Biocompatible Mesoporous Silica-Polydopamine Nanocomplexes as MR/Fluorescence Imaging Agent for Light-Activated Photothermal-Photodynamic Cancer Therapy In Vivo.

Conventional cancer phototherapy with single modality suffers from low therapeutic efficacy and undesired posttreatment damage for adjacent normal tissues. Therefore, the lower NIR laser irradiation power is vital to the reduction or preclusion of risk of scalds and burns in normal tissues. Herein, we rationally proposed a novel multifunctional nanocomplex, which enabled good magnetic resonance (MR) imaging contrast effect and promising photothermal conversion efficacy. The prepared core/shell nanocomplexes [MSN-Ce6@PDA (Mn)] were composed of chlorin e6-embedded mesoporous silica/nanoparticle composites as the cores, and then polydopamine and manganese ions were conjugated on the cores to form protective shells. The MSN-Ce6@PDA (Mn) nanocomplexes revealed superior properties in colloidal stability, photothermal conversion, reaction oxygen species generation, magnetic resonance imaging, etc. Under the guidance of MR and fluorescence imaging, these MSN-Ce6@PDA (Mn) nanocomplexes were found to be primarily accumulated in the MDA-MB-231 tumor area. Furthermore, the combined photodynamic and photothermal therapy exhibited strong inhibition to the growth of MDA-MB-231 tumor in vitro and in vivo. Besides, the MSN-Ce6@PDA (Mn) nanocomplexes also exhibited excellent biocompatibility and low damage to the healthy animals. Hence, the results demonstrated that the prepared MSN-Ce6@PDA (Mn) nanocomplex would be a promising potential for multimodal imaging-guided phototherapy.

Near-Infrared Light-Triggered Thermosensitive Liposomes Modified with Membrane Peptides for the Local Chemo/Photothermal Therapy of Melanoma.

PURPOSE: A near-infrared (NIR)-triggered trans-activating transcriptional activator (TAT)-based targeted drug delivery system for the combined chemo/photothermal therapy of melanoma, namely, TAT-TSL-TMZ (temozolomide)/IR820, was developed for the first time. METHODS: TAT-TSL-TMZ/IR820 liposomes were synthesized via thin-film dispersion and sonication. IR820 and TMZ were encased in the inner layer and lipid bilayer of the liposomes, respectively. RESULTS: Dynamic light scattering results showed that the liposomes had an average hydrodynamic size of 166.9 nm and a zeta potential of -2.55 mV. The encapsulation rates of TMZ and IR820 were 35.4% and 28.6%, respectively. The heating curve obtained under near-infrared (NIR) laser irradiation showed that TAT-TSL-TMZ/IR820 liposomes had good photothermal conversion efficiency. The in vitro drug release curve revealed that NIR laser irradiation could accelerate drug release from TAT-TSL-TMZ/IR820 liposomes. The results of inverted fluorescence microscopy and flow cytometry proved that the uptake of TAT-TSL-TMZ/IR820 liposomes by human melanoma cells (MV3 cells) was concentration-dependent and that the liposomes modified with membrane peptides were more likely to be ingested by cells than unmodified liposomes. Confocal laser scanning microscopy indicated that TAT-TSL-TMZ/IR820 liposomes entered MV3 cells via endocytosis and was stored in lysosomes. In addition, TAT-TSL-TMZ/IR820 liposomes exposed to NIR laser showed 89.73% reduction in cell viability. CONCLUSION: This study investigated the photothermal conversion, cell uptake, colocation and chemo/photothermal effect of TAT-TSL-TMZ/IR820 liposomes.

Grade-targeted nanoparticles for improved hypoxic tumor microenvironment and enhanced photodynamic cancer therapy.

Background: The hypoxia of the tumor microenvironment (TME), low transfer efficiency of photosensitizers and limited diffusion distance of reactive oxygen species restrict the application of photodynamic therapy (PDT). Aim: To produce TME-responsive and effective nanoparticles for sensitizing PDT. Materials & methods: CD44 and mitochondria grade-targeted hyaluronic acid (HA)-triphenylphosphine (TPP)-aminolevulinic acid (ALA)-catalase (CAT) nanoparticles (HTACNPs) were synthesized via a modified double-emulsion method. In vitro and in vivo experiments were performed to investigate the antitumor efficacy of HTACNP-mediated PDT. Results: HTACNPs specifically targeted MV3 cells and the mitochondria and produced O2 to relieve TME hypoxia. HTACNP-mediated PDT produced reactive oxygen species to induce irreversible cell apoptosis. HTACNP-PDT inhibited melanoma growth effectively in vivo. Conclusion: HTACNP-mediated PDT improved TME hypoxia and effectively enhanced PDT for cancer.

CD44-Targeting Oxygen Self-Sufficient Nanoparticles for Enhanced Photodynamic Therapy Against Malignant Melanoma.

OBJECTIVE: Nanotechnology-based photodynamic therapy (PDT) is a relatively new anti-tumor strategy. However, its efficacy is limited by the hypoxic state in the tumor microenvironment. In the present study, a poly(lactic-co-glycolic acid) (PLGA) nanoparticle that encapsulated both IR820 and catalase (CAT) was developed to enhance anti-tumor therapy. MATERIALS AND METHODS: HA-PLGA-CAT-IR820 nanoparticles (HCINPs) were fabricated via a double emulsion solvent evaporation method. Dynamic light scattering (DLS), transmission electron microscopy (TEM), laser scanning confocal microscopy, and an ultraviolet spectrophotometer were used to identify and characterize the nanoparticles. The stability of the nanoparticle was investigated by DLS via monitoring the sizes and polydispersity indexes (PDIs) in water, PBS, DMEM, and DMEM+10%FBS. Oxygen generation measurement was carried out via visualizing the oxygen bubbles with ultrasound imaging system and an optical microscope. Inverted fluorescence microscopy and flow cytometry were used to measure the uptake and targeting effect of the fluorescent-labeled nanoparticles. The live-dead method and tumor-bearing mouse models were applied to study the HCINP-induced enhanced PDT effect. RESULTS: The results showed that the HCINPs could selectively target melanoma cells with high expression of CD44, and generated oxygen by catalyzing H2O2, which increased the amount of singlet oxygen, ultimately inhibiting tumor growth significantly. CONCLUSION: The present study presents a novel nanoplatform for melanoma treatment.

Near-infrared laser-induced phase-shifted nanoparticles for US/MRI-guided therapy for breast cancer.

Breast cancer is a refractory malignancy particularly in women, with an accruing morbidity and mortality worldwide. The purpose of this study was to evaluate the efficacy of laser-induced near-infrared (NIR) PFP/Gd-DTPA/ICG@PLGA NPs (PGINPs) in US/MR imaging and regimen for breast cancer; gadolinium-DTPA (Gd-DTPA), perfluoropentane (PFP) and indocyanine green (ICG) were wrapped in the poly (lactic-co-glycolic) acid (PLGA) shell membrane via a double emulsion approach. In this study, under the irradiation of NIR laser, the ICG enriched in the cancerous tissue not only converted optic energy into thermal energy to rapidly heat up the cancer focus but also convert O2 to singlet oxygen (1O2), which can effectively destroy the cancer tissues through photothermal therapy (PTT) and photodynamic therapy (PDT). Meanwhile, the thermal energy thus generated could promote the gasification of PFP to enable visualization of cancer tissues under US imaging. Gd-DTPA in combination with US imaging can also significantly enhance MR imaging to provide US/MR dual-modal imaging. This study proves the efficacy of NIR-inspired multifunctional nano-system PGINPs to potentiate US/MR imaging and regimen for breast cancer.

Combination therapy with F5/35 fiber chimeric conditionally replicative adenoviruses expressing IL-24 enhances the antitumor effect of temozolomide against melanoma.

BACKGROUND: Temozolomide (TMZ) is widely used to treat melanoma; however, response rates to TMZ are low because of rapid and frequent resistance. Conditionally, replicative adenoviruses (CRAds) are an effective and promising approach. The receptor for adenovirus is coxsackie-adenovirus receptor (CAR), which is poorly expressed in most cells. However, CD46, which is the receptor of species B adenoviruses (Ads), is highly expressed in many cells. METHODS: We constructed CRAd F5/35-ZD55-IL-24, which uses the viral receptors CAR and CD46 for entry into cells. We investigated the antitumor effect of F5/35-ZD55-IL-24 in combination with TMZ to treat melanoma in vitro and in vivo. RESULTS: The \results indicated that F5/35-ZD55-IL-24 in combination with TMZ produced additive or synergistic antitumor and pro-apoptotic effects in melanoma cells. The combination of F5/35-ZD55-IL-24 and TMZ significantly inhibited the growth of melanoma in vivo. In addition, the antitumor effect of F5/35-ZD55-IL-24 was superior to that of ZD55-IL-24 and ZD55-IL-24 combined with TMZ. CONCLUSIONS: The use of F5/35-ZD55-IL-24 in conjunction with TMZ is a promising approach for anti-melanoma therapy. Our results indicated that F5/35-ZD55-IL-24 in combination with TMZ produced additive or synergistic antitumor effect and pro-apoptotic effect in melanoma cells highly expressed CD46. The combination of F5/35-ZD55-IL-24 and TMZ significantly inhibited the growth of melanoma in vivo. We also found the antitumor effect of F5/35-ZD55-IL-24 was superior to ZD55-IL-24, the combination of F5/35-ZD55-IL-24 and TMZ had a more significant antitumor effect than ZD55-IL-24 combining with TMZ.

Nanoparticle-based photothermal and photodynamic immunotherapy for tumor treatment.

Nanoparticle-based phototherapies, such as photothermal therapy (PTT) and photodynamic therapy (PDT), exhibit strong efficacy, minimal invasion and negligible side effects in tumor treatment. These phototherapies have received considerable attention and been extensively studied in recent years. In addition to directly killing tumor cells through heat and reactive oxygen species, PTT and PDT can also induce various antitumor effects. In particular, the resultant massive tumor cell death after PTT and PDT triggers immune responses, including the redistribution and activation of immune effector cells, the expression and secretion of cytokines and the transformation of memory T lymphocytes. The antitumor effects can be enhanced by immune checkpoint blockage therapy. This article reviewed the recent advances of nanoparticle-based PTT and PDT, summarized the studies on nanoparticle-based photothermal and photodynamic immunotherapies in vitro and in vivo, and discussed challenges and future research directions.