International Journal of Nanomedicine
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2018
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IF 4.37
Zhen Zhang,Hanqing Qian,Jie Huang,Huizi Sha,Hang Zhang,Lixia Yu,Baorui Liu,Dong Hua,Xiaoping Qian
Background Red blood cell membrane-coated nanoparticle (RBCm-NP) platform, which consist of natural RBCm and synthetic polymeric core, can extend circulation time in vivo with an improved biocompatibility and stability of this biomimetic nanocarrier. To achieve better bioavailability of antitumor drugs that were loaded in RBCm-NPs, the functionalization of coated RBCm with specific targeting ability is essential. Bispecific recombinant protein anti-EGFR-iRGD, containing both tumor penetrating peptide (internalizing RGD peptide) and EGFR single-domain antibody (sdAb), seems to be an optimal targeting ligand for RBCm-NPs in the treatment of multiple tumors, especially colorectal cancer with high EGFR expression. Materials and methods We modified the anti-EGFR-iRGD recombinant protein on the surface of RBCm-NPs by lipid insertion method to construct iE–RBCm–PLGA NPs and confirmed the presentation of active tumor-targeting ability in colorectal cancer models with high EGFR expression when compared with RBCm–PLGA NPs. In addition, potential anti-tumor drug gambogic acid (GA) was loaded into the NPs to endow the antitumor efficiency of iE–RBCm–GA/PLGA NPs. It was simultaneously evaluated whether GA can reach better biocompatibility benefiting from the improved antitumor efficiency of iE–RBCm–GA/PLGA NPs in colorectal cancer models. Results We successfully modified anti-EGFR-iRGD proteins on the surface of biomimetic NPs with integrated and stable “shell–core” structure. iE–RBCm–PLGA NPs showed its improved targeting ability in vitro (multicellular spheroids [MCS]) and in vivo (nude mice bearing tumors). Besides, no matter on short-term cell apoptosis at tumor site (terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]) and long-term tumor inhibition, iE–RBCm–GA/PLGA NPs achieved better antitumor efficacy than free GA in spite of the similar effects of cytotoxicity and apoptosis to GA in vitro. Conclusion We expect that the bispecific biomimetic nanocarrier can extend the clinical application of many other potential antitumor drugs similar to GA and become a novel drug carrier in the colorectal cancer treatment.
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高影响因子
Biomaterials Science
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2023
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IF 6.6
Ying Ji,Juan Li,Shilin Xiao,Hiu Yee Kwan,Zhaoxiang Bian,Chih-Chang Chu
Amino acid-based poly(ester urea urethane) (AA-PEUU) is developed from amino acid-based ester urea building blocks interconnected with urethane blocks functionalized with poly(ethylene glycol) (PEG). Each functional block consists of structural design features that could impact the properties and performances of AA-PEUU as a nanocarrier for the systemic delivery of gambogic acid (GA). The multifunctional AA-PEUU structure provides broad tunability to enable the optimization of nanocarriers. The study investigates the structure–property relationship by fine-tuning the structure of AA-PEUU, including the amino acid type, hydrocarbons, the ratio of functional building blocks, and PEGylation, to identify the nanoparticle candidate with optimized delivery performances. Compared to free GA, the optimized PEUU nanocarrier improves the intratumoral distribution of GA by more than 9-fold, which significantly enhances the bioavailability and persistence of GA after intravenous administration. In an MDA-MB-231 xenograft mouse model, GA delivered by the optimized AA-PEUU nanocarrier exhibits significant tumor inhibition, apoptosis induction, and the anti-angiogenesis effect. The study demonstrates the potency of engineering AA-PEUU nanocarriers with tailor-designed structures and versatile tunability for the systemic delivery of therapeutics in the treatment of triple negative breast tumor.
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Acta Biomaterialia
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2017
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IF 6.319
Yanan Kang,Lu Lu,Jinshuai Lan,Yue Ding,Jing Yang,Yong Zhang,Yuan Zhao,Tong Zhang,Rodney J.Y. Ho
A novel redox-sensitive system for co-delivering hydrophobic drugs and hydrophilic siRNA or shRNA was developed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs) through amide bonds, which is called GA-conjugated PAAs (PAG). PAG can self-assemble into micelles as amphiphilic block copolymers , which exhibits an excellent loading ability for the co-delivery of docetaxel (DTX) and MMP-9 shRNA with adjustable dosing ratios. In addition, confocal microscopy , flow cytometry and in vitro transfection analyses demonstrated more efficient cellular internalization of DTX and MMP-9 shRNA after incubation with PAG/DTX- MMP-9 shRNA micelles (PAG/DTX-shRNA) than with free drugs. Unlike traditional amphiphilic copolymer micelles, GA conjugated in PAG possesses an intrinsic anticancer efficacy. The presence of disulfide bonds in PAAs enables rapid disassembly of PAG micelles in response to reducing agents, inducing the release of loaded drugs (DTX, GA and MMP-9 shRNA). In vitro cellular assays revealed that PAG/DTX-shRNA micelles inhibited MCF-7 cell proliferation more efficiently than the single drug or single drug-loaded micelles. In vivo biodistribution and anti-tumor effect studies using an MCF-7 breast cancer xenograft mouse model have indicated that PAG/DTX-shRNA micelles can enhance drug accumulation compared with the free drug, thereby sustaining the therapeutic effect on tumors. Additionally, PAG/DTX-shRNA micelles displayed a greater anti-tumor efficacy than Taxotere® and PAG-shRNA micelles. These results suggest that the redox-sensitive PAG platform is a promising co-delivery system for combining drugs and gene therapy for the treatment of cancer. Statement of Significance The PAG micelles were designed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs), which would serve dual purposes as both gene and drugs co-delivery carrier and an anti-tumor prodrug. Unlike traditional amphiphilic micelles, GA conjugated in PAG could exert its intrinsic efficacy and provide synergistic antiproliferative effects with docetaxel (DTX) on MCF-7 cells. Disulfide bonds in PAG enables a rapid disassembly of PAG micelles in response to reducing agents and to release all loaded drugs (DTX, GA and MMP-9 shRNA) at tumor sites. PAG/DTX-shRNA micelles displayed greater anti-tumor efficacy than that of Taxotere®, indicating the design concept for PAG works well. And the strategy for PAG could be used to develop a series of similar co-delivery systems through conjugations of other small-molecule drugs with PAAs, such as doxorubicin , methotrexate and other drugs with carboxy groups in their structure.
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高影响因子
DRUG DELIVERY
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2018
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IF 3.095
Mang Mang Sang,Fu Lei Liu,Yang Wang,Ren Jie Luo,Xiao Xian Huan,Ling Fei Han,Zhong Tao Zhang,Feng Feng,Wei Qu,Wenyuan Liu,Feng Zheng
Gambogic acid (GA) is a naturally derived potent anticancer agent with extremely poor biocompatibility. In the present study, a novel of redox/pH dual-responsive multifunctional magnetic complex micelle (sPEG/HA/CSO-SS-Hex/Fe3O4/GA), which consisted of a reducible hexadecanol-modified chitosan oligosaccharide polymer micelle (CSO-SS-Hex) coated with hyaluronic acid (HA) and DCA grafted sheddable PEG-PLL (sPEG) copolymers and loaded with gambogic acid (GA) and Fe3O4 nanoparticles were developed for parenteral delivery for the treatment of triple negative breast cancer (TNBC). The ex vivo study showed that the sPEG shielded cationic HA/CSO-SS-Hex/Fe3O4/GA core at physiological pH but quickly shed off to re-expose the core due to its charge reversible property. The sPEG/HA/CSO-SS-Hex/Fe3O4/GA micelles effectively facilitated tumor-targeted GA delivery by HA, which is a targeting ligand for CD44 receptor of TNBC cells, meanwhile increase GA uptake at the acidic condition but diminished the drug uptake at neutral pH. The in vitro cellular uptake study and in vivo biodistribution and antitumor activity of the formulations were determined, all results showed that the complex micelle enhanced TNBC tumor cellular uptake and fast drug release due to the combined effect of magnet targeting, CD44 receptor-mediated internalization and redox/pH dual-responsive drug release. Hence, tumor-targeted delivery of GA with redox/pH dual-responsive multifunctional magnetic complex micelle sPEG/HA/CSO-SS-Hex/Fe3O4/GA might have potential implications for the chemotherapy of TNBC.
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Biomaterials Advances
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2025
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IF 6
Xin Zhang,Li Li,Haiqing Niu,Zixin Liang,Liuqi Sang,Ning Wang,Fengli Huang,Xingzhi Han,Zhihao Liu,Xiao Shi,Qun Zhang,Jing Hu,Xiaoping Qian
Background The prognosis of patients with colorectal liver metastasis (CRLM) is poor. The 5-year survival rate of those who cannot be treated by surgery is less than 5 %, thus, the management of patients with CRLM remains a significant challenge. Based on the anti-tumor activity of traditional Chinese medicine monomer and the local immune activation caused by low dose radiotherapy combined with immune checkpoint inhibitors, we jointly applied it to explore the tumor inhibitory effect and the change of local immune microenvironment in liver metastasis model. Methods We engineered biomimetic nanoparticles through macrophage membrane encapsulation of gambogic acid (GA)-loaded PLGA cores, employing a double emulsion-solvent evaporation method to fabricate M-PLGA@GA nanoparticles. In tumor-bearing mice with surgically induced colorectal liver metastasis via hemisplenectomy, therapeutic efficacy was evaluated through intratumoral administration of M-PLGA@GA combined with triple-modality therapy: low-dose radiotherapy (LDRT; 5 Gy), anti-programmed cell death protein 1 monoclonal antibody (anti-PD-1 mAb; 200 μg), and nanoparticle delivery. This combinatorial approach leveraged spatial-temporal control of tumor microenvironment modulation. Results The nanoparticles augmented the targeted delivery ability of drugs to tumor cells and in vivo circulation duration, coupled with improved aqueous solubility of the encapsulated therapeutic agent, all while preserving its therapeutic potency. The radiotherapy notably augments the population of Dendritic cells (DCs) and bolsters the presentation of antigens to the tumor cells. Moreover, the administration of GA induces modifications in the tumor's immune microenvironment and escalates the fraction of CD8+ T cells. Within the context of the mouse CRLM model, the amalgamation of M-PLGA@GA with low-dose radiotherapy and immunotherapy markedly attenuates the pace of tumor proliferation and extends the survival of mice. Conclusions Our findings propose that a novel therapeutic regimen combining radiotherapy, immunotherapy, and Nanoparticle gambogic acid can effectively impede tumor progression in the mouse model of CRLM. Therefore, our study provides novel insights into the role of combined antitumor therapy on innate and adaptive antitumor immunity modulation for CRLM.
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