and chemotherapeutic effects on triple-negative breast cancer cell lines.

Selective photothermal and photodynamic capabilities of conjugated polymer nanoparticles

Purpose This study investigates the therapeutic potential of copper-doped carbon quantum dots (Cu-CQDs), integrating photothermal and photodynamic approaches to enhance cancer treatment efficacy. Materials and methods Cu-CQDs were synthesized using citric acid via a hydrothermal method. Nanoparticle characterization was conducted using dynamic light scattering (DLS), spectrofluorometry, and UV–Vis spectrophotometry. Photothermal performance was assessed by measuring temperature increases under laser irradiation. Photodynamic activity was evaluated by oxidative activity detection (consistent with reactive oxygen species (ROS) production) with 2,7-dichlorofluorescein diacetate. Cytotoxicity was examined against MCF-7 breast cancer cells, with and without the addition of 5-aminolevulinic acid (5-ALA) as a photosensitizer. Results The Cu-CQDs demonstrated a fluorescence quantum yield of 2.96%. Upon laser irradiation at 25 mg/mL, the temperature rose above 60 °C within 10 minutes, indicating effective photothermal performance. The cytotoxicity of the synthesized nanotherapeutic against MCF-7 cancer cells was evaluated, revealing that the combined photothermal and photodynamic effects (CQD + 5-ALA+LASER) resulted in 65% cell viability, which was significantly different from the cell viability obtained with the photothermal effect alone (CQD+LASER). Conclusions The study presents a promising cancer treatment strategy by combining photothermal and photodynamic effects of Cu-CQDs. This dual-function approach may serve as an effective method for future cancer therapies.

BackgroundMagnetic materials mediated by mechanical forces to combat cancer cells are currently attracting attention. Firstly, the magnetic force penetrates deeper into tissues than the NIR laser alone to destroy tumours. Secondly, the synergistic effect of nano-magnetic-material characteristics results in a viable option for the targeted killing of cancer cells. Therefore, mechanical force (MF) produced by magnetic nanomaterials under low frequency dynamic magnetic field combined with laser technology is the most effective, safe and efficient tool for killing cancer cells and tumour growth.ResultsIn this study, we synthesized novel urchin-like hollow magnetic microspheres (UHMMs) composed of superparamagnetic Fe3O4. We demonstrated the excellent performance of UHMMs for killing laryngocarcinoma cancer cells through mechanical force and photothermal effects under a vibrating magnetic field and near-infrared laser, respectively. The killing efficiency was further improved after loading the synthesised UHMMs with Chlorin e6 relative to unloaded UHMMs. Additionally, in animal experiments, laryngocarcinoma solid tumour growth was effectively inhibited by UHMMs@Ce6 through magneto-mechanic force, photothermal and photodynamic therapy.ConclusionsThe biocompatibility and high efficiency of multimodal integrated therapy with the UHMMs prepared in this work provide new insights for developing novel nano therapy and drug loading platforms for tumour treatment. In vivo experiments further demonstrated that UHMMs/Ce6 are excellent tools for strongly inhibiting tumour growth through the above-mentioned characteristic effects.Graphical

Drug carriers play a very important role in pharmacy, especially in cancer therapy. Most drugs used in the treatment of cancer are characterized by poor solubility in water and lack of selectivity in their toxic effects on normal and cancer cells. Administration of the drug in the form of a complex with an appropriately selected carrier can significantly improve its therapeutic effect and reduce side effects. In this study, the possibility of using the cryptand L1, containing two diazacrown ethers and two saccharide groups, as a potential drug carrier is investigated. In order to determine whether it can form complexes with drugs, the cryptand L1 and its complexes with two anticancer drugs, busulfan (BSF) and lomustine (CCNU), were synthesized. Their selected structural and energetic properties were investigated using both experimental and computational methods. Additionally, water solubility and cytotoxicity tests were performed for all compounds. The measured 1H NMR spectra confirm that L1 forms complexes L1:BSF and L1:CCNU, the solubility of which in water appears to be much higher than that of the pure drugs. The results of DFT calculations made in water described with the implicit solvent model confirm high stability of L1:BSF and L1:CCNU and indicate that L1 forms with the drugs mainly non-inclusion complexes. However, additional tests with 20 H2O molecules explicitly included in the model suggest that both inclusion and non-inclusion forms can occur in a real solution. Cytotoxicity studies show that the macrocycle L1 is non-toxic towards both normal and cancer cells, and its complexes with drugs show greater selectivity towards cancer cells. Interestingly, while the cytotoxicity of the L1:BSF complex is stronger than that of pure BSF, the relationship is opposite in the case of L1:CCNU and CCNU. Therefore, L1 can be considered as a potential drug carrier, especially for those drugs that have weak activity on cancer cells.

Gene transfer involving p53 is viewed as a potentially effective cancer therapy, but does not result in a good therapeutic response in all human cancers. Several p53 target genes have an inhibitory effect on p53-mediated apoptosis. Therefore, if the induction of these genes by p53 is selectively suppressed, the therapeutic effectiveness would be improved. In previous study, we constructed a replication-deficient recombinant adenovirus that encoded co-cistronic p53 and artificial microRNAs (miRNAs) targeting p21, a representative p53 target gene which have an anti-apoptotic effect, resulting in p53 expression and the suppression of p21 induction simultaneously. In colorectal and hepatocellular carcinoma cells, the infection with the adenovirus vector augmented apoptosis and suppressed tumor growth as compared to an adenovirus that expressed p53 alone in vitro and in vivo. In this study, we simultaneously infected the vectors which express artificial miRNAs targeting other anti-apoptotic genes and evaluated the therapeutic effectiveness of p53 expression in combination with the suppression of several anti-apoptotic p53 target genes. Co-infection with these vectors suppressed the induction of anti-apoptotic target genes and induced apoptosis more efficiently in cancer cells. To identify other RNAi targets which prevent p53-induced apoptosis, we have screened the genome-wide lentiviral shRNA library in the cancer cells which resist p53-induced apoptosis. After the infection with p53 or control adenovirus, the cell populations expressing each shRNA were quantified by microarray. As a result, we found that several cell populations expressing specific shRNAs were significantly decreased in p53-infected cells compared with control cells. This result indicated that the suppression of specific targets by RNAi restored the apoptotic response by p53 transduction in cancer cells which originally resist p53-induced apoptosis. These results suggest that the transduction of p53 and specific miRNAs may be effective as a cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5405. doi:10.1158/1538-7445.AM2011-5405

Attributed to its simplicity, noninvasive features, and excellent therapeutic effect, phototherapy has recently received considerable interest. The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) holds great promise in the treatment of tumors, and in order to achieve satisfactory antitumor efficacy, suitable photosensitizers are a prerequisite. In this paper, highly monodispersed covalent organic framework (COF) nanoparticles were first prepared by a mild solution-phase synthesis method at room temperature. The as-synthesized nonporphyrin containing COF nanoparticle was employed as a novel photosensitizer for PDT, which exhibited an excellent photodynamic effect under 650 or 808 nm laser irradiation. Then, CuSe nanoparticles, an ideal photothermal agent, were successfully conjugated with COF to form a dual functional photosensitizer for phototherapy. The resultant COF-CuSe platform possesses an excellent synergistic photothermal and photodynamic effect. The in vitro and in vivo experiments indicated an enhanced therapeutic effect on killing cancer cells and inhibiting the tumor growth. This work demonstrates the great potential of nonporphyrin containing COF as a photosensitizer for photodynamic cancer therapy and provides a facile and efficient approach to construct COF-based multifunctional theranostic agents for cancer diagnosis and treatment by combining COFs with other functional materials.

Cancer cell killing efficiencies based on the photothermal effect caused by the surface plasmon resonance of metal nanoparticles (NPs) and the photodynamic effect caused by the singlet oxygen generation of a photosensitizer rely on the cell uptake efficiency of metal NP and photosensitizer. Perforation and heating can increase cell membrane permeability and hence can increase the cell uptake efficiency of NPs and drugs. In this paper, we demonstrate the variations of the cell damage efficiency under the illuminations of different lasers, which can produce mainly photothermal effect, mainly photodynamic effect, and mixed effect, when a pre-perforation and a pre-heating processes are applied. Au nanorings (NRIs) with their localized surface plasmon resonance wavelength around 1064 nm are used. The perforation process is undertaken by illuminating the cell samples by a femtosecond laser at 1064 nm with the power density lower than the cell damage threshold intensity. The heating process is implemented by illuminating cells with a low power continuous laser at 1064 nm. It is found that with the pre-perforation and pre-heating processes, the photodynamic effect is enhanced because the internalized Au NRI number and hence the internalized photosensitizer (AlPcS) molecule number are increased. However, the photothermal effect can be reduced because the adsorbed Au NRIs on cell membrane are effectively internalized during the pre-perforation and pre-heating processes. The photothermal effect is more effective when Au NRIs are adsorbed on cell membrane.