Enzyme- and pH-Sensitive Branched Polymer-Doxorubicin Conjugate-Based Nanoscale Drug Delivery System for Cancer Therapy.
Owing to their dendritic architectural features, branched copolymers have been investigated as drug delivery systems. In this paper, an enzyme- and pH-sensitive branched poly[N-(2-hydroxypropyl)methacrylamide] (polyHPMA) copolymer-doxorubicin (DOX) conjugate possessing a molecular weight (MW) of 165 kDa was designed and prepared via a one-pot reaction and drug conjugation. This conjugate's potential as a smart, nanoscale drug delivery system (NDDS) is also investigated. The branched conjugate was capable of forming nanoparticles with a negative surface charge. The self-assembled nanoparticles were 102 nm in diameter as measured by dynamic light scattering (DLS) and 95 nm in diameter via scanning electron microscopy, respectively. The nanoparticles were degraded to low-MW products (23∼25 kDa) in the presence of papain or cathepsin B, and the degradation was monitored via DLS and size-exclusion chromatography. The nanoparticles demonstrated pH-sensitive drug release, as the DOX was attached to the branched copolymer via a hydrazone bond. In comparison to free DOX, the conjugate-based nanoparticles exhibited greater accumulation in breast tumors, resulting in enhanced antitumor therapeutic indexes. Furthermore, widespread dissemination of the conjugate among breast tumor cells was confirmed by immunohistochemical assay. Finally, no obvious systemic toxicities were observed in vivo in normal mice. Thus, the branched HPMA copolymer-DOX conjugate may be employed as a safe and efficient pH- and enzyme-responsive NDDS for cancer therapy.
Huaxi MR Research Center (HMRRC), Department of Radiology, ‡Laboratory of Stem Cell Biology, State Key Laboratory of BiotherapyWest, and §Regenerative Medicine Research Center, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
Xiaoli
X
Wei
Huaxi MR Research Center (HMRRC), Department of Radiology, ‡Laboratory of Stem Cell Biology, State Key Laboratory of BiotherapyWest, and §Regenerative Medicine Research Center, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
Qiang
Q
Luo
Huaxi MR Research Center (HMRRC), Department of Radiology, ‡Laboratory of Stem Cell Biology, State Key Laboratory of BiotherapyWest, and §Regenerative Medicine Research Center, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
Ling
L
Sun
Huaxi MR Research Center (HMRRC), Department of Radiology, ‡Laboratory of Stem Cell Biology, State Key Laboratory of BiotherapyWest, and §Regenerative Medicine Research Center, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
Xue
X
Li
Huaxi MR Research Center (HMRRC), Department of Radiology, ‡Laboratory of Stem Cell Biology, State Key Laboratory of BiotherapyWest, and §Regenerative Medicine Research Center, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
Hongyan
H
Zhu
Huaxi MR Research Center (HMRRC), Department of Radiology, ‡Laboratory of Stem Cell Biology, State Key Laboratory of BiotherapyWest, and §Regenerative Medicine Research Center, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
Pujun
P
Guan
Huaxi MR Research Center (HMRRC), Department of Radiology, ‡Laboratory of Stem Cell Biology, State Key Laboratory of BiotherapyWest, and §Regenerative Medicine Research Center, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
Min
M
Wu
Huaxi MR Research Center (HMRRC), Department of Radiology, ‡Laboratory of Stem Cell Biology, State Key Laboratory of BiotherapyWest, and §Regenerative Medicine Research Center, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
Kui
K
Luo
Huaxi MR Research Center (HMRRC), Department of Radiology, ‡Laboratory of Stem Cell Biology, State Key Laboratory of BiotherapyWest, and §Regenerative Medicine Research Center, West China Hospital, Sichuan University , Chengdu, Sichuan 610041, China.
Qiyong
Q
Gong
D000178:Acrylamides; D000818:Animals; D004317:Doxorubicin; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D009369:Neoplasms; D011108:Polymers
D000178:Acrylamides; D011108:Polymers; D004317:Doxorubicin; C032976:N-(2-hydroxypropyl)methacrylamide
HPMA; anticancer; hyperbranched polymer; nanoscale; smart drug delivery systems