ABSTRACT
Herein, we report a turn-on strategy for selectively killing the tumor cell via combining the singlet-oxygen quenching MnO2 and tumor cell-targeting aptamer. The photosensitizers were in the quenching state when loaded in the mesoporous MnO2 (mMnO2) nanoparticles and sealed by the aptamer on the particle surface. The aptamer can selectively recognize the specific membrane protein on the tumor cell and release the photosensitizers, activating the photosensitizer and killing the tumor cells. The specific binding-induced "off-on" switching of singlet oxygen generation reduced the damage to the nearby healthy cells to a large extent. The high loading ability for photosensitizer and the GSH consumption property of mMnO2 endow the system with high local concentration of singlet-oxygen for killing the target tumor cell. The high selectivity and efficiency of the constructed singlet oxygen regulating system will pave a new way for utilizing PDT in cancer precise treatment.
Subject(s)
Antineoplastic Agents/pharmacology , Aptamers, Nucleotide/pharmacology , Breast Neoplasms/drug therapy , Manganese Compounds/pharmacology , Oxides/pharmacology , Photochemotherapy , Photosensitizing Agents/pharmacology , Reactive Oxygen Species/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Aptamers, Nucleotide/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Female , Humans , MCF-7 Cells , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Manganese Compounds/chemical synthesis , Manganese Compounds/chemistry , Mice , Oxides/chemical synthesis , Oxides/chemistry , Particle Size , Photosensitizing Agents/chemistry , Surface PropertiesABSTRACT
Tumor vascular endothelium and extracellular matrix (ECM) as the major barriers of anticancer nanomedicine greatly limited the anticancer efficacy of treatment, but few strategies were available to overcome them simultaneously. Thus, herein a strategy was presented to utilize reversible vasodilatation effect of nitric oxide (NO) and size-controlled characteristic of ultrasound responsive liposome (URL) to construct a non-destructive nanomedicine, which was able to cross both obstacles simultaneously. In this work, URL was built as a carrier via forming a gas layer between lipid bilayer to encapsulate small particles PAMAM@DOX (PD, ~10nm) and NO donation-nitrosoglutathione (GSNO). Under ultrasound (US) stimulation, GSNO fastly generated NO that acting on tumor vascular smooth muscle, resulting in tumor vascular vasodilatation, meanwhile the URL lipid bilayer was destroyed, leading to release sharply of small nanoparticles PD. Combination vasodilatory effect of NO and size-controlled characteristic of URL allowed vast drugs to extravasate through endothelial gap and penetrate into tumor deep. Upon different types of cancers vary greatly in vascular structure, two distinctly different tumor, MCF-7 human breast carcinoma and MiaPaCa-2 human pancreatic carcinoma, were chosen to test the anticancer efficacy of URL. As a result, URL-based nanosystem was significantly more effective than the conventional liposome (CL) in tumor treatment, particularly in much less leaky MiaPaCa-2 tumor treatment (tumor therapeutic efficiency of URL/PD/GSNO+US increased by 32.5% and 56.5% compared to CL/DOX in MCF-7 and MiaPaCa-2 tumor treatment). This study offers a new method to enhance tumor drug accumulation along with minimal toxicity for future clinical cancer treatments.
