Redox/photo dual-responsive, self-targeted, and photosensitizer-laden bismuth sulfide nanourchins for combination therapy in cancer.

Targeted and stimuli-sensitive nanobombs for the release of therapeutic agents after laser irradiation of the tumor site are gaining widespread attention as personalized anticancer regimens. In this study, redox and photo dual-responsive, folate receptor-targeted nanourchin carriers for chemo-, photodynamic, and photothermal therapy were constructed by the amalgamation of an outer layer of polyethylene glycol (PEG)-S-S-methotrexate (MTX) and an inner core of indocyanine green (ICG)-loaded bismuth sulfide (Bi2S3) nanoparticles for cancer treatment. MTX introduces the carrier to folate receptors resulting in the internalization of nanoparticles into cancer cells, specifically and increasingly. In the reducing environment inside cancer cells, MTX was cleaved, resulting in a burst release that effectively inhibited tumor growth. Simultaneously, the fusion of Bi2S3 and ICG in the inner core absorbed energy from a near-infrared radiation (NIR) laser to generate heat and reactive oxygen species, which further ablated the tumors and synergistically enhanced the anticancer activity of MTX. These results indicate the successful preparation of combined nanourchins (NUs) showing GSH-induced and laser-responsive release of MTX and ICG, accompanied by hyperthermia via Bi2S3 and ICG. Effective in vitro cellular internalization, cellular cytotoxicity, and pro-apoptotic behavior of the nanosystem were achieved through a targeting, redox, and NIR-responsive combination strategy. In vivo biodistribution and photothermal imaging also revealed tumor-selective and -retentive, as well as thermally responsive attributes. Ultimately, this in vivo antitumor study shows an effective tumor ablation by these nanourchins without affecting the vital organs. Our findings indicate that using these targeted redox- and laser-responsive combination therapeutic carriers can be a promising strategy in folate receptor-expressing tumors.

Stealth Polymer-Coated Graphene Oxide Decorated Mesoporous Titania Nanoplatforms for In Vivo Chemo-Photodynamic Cancer Therapy.

PURPOSE: The goal of this study was to develop chemotherapeutic drug-loaded photoactivable stealth polymer-coated silica based- mesoporous titania nanoplatforms for enhanced antitumor activity. METHODS: Both in vitro and in vivo models of solvothermal treated photoactivable nanoplatforms were evaluated for efficient chemo-photothermal activity. A versatile nanocomposite that combined silica based- mesoporous titania nanocarriers (S-MTN) with the promising photoactivable agent, graphene oxide (G) modified with a stealth polymer (P) was fabricated to deliver chemotherapeutic agent, imatinib (I), (referred as S-MTN@IG-P) for near-infrared (NIR)-triggered drug delivery and enhanced chemo-photothermal therapy. RESULTS: The fabricated S-MTN@IG-P nanoplatform showed higher drug loading (~20%) and increased drug release (~60%) in response to light in acidic condition (pH 5.0). As prepared nanoplatform significantly converted NIR light into thermal energy (43.2°C) to produce reactive oxygen species (ROS). The pronounced cytotoxic effect was seen in both colon cancer cells (HCT-116 and HT-29) that was mediated through the chemotherapeutic effect of imatinib and the photothermal and ROS generation effects of graphene oxide. In vivo study also showed that S-MTN@IG-P could significantly accumulate into the tumor area and suppress the tumor growth under NIR irradiation without any biocompatibility issues. CONCLUSION: Cumulatively, the above results showed promising effects of S-MTN@IG-P for effective chemo-phototherapy of colon cancer.

Tailored Black Phosphorus for Erythrocyte Membrane Nanocloaking with Interleukin-1α siRNA and Paclitaxel for Targeted, Durable, and Mild Combination Cancer Therapy.

Several therapeutic nanosystems have been engineered to remedy the shortcomings of cancer monotherapies, including immunotherapy (stimulating the host immune system to eradicate cancer), to improve therapeutic efficacy with minimizing off-target effects and tumor-induced immunosuppression. Light-activated components in nanosystems confer additional phototherapeutic effects as combinatorial modalities; however, systemic and thermal toxicities with unfavorable accumulation and excretion of nanoystem components now hamper their practical applications. Thus, there remains a need for optimal multifunctional nanosystems to enhance targeted, durable, and mild combination therapies for efficient cancer treatment without notable side effects. Methods: A nanosystem constructed with a base core (poly-L-histidine [H]-grafted black phosphorus [BP]) and a shell (erythrocyte membrane [EM]) is developed to offer a mild photoresponsive (near-infrared) activity with erythrocyte mimicry. In-flight electrostatic tailoring to extract uniform BP nanoparticles maintains a hydrodynamic size of <200 nm (enabling enhanced permeability and retention) after EM cloaking and enhances their biocompatibility. Results: Ephrin-A2 receptor-specific peptide (YSA, targeting cancer cells), interleukin-1α silencing small interfering RNA (ILsi, restricting regulatory T cell trafficking), and paclitaxel (X, inducing durable chemotherapeutics) are incorporated within the base core@shell constructs to create BP-H-ILsi-X@EM-YSA architectures, which provide a more intelligent nanosystem for combination cancer therapies. Conclusion: The in-flight tailoring of BP particles provides a promising base core for fabricating <200 nm EM-mimicking multifunctional nanosystems, which could be beneficial for constructing smarter nanoarchitectures to use in combination cancer therapies.

Multifaceted NIR-responsive polymer-peptide-enveloped drug-loaded copper sulfide nanoplatform for chemo-phototherapy against highly tumorigenic prostate cancer.

Targeted, biocompatible, and synergistic "all in one" systems should be designed to combat the heterogeneity of cancer. In this study, we constructed a dual function nanosystem, copper sulfide nanoplatform loaded with the chemotherapeutic drug docetaxel wrapped by a conjugated polymer-peptide for targeted chemo-phototherapy. The nanoconstruct has been successfully designed with a size of 186.1 ±â€¯5.2 nm, a polydispersity index of 0.18 ±â€¯0.01, and zeta potential of -16.4 ±â€¯0.1 mV. The enhanced uptake and near-infrared-responsive behavior of the nanosystem resulted in efficient drug release, photothermal ablation, effective cytotoxic activity, and potentiated reactive oxygen species generation. The induction of apoptotic markers, enhanced accumulation in the tumor site, and maximum tumor growth inhibition were seen during in vivo studies compared to non-targeted nanoformulations and free drug. Cumulatively, our results indicate that, with low systemic toxicity and better biocompatibility, this nanoconstruct could provide a promising strategy for treating prostate cancer.

Aerosol technique-based carbon-encapsulated hollow mesoporous silica nanoparticles for synergistic chemo-photothermal therapy.

Near-infrared (NIR)-responsive drug delivery systems have enhanced tumor ablative efficiency through permeation and retention effects. Graphene oxide (GO) has shown great potential both in photothermal therapy and in drug delivery. Thus, in this study, we designed an ambient spark-generated GO, wrapped on topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSN-NH2-TPT-CGO), to function as an efficient platform for pH-dependent sustained release of TPT. HMSN-NH2-TPT-CGO also exhibited a combined chemo-photothermal effect within a single carrier system. This developed system was stable with a uniform particle size (∼190 nm) and was demonstrated to possess a sufficient heat-absorbing capacity to induce tumor cell ablation. We performed the ablation of tumor cells both in vitro and in vivo in combination with photothermal therapy and chemotherapy using the spark-generated functional GO and HMSN. The prepared nanocarriers demonstrated high cellular uptake, apoptosis, and G0/G1 cell cycle arrest. In vivo study using the MDA-MB-231 xenograft model revealed the ultraefficient tumor ablative performance of HMSN-NH2-TPT-CGO compared with that of free TPT, with no toxic effect on vital organs. Altogether, the optimized nanocarriers presented a significant potential to act as a vehicle for cancer treatment. STATEMENT OF SIGNIFICANCE: This is the first study that uses spark-generated graphene oxide nanoflakes to cover the topotecan (TPT)-loaded hollow mesoporous silica nanoparticles (HMSNs) to treat breast cancer. Dense silica was used as a hard template to prepare the HMSNs attributing to a high drug payload. The concentration of Na2CO3 was precisely controlled to minimize the silica etching time within 70 min. The use of the nanographene flakes served a dual purpose, first, by acting as a capping agent to prevent the premature release of drug and, second, by serving as a nano heater that significantly ablates the tumor cells. The prepared nanocarriers (NCs) exhibited effective and enhanced in vitro and in vivo apoptosis, as well as significant tumor growth inhibition even after 15 days of treatment time, with no toxic effect to the vital organs. The NCs enhanced in vitro tumor cell killing effects and served as an effective carrier for in vivo tumor regression, thereby highlighting the enormous potential of this system for breast cancer therapy.

Transferrin-conjugated pH-sensitive platform for effective delivery of porous palladium nanoparticles and paclitaxel in cancer treatment.

Porous palladium (Pd) nanoparticles have garnered great research attention due to their potential anticancer activity and photothermal effect. In this study, a transferrin-conjugated pH-sensitive platform (Tf-PPP), comprising porous Pd nanoparticles (PdNPs) and paclitaxel (PTX), was successfully developed for combined chemo-phototherapy. Tf-PPPs have a small size of 164.6 ± 8.7 nm, PDI of 0.278 ± 0.029, and negative charge (-13.2 ± 1.8 mV). Poly(acrylic acid)-poly(ethylene oxide) (PAA-PEO), a pH sensitive polymer, was used to achieve pH-dependent drug release from nanoparticles. Transferrin (Tf) conjugated on the surface of nanoplatforms could enhance the cellular uptake and prolong nanoparticle accumulation in the tumor site. The combination of phototherapy induced by PdNPs and chemotherapeutic agent (PTX) could exhibit synergistic anticancer activities. Consistent findings were observed in both in vitro experiments including cytotoxicity, live/dead assay, and assessment of apoptotic protein levels, and in vivo antitumor study in MCF-7 tumor-bearing mice, with results decreasing in the following order: Tf-PPPs + NIR > Tf-PPPs > PPPs + NIR > PPPs > PTX > PdNPs. These findings suggest that the administration of Tf-PPPs, followed by NIR irradiation could be a promising strategy in the treatment of cancer.

Combination of NIR therapy and regulatory T cell modulation using layer-by-layer hybrid nanoparticles for effective cancer photoimmunotherapy.

The efficacy of combined near-infrared (NIR) and immune therapies for inhibiting tumor growth and recurrence has gained increasing research attention. Regulatory T cells in the tumor microenvironment constitute a major obstacle in achieving robust CD8+ T cell antitumor immunotherapy. In the present study, we designed a photoimmunotherapy-based strategy involving a combination of photothermal and photodynamic therapies, followed by Treg cell suppression, for eliciting an immune response with IR-780- and imatinib-loaded layer-by-layer hybrid nanoparticles. Methods: The layer-by-layer hybrid nanoparticles were prepared through electrostatic interactions. Their photothermal effect, photodynamic effect as well as their effect on inhibiting Treg cells' suppressive function were investigated in vitro and in vivo. Their antitumor effect was evaluated using B16/BL6 and MC-38 tumor-bearing mice. Results: The layer-by-layer hybrid nanoparticles, which were pH-sensitive, enabled the release of IR-780 dye for NIR-induced photothermal and photodynamic effects, and the release of imatinib-loaded glucocorticoid-induced TNF receptor family-related protein/poly(lactic-co-glycolic acid) (GITR-PLGA) nanoparticles to initiate antitumor immunotherapy. The photothermal and photodynamic effects caused by IR-780 under NIR exposure resulted in direct tumor apoptosis/necrosis and the production of tumor-associated antigen, promoted dendritic cell maturation, and enhanced the presentation of tumor-associated antigen to T cells, while the imatinib-loaded GITR-PLGA cores reduced the suppressive function of Treg cells, and consequently activated effective CD8+ T cells towards tumors. Conclusion: With the significant photothermal, photodynamic and immunotherapies, the system successfully eradicated tumor growth, diminished tumor recurrence, and improved survival in vivo. The proposed nanoparticles provide a novel and versatile approach to boost antitumor photoimmunotherapy.

In situ fabrication of mesoporous silica-coated silver-gold hollow nanoshell for remotely controllable chemo-photothermal therapy via phase-change molecule as gatekeepers.

This study reports a new strategy for in situ fabrication of plasmonic hollow silver-gold nanoshell (with resonance tuned to NIR region) encased in the hollow mesoporous silica as an efficient platform to efficiently and precisely regulate the release of 5-fluorouracil (anticancer drug) for prostate cancer therapy and photothermal therapy. The mesopores were capped with thermosensitive phase-change material lauric acid, which allowed for remote, precise, and spatiotemporal control of drug release via external heating or photothermal heating of plasmonic silver-gold nanoshell via NIR laser irradiation. The system was nanometric, monodispersed, and showed negative surface charge. The nanocarrier showed better pH stability and thermodynamic stability compared to dense silica-coated gold nanoshells. The drug release could be triggered remotely by applying low powered continuous wave NIR laser (λ = 808 nm). The nanocarrier showed improved internalization by cancer cells, which was further enhanced by laser irradiation. High powered laser directly killed the cancer cells via photothermal effect in the region irradiated. Thus, this system fabricated by novel synthetic strategy provided efficient chemo- and phototherapy.