ABSTRACT
An ideal cancer therapeutic strategy should not only reverse multidrug resistance (MDR), but also prevent cancer metastasis. In this study, bovine serum albumin (BSA) was hybridized with Mn2+via biomineralization to develop a hybrid protein oxygen nanocarrier, which contained doxorubicin (DOX) and small interfering RNA (siRNA). The nanohybrid has the function of producing oxygen and chemotherapy synergistic gene therapy. FA-BSA-MnO2/DOX/siRNA was favorable for increasing the sensitivity of MCF-7/ADR cells to DOX. Moreover, FA-BSA-MnO2/DOX/siRNA NPs were also able to generate oxygen (O2) by reaction with endogenous hydrogen peroxide (H2O2) in tumor, thereby down-regulating the expression of hypoxia inducible factor-1α (HIF-1α), and then the expression of the vascular endothelial growth factor (VEGF) was down-regulated. At the same time, siRNA can directly or indirectly suppress the expression of the VEGF and HIF-1α. Therefore, the combination of two pathways and the chemo-gene therapy strategy can interactively overcome tumor hypoxia-associated MDR and metastasis, which will enhance therapeutic efficacy in the future.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Drug Carriers/chemistry , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Metal Nanoparticles/chemistry , Animals , Cattle , Cell Movement/drug effects , Down-Regulation/drug effects , Doxorubicin/therapeutic use , Drug Carriers/toxicity , Female , Folic Acid/chemistry , Folic Acid/toxicity , Humans , Hydrogen Peroxide/chemistry , Hydrogen Peroxide/metabolism , Hydrogen-Ion Concentration , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , MCF-7 Cells , Manganese Compounds/chemistry , Metal Nanoparticles/toxicity , Mice, Inbred BALB C , Neoplasm Metastasis/prevention & control , Oxides/chemistry , Oxides/toxicity , Oxygen/metabolism , RNA, Small Interfering/therapeutic use , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/toxicity , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Currently, immunochemotherapy based on tumor-associated macrophages (TAMs) is mainly used for elimination of M2 macrophages. However, these methods cannot make full use of the positive immune-modulatory effects of macrophages. This study explores a two-way cruise strategy for combining immunotherapy based on TAM phenotype reversal with classical chemotherapy, the nanosatellites (DOX@HFn-PGZL@Res) are proposed to accurately deliver the chemotherapeutic agents and immune activators to their respective target cells. When the delivery system is recruited to tumor microenvironment, the nanosatellites are separated into DOX@HFn and Res@GZL nanoparticles, which can enter cancer cells and M2-TAMs, respectively. The data show that DOX@HFn-PGZL@Res successfully re-educate M2 to M1 macrophages, resulting in an activated immune response and inhibition of tumor invasion and metastasis. In general, this work describes a two-way homing nanoplatform for the integration of immunotherapy and chemotherapy, which provides a new idea for the "attack-defense" integrated treatment of tumor.
Subject(s)
Antineoplastic Agents/chemistry , Immunotherapy , Nanoparticles/chemistry , Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Humans , Liposomes/chemistry , Liposomes/pharmacology , Macrophages/drug effects , Macrophages/immunology , Nanoparticles/therapeutic use , Neoplasm Invasiveness/genetics , Neoplasm Invasiveness/pathology , Neoplasm Metastasis , Neoplasms/genetics , Neoplasms/pathology , Tumor Microenvironment/drug effectsABSTRACT
Tumor pH detection and pH value change monitoring have been of great interest in the field of nanomedicine. In this study, a pH-sensitive near-infrared fluorescence probe SiRB (Si-rhodamine and Boronic acid group) was synthesized by introducing a boronic acid group into the silicon rhodamine structure. ICG (Indocyanine green) as the fluorescence internal standard and SiRB were loaded into PLGA (poly lactic-co-glycolic acid) to form PLGA-SiRB-ICG nanoparticle. The experiments showed that the size of the nanoparticle was about 90â¯nm, which can reach tumor passively by enhancing permeability and retention effect. PLGA in the acidic environment will accelerate the release of cleavage, and the fluorescence ratio of the two probes can reflect the specific pH value in the tumor. The results indicated that the nanoparticle could quantitatively measure the pH value of the tumor site, which is expected to be used in tumor research and treatment.
Subject(s)
Fluorescent Dyes/administration & dosage , Nanoparticles/administration & dosage , Neoplasms/chemistry , Animals , Boronic Acids/administration & dosage , Boronic Acids/chemistry , Cell Survival/drug effects , Fluorescence , Fluorescent Dyes/chemistry , Humans , Hydrogen-Ion Concentration , Indocyanine Green/administration & dosage , Indocyanine Green/chemistry , Lactic Acid/administration & dosage , Lactic Acid/chemistry , MCF-7 Cells , Mice , Microscopy, Confocal , Nanoparticles/chemistry , Neoplasms/metabolism , Optical Imaging , Polyglycolic Acid/administration & dosage , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Rhodamines/administration & dosage , Rhodamines/chemistry , Silicon/administration & dosage , Silicon/chemistryABSTRACT
Hypoxia in tumors can lead to insufficient oxygen supply during sonodynamic therapy (SDT), which in turn strengthens tumor resistance to sonodynamic efficacy. To conquer hypoxia in tumors and improve the treatment effectiveness, we developed oxygen self-production red blood cell (RBC) carrier system to decompose tumor endogenic H2O2 into O2 and combine triplex cancer therapy: ferryl-hemoglobin (ferryl-Hb), sonodynamic, and chemical therapy. Both hydrophilic sonosensitizer and doxorubicin (DOX) were encapsulated inside RBCs (DOX/Mn-TPPS@RBCs). The drug release can be improved by combining the effects of H2O2 and ultrasonic irradiation. Here, we introduced a contrast agent, meso-tetra (4-sulfonatephenyl) porphyrinate manganese(III) complex (Mn-TPPS), which could be used to enhance the signal intensity of magnetic resonance imaging (MRI) of the tumor site. The feasibility of Mn-TPPS as a sonosensitizer was investigated during SDT. Importantly, DOX/Mn-TPPS@RBCs overcame hypoxia in the tumor and improved the efficacy of SDT owing to the O2 generation by the catalase-catalyzed decomposition of tumor endogenic H2O2. Hemoglobin was simultaneously oxidized into highly oxidative ferryl-Hb species by H2O2 and reactive oxygen species, resulting in cytotoxicity. Overall, this drug delivery system is a promising therapeutic agent involving in situ production of oxygen inside the tumor, triplex therapy, and MRI.
