title: Dual-pH Sensitive Charge-Reversal Polypeptide Micelles for Tumor-Triggered Targeting Uptake and Nuclear Drug Delivery.
abstract: A novel dual-pH sensitive charge-reversal strategy is designed to deliver antitumor drugs targeting to tumor cells and to further promote the nuclei internalization by a stepwise response to the mildly acidic extracellular pH (≈6.5) of a tumor and endo/lysosome pH (≈5.0). Poly(L-lysine)-block-poly(L-leucine) diblock copolymer is synthesized and the lysine amino residues are amidated by 2,3-dimethylmaleic anhydride to form β-carboxylic amide, making the polypeptides self-assemble into negatively charged micelles. The amide can be hydrolyzed when exposed to the mildly acidic tumor extracellular environment, which makes the micelles switch to positively charged and they are then readily internalized by tumor cells. A nuclear targeting Tat peptide is further conjugated to the polypeptide via a click reaction. The Tat is amidated by succinyl chloride to mask its positive charge and cell-penetrating function and thus to inhibit nonspecific cellular uptake. After the nanoparticles are internalized into the more acidic intracellular endo/lysosomes, the Tat succinyl amide is hydrolyzed to reactivate the Tat nuclear targeting function, promoting nanoparticle delivery into cell nuclei. This polypeptide nanocarrier facilitates tumor targeting and nuclear delivery simultaneously by simply modifying the lysine amino residues of polylysine and Tat into two different pH-sensitive β-carboxylic amides.
authors: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China.
authors: Shi-Song
authors: SS
authors: Han
authors: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China.
authors: Ze-Yong
authors: ZY
authors: Li
authors: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China.
authors: Jing-Yi
authors: JY
authors: Zhu
authors: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China.
authors: Kai
authors: K
authors: Han
authors: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430072, P.R. China.
authors: Zheng-Yang
authors: ZY
authors: Zeng
authors: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430072, P.R. China.
authors: Wei
authors: W
authors: Hong
authors: State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430072, P.R. China.
authors: Wen-Xin
authors: WX
authors: Li
authors: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China.
authors: Hui-Zhen
authors: HZ
authors: Jia
authors: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China.
authors: Yun
authors: Y
authors: Liu
authors: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China.
authors: Ren-Xi
authors: RX
authors: Zhuo
authors: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan, 430072, P.R. China.
authors: Xian-Zheng
authors: XZ
authors: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D011107:Polylysine / Q000737:chemistry; D055503:Protein Multimerization; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D010455:Peptides; D054322:tat Gene Products, Human Immunodeficiency Virus; D011107:Polylysine; C027819:polyleucine; D004317:Doxorubicin
keywords: cellular uptake; drug delivery; nuclear delivery; pH sensitive; polypeptide micelles; targeting; tumors