International Journal of Nanomedicine
·
2023
·
IF 8
Yongchao Chu,Ning Chen,Huajun Yu,Hongjie Mu,Bin He,Hongchen Hua,Aiping Wang,Kaoxiang Sun
A nanoparticle (NP) was developed to target choroidal neovascularization (CNV) via topical ocular administration. The NPs were prepared through conjugation of internalizing arginine-glycine-aspartic acid RGD (iRGD; Ac-CCRGDKGPDC) and transactivated transcription (TAT) (RKKRRQRRRC) peptide to polymerized ethylene glycol and lactic-co-glycolic acid. The iRGD sequence can specifically bind with integrin αvβ3, while TAT facilitates penetration through the ocular barrier. 1H nuclear magnetic resonance and high-performance liquid chromatography demonstrated that up to 80% of iRGD and TAT were conjugated to poly(ethylene glycol)– poly(lactic-co-glycolic acid). The resulting particle size was 67.0±1.7 nm, and the zeta potential of the particles was −6.63±0.43 mV. The corneal permeation of iRGD and TAT NPs increased by 5.50- and 4.56-fold compared to that of bare and iRGD-modified NPs, respectively. Cellular uptake showed that the red fluorescence intensity of iRGD and TAT NPs was highest among primary NPs and iRGD- or TAT-modified NPs. CNV was fully formed 14 days after photocoagulation in Brown Norway (BN) rats as shown by optical coherence tomography and fundus fluorescein angiography analyses. Choroidal flat mounts in BN rats showed that the red fluorescence intensity of NPs followed the order of iRGD and TAT NPs > TAT-modified NPs > iRGD-modified NPs > primary NPs. iRGD and TAT dual-modified NPs thus displayed significant targeting and penetration ability both in vitro and in vivo, indicating that it is a promising drug delivery system for managing CNV via topical ocular administration.
研究领域:
药剂学
·
眼科
·
分子生物学
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DOI
PubMed
高影响因子
CURRENT TOPICS IN MEDICINAL CHEMISTRY
·
2020
·Vol. 20
·期 27
·2493-2505
·
IF 3.218
Huang Sixi,Ren Di,Wu Xinrong,Li Ming,Yu Xuesong,Nie Xiaoling,Wang Ying,Wang Yan
Background: Surgery remains the front-line therapeutic strategy to treat early hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC patients are high. 10- Hydroxycamptothecin (10-HCPT) is a known anti-HCC agent but its poor solubility and bioavailability have
limited its clinical use. Objective: In this study, we developed a novel nanoliposome encapsulated 10-hydroxycamptothecin modified with glycyrrhetinic acid (GA) and TAT peptide (GA/TAT-HCPT-LP) for the treatment of HCC. Dual modified GA and TAT can enhance tumor targeting and tumor penetration.
Methods: The GA/TAT-HCPT-LP NPs were synthesized using the thin-film dispersion method. GA/TAT-HCPT-LP were characterized for particle size, zeta potential and morphology. Drug release from the GA/TAT-HCPT-LP liposomes was measured by dialysis. Cell-uptake was assessed by microscopy and
flow cytometry. Cell proliferation, migration and apoptosis were measured to evaluate in vitro antitumor activity of GA/TAT-HCPT-LP via CCK-8 assays, Transwell assays, and flow cytometry, respectively. The in vivo distribution of GA/TAT-HCPT-LP was evaluated in HCC animal models. Tumor- bearing
mouse models were used to assess the in vivo therapeutic efficacy of GA/TAT-HCPT-LP. Results: The mean particle size and mean zeta potential of GA/TAT-HCPT-LP were 135.55 ± 2.76 nm and -4.57 ± 0.23 mV, respectively. Transmission electron micrographs (TEM) showed that the
GA/TAT-HCPT-LP had a near spherical shape and a double-membrane structure. GA/TAT-HCPT-LP led to slow and continuous drug release, and could bind to HepG2 cells more readily than other groups. Compared to control groups, treatment with GA/TAT-HCPT-LP had a significantly large effect on inhibiting
cell proliferation, tumor cell migration and cell apoptosis. In vivo assays showed that GA/TATHCPT- LP selectively accumulated in tumor tissue with obvious antitumor efficacy. Conclusion: In conclusion, the synthesized GA/TAT-HCPT-LP could effectively target tumor cells and enhance cell
penetration, highlighting its potential for hepatocellular cancer therapy.
研究领域:
药理学
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肿瘤学
·
纳米医学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2016
·
IF 3.994
Jingjing Li,Xuemei Zhang,Meng Wang,Xuejuan Li,Hongjie Mu,Aiping Wang,Wanhui Liu,Youxin Li,Zimei Wu,Kaoxiang Sun
The dual-ligand dendritic polyamidoamine-(polyethylene glycol) n -cyclic RGDyC peptide-(TAT peptide) (PP n R(T)) with various supplied molar ratios of polyethylene glycol (PEG) to polyamidoamine (PAMAM) (n = 5, 15, 30) were designed as drug-carriers for the treatment of neovascular diseases; their targeting and penetrating effects were subsequently evaluated. 1 H NMR demonstrated PP n R(T) was successfully synthesized. Compared with the unmodified PAMAM, in vitro cytotoxicity of PP n R(T) to αvβ3 negative cells (αvβ3-) was significantly reduced, whereas the lethality to pathologic neovascular endothelial cells (αvβ3+) was efficiently increased compared to PP n . Compared to PP 5 R(T) and PP 15 R(T), PP 30 R(T) exhibited the most selective and efficient cellular uptake by human umbilical vein endothelial cells (HUVECs, αvβ3+). Membrane interaction study indicated the cellular uptake process of PP 30 R(T) of HUVECs mainly involved specific RGD-αvβ3 recognition as well as electrostatic interactions. Intracellular localization results confirmed PP 30 R(T) was distributed in the cytoplasm in HUVECs. 3D tumor spheroids penetration studies demonstrated that PP 30 R(T) penetrated the A549 cells to reach the depths of the avascular tumor spheroids. In vivo imaging further demonstrated that PP 30 R(T) achieved profoundly improved distribution in tumor tissues where angiogenesis existed. Therefore, the bi-functional dendrimer PP 30 R(T) displayed great potential as a nano-carrier for targeted drug delivery both in vitro and in vivo , and had broad prospects as nanocarriers for the targeted treatment of neovascular diseases.
研究领域:
药学
·
分子生物学
·
纳米医学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2014
·
IF 8.312
Qi-Ming Wang,Zhonggao Gao,Shan Liu,Bo Fan,Lin Kang,Wei Huang,Mingji Jin
The bioactive polymer poly( l -glutamic acid) n - b -poly( d , l -lactic acid) m was synthesized and used to form doxorubicin-loaded hybrid polymeric micelles to treat melanoma. These polymers exhibited pH-responsive changes in conformation, which controlled the diverse functionalities of the micelles. During circulation, poly( l -glutamic acid) n - b -poly( d , l -lactic acid) m protected Tat peptides on the micelles from proteolysis . Under tumor-acidic conditions, polymers with shorter poly( l -glutamic acid) blocks underwent a conformational change to form channels that accelerated the release of doxorubicin . The conformational change also exposed the Tat peptides to tumor cells, thereby promoting cellular internalization of the micelles. Enhanced cellular uptake of the micelles induced significant apoptosis of A375 melanoma cells in tumor-acidic conditions. In vivo studies demonstrated that the micelles with shorter poly( l -glutamic acid) blocks could effectively accumulate in tumor tissues, suppress tumor growth and help maintain the body weight of tumor-bearing mice. However, micelles with longer poly( l -glutamic acid) blocks did not undergo a conformational change under acidic conditions and performed poorly in both in vitro and in vivo evaluations. Our work provides a strategy for applying bioactive polymers to the rational construction of pH-responsive delivery systems for solid tumors and lends insight into possible conformational effects on the bioactivity of drug carriers.
研究领域:
药剂学
·
肿瘤学
·
生物材料学
✓ 已验证
DOI
PubMed
高影响因子
MACROMOLECULAR BIOSCIENCE
·
2019
·Vol. 19
·期 4
·1800364
·
IF 2.895
Yang Ming,Yao Xiao,Yuan Tian,Shaobing Zhou
Considerable efforts have been devoted to enhancing the cell penetration of nanoparticles by coating cell-penetrating peptides (CPPs) on the surface. However, the internalization mechanism for a CPP at different concentrations varies a lot. It is acknowledged that the mechanism is restricted to endocytic pathway at relatively low concentrations; however, direct translocation becomes dominant at high concentrations. This raises an interesting question on how the surface Tat coating density of the nanoparticles would influence their cell–membrane interaction and the consequent internalization behavior. This study systematically investigates the effect of Tat peptides on the internalization behavior of polymeric micelles by tuning surface Tat coating density, incubation concentrations, incubation time, and other factors using poly(ethylene glycol)–poly(ε-caprolactone) copolymer (PEG-PCL) micelles. It is found that both energy-dependent and energy-independent pathways are involved in the cellular uptake process, and the Tat-conjugated polymeric micelles strongly accumulated on the cell surface at initial stage. The membrane-anchoring and internalization rate increase with the increasing Tat coating density. Furthermore, the increasing of Tat coating density accelerates the energy-independent pathway. It is envisioned that this finding will further shed light on the surface modification of nanoparticles for enhanced cell penetration and direct translocation into cell cytoplasm.
研究领域:
生物医学工程
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药剂学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Hui Li,Yuan Fan,Yizhe Shen,Huashan Xu,Huijie Zhang,Fuxue Chen,Shini Feng
The evolution of nano-drug delivery systems addresses the limitations of conventional cancer treatments with stimulus-responsive nanomaterial-based delivery systems presenting temporal and spatial advantages. Among various nanomaterials, boron nitride nanoparticles (BNNs) demonstrate significant potential in drug delivery and cancer treatment, providing a high drug loading capacity, multifunctionality, and low toxicity. However, the challenge lies in augmenting nanomaterial accumulation exclusively within tumors while preserving healthy tissues. To address this, we introduce a novel approach involving cancer cell membrane-functionalized BNNs (CM-BIDdT) for the codelivery of doxorubicin (Dox) and indocyanine green to treat homologous tumor. The cancer cell membrane biomimetic CM-BIDdT nanoparticles possess highly efficient homologous targeting capabilities toward tumor cells. The surface modification with acylated TAT peptides (dTAT) further enhances the nanoparticle intracellular accumulation. Consequently, CM-BIDdT nanoparticles, responsive to the acidic tumor microenvironment, hydrolyze amide bonds, activate the transmembrane penetrating function, and achieve precise targeting with substantial accumulation at the tumor site. Additionally, the photothermal effect of CM-BIDdT under laser irradiation not only kills cells through thermal ablation but also destroys the membrane on the surface of the nanoparticles, facilitating Dox release. Therefore, the fabricated CM-BIDdT nanoparticles orchestrate chemo–photothermal combination therapy and effectively inhibit tumor growth with minimal adverse effects, holding promise as a new modality for synergistic cancer treatment.
研究领域:
纳米医学
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癌症治疗
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生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2024
·Vol. 12
·期 45
·11696-11707
·
IF 6.1
Songyan Guo,Youbei Qiao,Chaoli Wang,Yuming Zhang,Tiehong Yang,Hong Wu
Nanoparticles (NPs) derived from branched copolymers of poly (β-L-malic acid) (PMLA) have been extensively investigated for drug delivery due to their high density of pendant carboxyl groups. This abundant functional group availability enhances their potential as effective drug delivery systems; however, the strong negative charge of PMLA poses a challenge in its uptake by cancer cells due to electrostatic repulsion. In this study, we developed novel enzyme- and pH-sensitive nanoparticles (EP-NPs) based on PMLA, demonstrating tumor-specific behavior and selective activation within tumor tissues. To enhance the cellular internalization of the nanoparticles, we incorporated transactivator of transcription (TAT). In summary, long-chain polyethylene glycol (PEG) was conjugated to PMLA to confer specificity to the TAT peptide. This was achieved using a tetrapeptide linker: alanine–alanine–asparagine–leucine (AANL), which serves as a substrate for legumain. Legumain is a highly conserved cysteine protease primarily found in lysosomes and blood vessels, initially discovered in legumes. It is markedly overexpressed in numerous solid tumors, as well as in endothelial cells and tumor-associated macrophages. The release of doxorubicin in tumor cells was sustained due to the low pH (5.0–5.5) and degradation of PMLA. The PEG modification optimized the particle size and shielded the nanoparticles from plasma proteins and detection by the reticuloendothelial system, thereby prolonging their long circulation time. Once the nanoparticles reached the tumor microenvironment, the AANL was cleaved by legumain, exposing the TAT peptide on the surface, which enhances cellular internalization. Both in vitro and in vivo efficacy studies demonstrated that these EP-NPs significantly inhibited tumor growth while exhibiting negligible systemic toxicity, thereby suggesting that the developed enzyme/pH-sensitive PMLA-based nanoparticle holds great promise as an anti-tumor drug delivery system.
研究领域:
药学
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生物医学工程
·
肿瘤学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 5
·4646
·
IF 5.6
Longkun Wang,Chunqian Zhao,Lu Lu,Honglei Jiang,Fengshan Wang,Xinke Zhang
Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.Keywords:paclitaxel;peptide-drug conjugate;TAT peptide;A7R peptide;targeted delivery;anticancer therapy;transcytosis
研究领域:
药学
·
肿瘤学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2020
·Vol. 412
·期 26
·7349-7356
·
IF 3.637
Li Jun,Wang Man,Fan Yao-Yao,Duan Hui-Ling,Deng Xu,Zhang Zhi-Qi
The application of the dye-labeled fluorescence method in a ligand-RNA interaction assay is a complex and costly process prone to steric hindrance. Fluorescent nanomaterials offer an attractive alternative due to their simple, low-cost synthesis and effective screening properties. Here, CdTe@ZIF-8 core-shell nanocomposites were used as fluorescence signal transducer in the ligand-TAR RNA interaction assay. Different experimental strategies were developed based on the size-selective nature of the CdTe@ZIF-8 nanocomposites. When ligands can quench fluorescence, two assays of fluorescence recovery with TAR RNA and Tat peptide competitive displacement are carried out successively, which can not only distinguish ligands binding to TAR RNA but also screen potential Tat protein antagonists. When ligands cannot quench fluorescence, the mitoxantrone-TAR RNA complex is used in the competitive displacement assay. Ligands that displaced mitoxantrone from the mitoxantrone-TAR RNA complex signaled the interaction with TAR RNA. Eight ligands, including known and unknown TAR RNA-binding ligands, were tested via the above strategies. The results showed that this method was effective at distinguishing the known RNA-binding partner and screening the Tat antagonist from the test ligands. This simple and effective strategy is expected to be suitable for actual drug screening.
Graphical abstract
研究领域:
生物化学
·
分子生物学
·
纳米技术
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2014
·
IF 3.552
Wenjing Zhang,Zhengwei Mao,Changyou Gao
Thermo-sensitive microgel particles may exert a swelling force inside cells and influence on cell viability due to their volume transition in response to external temperature change. In this study, cross-linked poly(N-isopropylacrylamide) (PNIPAM) microgel particles with a thermo-responsive volume expansion ability were prepared by precipitation polymerization of NIPAM, poly(ethylene glycol) diacrylate and acrylic acid. To endow the microgel particles with enhanced cellular uptake and visualization, cell penetrating peptide TAT and fluorescent probe were further covalently immobilized. The cellular uptake, intracellular distribution and thermo-responsive cytotoxicity of the microgel particles were studied by co-culture with lung adenocarcinoma (A549) cells. The PNIAPM microgel particles were largely ingested by A549 cells and mainly located in lysosomes. TAT modification enhanced the cellular internalization of particles but did not alter their intracellular distribution. While the PNIPAM microgel particles did not show significant impact on cell viability at 37 °C, they caused cytotoxicity to some extent when being cultured at 25 °C for 4 h. Doxorubicin loaded PNIPAM microgel particles showed the strongest cytotoxicity when being cultured at 25 °C for 4 h, suggesting the combinational effect of intracellular volume expansion and drug release on cells.
研究领域:
材料科学
·
生物医学工程
·
药学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oncotarget
·
2016
·
IF 5.008
Jianwen Zhao,Fengfeng Zhao,Xiyong Wang,Xiaobo Fan,Guoqiu Wu
A novel multifunctional nano-drug delivery system based on reversal of peptide charge was successfully developed for anticancer drug delivery and imaging. Mesoporous silica nano-particles (MSN) ~50 nm in diameter were chosen as the drug reservoirs, and their surfaces were modified with HIV-1 transactivator peptide-fluorescein isothiocyanate (TAT-FITC) and YSA-BHQ1. The short TAT peptide labeled with FITC was used to facilitate intranuclear delivery, while the YSA peptide tagged with the BHQ1 quencher group was used to specifically bind to the tumor EphA2 membrane receptor. Citraconic anhydride (Cit) was used to invert the charge of the TAT peptide in neutral or weak alkaline conditions so that the positively charged YSA peptide could combine with the TAT peptide through electrostatic attraction. The FITC fluorescence was quenched by the spatial approach of BHQ1 after the two peptides bound to each other. However, the Cit-amino bond was unstable in the acidic atmosphere, so the positive charge of the TAT peptide was restored and the positively charged YSA moiety was repelled. The FITC fluorescence was recovered after the YSA-BHQ1 moiety was removed, and the TAT peptide led the nano-particles into the nucleolus. This nano-drug delivery system was stable at physiological pH, rapidly released the drug in acidic buffer, and was easily taken up by MCF-7 cells. Compared with free doxorubicin hydrochloride at an equal concentration, this modified MSN loaded with doxorubicin molecules had an equivalent inhibitory effect on MCF-7 cells. This nano-drug delivery system is thus a promising method for simultaneous cancer diagnosis and therapy.
研究领域:
纳米技术
·
药学
·
癌症研究
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2015
·Vol. 11
·期 21
·2543-2554
·
IF 8.368
Shi-Song Han,Ze-Yong Li,Jing-Yi Zhu,Kai Han,Zheng-Yang Zeng,Wei Hong,Wen-Xin Li,Hui-Zhen Jia,Yun Liu,Ren-Xi Zhuo,Xian-Zheng Zhang
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.
研究领域:
药学
·
纳米技术
·
癌症治疗
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）