Photodynamic Therapy Induced Enhancement of Tumor Vasculature Permeability Using an Upconversion Nanoconstruct for Improved Intratumoral Nanoparticle Delivery in Deep Tissues.
Photodynamic therapy (PDT) has recently emerged as an approach to enhance intratumoral accumulation of nanoparticles. However, conventional PDT is greatly limited by the inability of the excitation light to sufficiently penetrate tissue, rendering PDT ineffective in the relatively deep tumors. To address this limitation, we developed a novel PDT platform and reported for the first time the effect of deep-tissue PDT on nanoparticle uptake in tumors. This platform employed c(RGDyK)-conjugated upconversion nanoparticles (UCNPs), which facilitate active targeting of the nanoconstruct to tumor vasculature and achieve the deep-tissue photosensitizer activation by NIR light irradiation. Results indicated that our PDT system efficiently enhanced intratumoral uptake of different nanoparticles in a deep-seated tumor model. The optimal light dose for deep-tissue PDT (34 mW/cm(2)) was determined and the most robust permeability enhancement was achieved by administering the nanoparticles within 15 minutes following PDT treatment. Further, a two-step treatment strategy was developed and validated featuring the capability of improving the therapeutic efficacy of Doxil while simultaneously reducing its cardiotoxicity. This two-step treatment resulted in a tumor inhibition rate of 79% compared with 56% after Doxil treatment alone. These findings provide evidence in support of the clinical application of deep-tissue PDT for enhanced nano-drug delivery.
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Weidong
W
Gao
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Zhaohui
Z
Wang
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Liwei
L
Lv
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Deyan
D
Yin
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Dan
D
Chen
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Zhihao
Z
Han
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Yi
Y
Ma
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Min
M
Zhang
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Man
M
Yang
State Key Laboratory of Natural Medicines, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 210009, P. R. China.
Yueqing
Y
Gu
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001808:Blood Vessels / Q000187:drug effects*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D064593:Heterografts; D008297:Male; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage*; D010539:Permeability / Q000187:drug effects*; D010778:Photochemotherapy / Q000379:methods*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011471:Prostatic Neoplasms / Q000628:therapy*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
Drug delivery.; EPR; Nanoparticles; Photodynamic therapy; Upconversion