A boronate-linked linear-hyperbranched polymeric nanovehicle for pH-dependent tumor-targeted drug delivery.
Advanced drug delivery systems, which possess post-functionalization feasibility to achieve targetability and traceability, favorable pharmacokinetics with dynamic but controllable stability, and preferable tumor accumulation with prolonged drug residence in disease sites, represent ideal nanomedicine paradigm for tumor therapy. To address this challenge, here we reported a dynamic module-assembly strategy based on reversible boronic acid/1,3-diol bioorthogonality. As a prototype, metastable hybrid nanoself-assembly between hydrophobic hyperbranched diol-enriched polycarbonate (HP-OH) and hydrophilic linear PEG terminated with phenylboronic acid (mPEG-PBA) is demonstrated in vitro and in vivo. The nanoconstruction maintained excellent stability with little leakage of loaded drugs under the simulated physiological conditions. Such a stable nanostructure enabled the effective in vivo tumor accumulation in tumor site as revealed by NIR imaging technique. More importantly, this nanoconstruction presented a pH-labile destruction profile in response to acidic microenvironment and simultaneously the fast liberation of loaded drugs. Accordingly at the cellular level, the intracellular structural dissociation was also proved in terms of the strong acidity in late endosome/lysosome, thus favoring the prolonged retention of remaining drug-loaded HP-OH aggregates within tumor cells. Hence, our delicate design open up a dynamical module-assembly path to develop site and time dual-controlled nanotherapeutics for tumor chemotherapy, allowing enhanced tumor selectivity through prolonged retention of delivery system in tumor cells followed by a timely drug release pattern.
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
Hui-zhen
HZ
Jia
The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, and Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Jun-yi
JY
Zhu
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84108, USA.
Xu-li
XL
Wang
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
Han
H
Cheng
The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, and Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Gang
G
Chen
The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, and Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Yi-fang
YF
Zhao
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
Xuan
X
Zeng
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China. Electronic address: fengjun@whu.edu.cn.
Jun
J
Feng
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
Xian-zheng
XZ
Zhang
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan 430072, China.
Ren-xi
RX
Zhuo
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001897:Boronic Acids / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011076:Polycarboxylate Cement / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D004337:Drug Carriers; D011076:Polycarboxylate Cement; D011108:Polymers; C005506:polycarbonate; C010686:benzeneboronic acid
Boronate linkage; Dual-controlled drug delivery; Nanoassembly; Passive tumor targeting; pH-sensitivity