Breaching the Hyaluronan Barrier with PH20-Fc Facilitates Intratumoral Permeation and Enhances Antitumor Efficiency: A Comparative Investigation of Typical Therapeutic Agents in Different Nanoscales.
In contrast to traditional strategies based on external driving forces, an internal path for intratumoral delivery is explored by degrading the tumor microenvironment component hyaluronan. Natural hyaluronidase PH20 and constructed long-acting PH20-Fc have been used to achieve this objective. It has been then evaluated how these agents facilitate the diffusion of the following typical therapeutic agents varying in nanoscales: doxorubicin (≈1.5 × 1.0 × 0.7 nm) chemotherapy, trastuzumab (10-15 nm) biotherapy, and gold nanorod (≈100 × 35 nm) thermotherapy. In traditional 2D cultures, PH20 and PH20-Fc have little influence on cytotoxicity due to lack of a tumor microenvironment. However, the cytotoxicities of the three therapeutic agents in 3D tumor spheroids are all enhanced by PH20 or PH20-Fc because hyaluronan degradation facilitates therapeutic penetration and accumulation. Furthermore, in vivo evaluations reveal that the significantly prolonged circulation time of PH20-Fc leads to accumulation in the tumor and subsequent hyaluronan degradation. Consequently, PH20-Fc coadministration further inhibits tumor growth. The performance of PH20-Fc varies for the three therapeutic agents due to their different nanoscales. Trastuzumab benefits most from combination with PH20-Fc. The results provide here novel insights that can aid in the development of more effective hyaluronidase-based therapeutic systems.
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China.|University of Chinese Academy of Sciences, Beijing, 100049, China.
Shan
S
Liu
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China.
Wei
W
Wei
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China.
Bo
B
Xie
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China.
Hua
H
Yue
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China.|University of Chinese Academy of Sciences, Beijing, 100049, China.
Dezhi
D
Ni
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China.
Yali
Y
Bao
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China.|Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing, 210009, China.
Guanghui
G
Ma
State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100190, China.
Zhiguo G
ZG
Su
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D003412:Cricetulus; D004317:Doxorubicin / Q000008:administration & dosage; D006820:Hyaluronic Acid / Q000008:administration & dosage*; D006821:Hyaluronoglucosaminidase / Q000008:administration & dosage*; D006979:Hyperthermia, Induced / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D036103:Nanotechnology / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy*; D010539:Permeability / Q000187:drug effects*; D000068878:Trastuzumab / Q000008:administration & dosage; D059016:Tumor Microenvironment / Q000187:drug effects
D000970:Antineoplastic Agents; D004317:Doxorubicin; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; D000068878:Trastuzumab
doxorubicin; gold nanorods; novel drug delivery systems; trastuzumab; tumor microenvironment and modification