Journal of Materials Chemistry B
·
2017
·Vol. 5
·期 48
·9546-9557
·
IF 4.543
Shao-Lu Li,Yaoyi Wang,Jingfang Zhang,Wei Wei,Hua Lu
We describe here a novel targeting polyion complex (Tg-PIC) system for the delivery and intracellular release of cisplatin. Briefly, a guanidinium-pendant Pt(IV)-backboned poly-prodrug termed P(DSP-Gu) is prepared with excellent aqueous solubility, high drug-loading and high potency. To enable prolonged circulation and selective cellular internalization, P(DSP-Gu) is complexed with anisamide-end-capped poly(ethylene glycol)-block-poly(L-phosphotyrosine)-block-poly(L-leucine) (AA-PEG-PpY-PLeu) to yield Tg-PIC via electrostatic coacervation. Tg-PIC is stabilized by hydrogen bonding between phosphate and guanidinium, the PEG corona, and the helical poly(L-leucine) segment forming the hydrophobic core. The anisamide group, a high affinity ligand recognizing the sigma (σ) receptors that are overexpressed on many human malignancies including prostate cancer, is incorporated at the surface of the Tg-PIC for active targeting and efficient internalization. In vitro, the Tg-PICs show targeted and efficient internalization into sigma receptor-positive PC3 cells, and can release toxic Pt(II) species due to the degradation of P(DSP-Gu) under the intracellular reducing conditions. In vivo, the Tg-PICs exhibit superior antitumor efficacy with reduced toxicity. Thus, the system holds considerable promise towards more effective and safe nanomedicine.
研究领域:
肿瘤学
·
药剂学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2021
·
IF 5.875
Xinming Li,Juan Zhang,Peng Liu
More precise drug release is expected by conjugating the drug structural units in the polyprodrugs with dynamic covalent bonds responding to different stimuli. Here, amphiphilic acid/hypoxia co-triggered degradable diblock polyprodrug was designed via a facile one-pot method with drug content of 78.6% (1.22 mmol/g) and relatively molecular weight of 2.08 × 10 4 , by condensation polymerization of acid-sensitive dimer of doxorubicin (D-DOX ADH ) with 2-iminothiolane, in presence of PEGylated D-DOX ADH as end capping reagent for the PEGylation. Polyprodrug nanoparticles were easily obtained with mean hydrodynamic diameter of 177.6 ± 8.9 nm via self-assembly, which showed excellent acid/hypoxia co-triggered degradation and drug release performance. The ideal tumor selective cytotoxicity and enhanced antitumor efficacy were revealed with the in vitro cellular experiments. Such features make the proposed amphiphilic acid/hypoxia co-triggered degradable diblock polyprodrug a promising candidate for tumor chemotherapy.
研究领域:
药学
·
生物医学工程
·
肿瘤学
✓ 已验证
DOI
高影响因子
BIOMACROMOLECULES
·
2024
·
IF 5.5
Yufei Cao,Moujiang Zheng,Jiahong Shi,Jiale Si,Guopu Huang,Yuanyuan Ji,Yuzhu Hou,Zhishen Ge
X-ray-induced photodynamic therapy (XPDT) can penetrate deeply into the tumor tissues to overcome the disadvantage of conventional PDT. However, the therapeutic efficacy of XPDT in cancer therapy is still restricted due to the insufficient reactive oxygen species (ROS) generation at a relatively low irradiation dosage. Herein, we present the tumor pH and ROS-responsive polyprodrug micelles to load the X-ray photosensitizer verteporfin (VP) as an ROS production enhancer. The block copolymer polyprodrug consisting of hydrophilic poly(ethylene glycol) (PEG) as well as the segments of thioketal-linked camptothecin (CPT) methacrylate (CPTKMA) and 2-(pentamethyleneimino)ethyl methacrylate (PEMA) (PEG-b-P(CPTKMA-co-PEMA)) can self-assemble into micelles in aqueous solution and encapsulate VP with a high loading efficiency of 67%. Inside tumor tissues, the zeta potential of the micelles can transform from neutral to positive for promoted cellular internalization under tumor acidity. Followed by X-ray irradiation at the dose of 4 Gy, efficient ROS generation in the presence of VP triggers CPT release. The VP-loaded polyprodrug micelles can finally ablate tumors efficiently via synergistic radiochemotherapy due to deep penetration of X-ray inside tumor tissues, ROS generation enhancement, and triggered CPT release. Consequently, this promising strategy represents a robust therapeutic modality for the enhanced radiochemotherapy of cancers.
研究领域:
肿瘤学
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Polymers
·
2020
·Vol. 13
·期 1
·67
·
IF 3.426
Honglei Zhang,Yanjuan Wu,Xiao Xu,Chen Chen,Xiukun Xue,Ben Xu,Tianduo Li,Zhaowei Chen
The conventional mono-chemotherapy still suffers from unsatisfied potency for cancer therapy due to tumor heterogeneity and the occurrence of drug resistance. Combination chemotherapy based on the nanosized drug delivery systems (nDDSs) has been developed as a promising platform to circumvent the limitations of mono-chemotherapy. In this work, starting from cisplatin and curcumin (Cur), we prepared a dual drug backboned shattering polymeric nDDS for synergistic chemotherapy. By in situ polymerization of the Cur, platinum (IV) complex-based prodrug monomer (DHP), L-lysine diisocyanate (LDI), and then conjugation with a hydrophilic poly (ethylene glycol) monomethyl ether (mPEG) derivative, a backbone-type platinum (IV) and Cur linkage containing mPEG-poly(platinum-co-Cur)-mPEG (PCPt) copolymer was synthesized. Notably, the platinum (IV) (Pt (IV)) and Cur were incorporated into the hydrophobic segment of PCPt with the fixed drugs loading ratio and high drugs loading content. The batch-to-batch variability could be decreased. The resulting prodrug copolymer then self-assembled into nanoparticles (PCPt NPs) with an average diameter around 100 nm, to formulate a synergetic nDDS. Importantly, PCPt NPs could greatly improve the solubility and stability of Cur. In vitro drug release profiles have demonstrated that PCPt NPs were stable in PBS 7.4, rapid burst release was greatly decreased, and the Pt and Cur release could be largely enhanced under reductive conditions due to the complete dissociation of the hydrophobic main chain of PCPt. In vitro cell viability test indicated that PCPt NPs were efficient synergistic chemotherapy units. Moreover, PCPt NPs were synergistic for cisplatin-resistant cell lines A549/DDP cells, and they exhibited excellent reversal ability of tumor resistance to cisplatin. This work provides a promising strategy for the design and synthesis of nDDS for combination chemotherapy.Keywords:nanosized drug delivery system;dual drug;backboned;combination chemotherapy;polyprodrug
研究领域:
生物医学工程
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
Nano Today
·
2024
·
IF 13.2
Yaqiao Li,Lingxiao Li,Yanzhong Hao,Jingxuan Zhang,Cuiyun Liu,Erwei Zhao,XianBao Shi,Xiaohui Pu,Jin Sun,Zhonggui He,Bingjun Sun
Dimeric prodrug self-assembly nanoparticles (DPS NPs) present promising avenues for chemotherapeutic delivery, yet optimizing the linker design for effective SN38 delivery remains challenging. We developed various SN38 dimeric prodrugs with differing linker lengths to explore how linker length impacts DPS NP performance. Our study reveals that linker length critically affects the nanoparticles assembly stability and activation efficiency. Specifically, too short linkers compromise assembly stability and lead to premature drug activation in the bloodstream, raising safety concerns. Conversely, too long linkers hinder both assembly stability and activation efficiency within tumor cells, diminishing anti-tumor effectiveness. The optimal linker (C12) achieved the best balance, ensuring robust assembly stability and high activation efficiency, thereby enhancing anti-tumor efficacy while maintaining a favorable safety profile. This work underscores the significance of linker length in designing effective DPS NPs for cancer treatment.
研究领域:
药物化学
·
纳米医学
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
Acta Biomaterialia
·
2022
·
IF 10.633
Wenhao Zhong,Xinyu Zhang,Xiao Duan,Hengyu Liu,Yifen Fang,Moucheng Luo,Zhengwen Fang,Congxiu Miao,Dongjun Lin,Jun Wu
Gemcitabine , as a standard and classic strategy for B-cell lymphoma in the clinic, is limited by its poor pharmacodynamics . Although stimuli-responsive polymeric nanodelivery systems have been widely investigated in the past decade, issues such as complicated procedures, low loading capacity, and uncontrollable release kinetics still hinder their clinical translation. In view of the above considerations, we attempt to construct hyperbranched polyprodrug micelles with considerable drug loading via simple procedures and make use of the particularity of the tumor microenvironment to ensure that the micelles are “inactivated” in normal tissues and “activated” in the tumor microenvironment. Hence, in this work, a redox-responsive polymeric gemcitabine-prodrug (GEM-S-S-PEG) was one-pot synthesized via facile esterification and acylation . The self-assembled subsize (< 100 nm) GEM-S-S-PEG (GSP NPs) with considerable loading capacity (≈ 24.6%) exhibited on-demand and accurate control of gemcitabine release under a simulated tumor microenvironment and thus significantly induced the apoptosis of B-cell lymphoma in vitro . Moreover, in the A20 tumor xenograft murine model, GSP NPs efficiently decreased the expansion of tumor tissues with minimal systemic toxicity. In summary, these redox-responsive and self-assembling GSP NPs with a facile one-pot synthesis procedure may hold great potency in clinical translation for enhanced chemotherapy of B-cell lymphoma. Statement of significance A redox-responsive polymeric gemcitabine-prodrug (GEM-S-S-PEG) was one-pot synthesized via facile esterification and acylation. The self-assembled subsize (< 100 nm) GEM-S-S-PEG (GSP NPs) exhibited significant tumor therapeutic effects in vitro and in vivo . The polyprodrug GEM-S-S-PEG prepared in this study shows the great potential of redox-responsive nanodrugs for antitumor activity , which provides a reference value for the optimization of the design of functional polyprodrugs.
研究领域:
肿瘤学
·
药剂学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2021
·
IF 7.328
Xinming Li,Peng Liu
Acid-triggered degradable polyprodrug P(DOX-AH) was designed for long-acting drug delivery with minimal leakage and enhanced antitumor efficacy. By facile polymerization of doxorubicin (DOX) and N-(tert-butoxycarbonyl)acryloylhydrazine (Boc-AH), P(DOX-AH) with drug as unique repeating unit was obtained, possessing an ultrahigh drug content. It was stable in the neutral media but could degrade completely into DOX-AH in the acidic media without any other by-product. The cleavage of the hydrazone linkage between the DOX-AH repeating units was revealed by the LC-MS/MS analysis. Furthermore, a slow solubility-controlled drug release performance was achieved in the acidic media because of the low solubility of the released DOX-AH. Even with the slow DOX-AH releasing, the enhanced antitumor efficacy was obtained than free DOX in the in vitro cellular experiments. These features demonstrated the promising potential of the proposed polyprodrug for long-acting drug delivery in future tumor chemotherapy.
研究领域:
药学
·
肿瘤学
·
生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2024
·Vol. 14
·期 8
·5577-5587
·
IF 3.9
Kai Li,Sinan Tian,Ke Sun,Qingguo Su,Yanhui Mei,Wenjie Niu
Prostate cancer is the most common malignant tumor in the male reproductive system, and its incidence increases with age. Chemotherapy is one of the main strategies for treating prostate cancer, but it often comes with unavoidable side effects. Nanocarriers can improve drug utilization and targeting, and cationic carriers can also carry nucleic acids for gene therapy. In this study, we prepared a cationic micelle constructed from a polyprodrug that can deliver both chemotherapeutic drugs and nucleic acids simultaneously. The typical chemotherapeutic drug hydroxycamptothecin (HCPT) was linked by reactive oxygen species (ROS)-responsive coupling agents and forms amphiphilic block polymers with low molecular weight polyethyleneimine (PEI). The resulting cationic micelles can be triggered by high levels of ROS in tumor cells and collapse to release HCPT and suicide genes to kill tumor cells. At the same time, it reduces the killing of normal cells. In prostate cancer cells, it has been confirmed that the co-delivery carriers combined with chemotherapy and a suicide gene prodrug system have shown an ideal therapeutic effect on prostate cancer.
研究领域:
肿瘤学
·
药剂学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TALANTA
·
2023
·
IF 6.1
Ying Sun,Qimeng Wu,Quanyou Fu,Hailin Cong,Youqing Shen,Bing Yu,Hao Hu
Combination chemotherapy is a common strategy to enhance treatment efficacy and avoid multidrug resistance (MDR) in clinical practice. However, it is difficult to ensure the co-enrichment and reasonable ratio of synergistic drugs in the lesion site after intravenous administration. Integrating synergistic drugs into a nanocarrier can improve drug stability, targeting, drug loading, and importantly, ensure that synergistic drugs work at one destination. This study uses 10-hydroxycamptothecin (HCPT) to construct a polymeric prodrug micelle , and the demethylcantharidin (DMC) is proportionally encapsulated within the micelle. Triggered by reactive oxygen species (ROS), HCPT and DMC were released simultaneously from the co-delivery platform in tumor cells. DMC promotes abnormal cell division by inhibiting the synthesis of the cell cycle checkpoint kinase Protein phosphatase 2A (PP2A), leading to increased cell vulnerability to DNA damage, disordered replication, and death. The co-delivery platform exhibited satisfactory biosafety and antitumor efficacy in vivo . The proposed co-delivery platform may provide a valuable reference for the translation of clinical combination chemotherapy regimens into nano-drug delivery systems.
研究领域:
药学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2021
·Vol. 10
·期 20
·2100938
·
IF 9.933
Gaizhen Kuang,Hongtong Lu,Shasha He,Hejian Xiong,Jie Yu,Qingfei Zhang,Yubin Huang
Stimuli-responsive nanosystems have been widely applied as effective modalities for drug/gene co-delivery in cancer treatment. However, precise spatiotemporal manipulations of drug/gene co-delivery, as well as multi-modality imaging-guided cancer therapy, still remain a daunting challenge. Here, multifunctional polyprodrug/siRNA loaded upconversion nanoparticles (UCNPs) are reported that combine computed tomography (CT), magnetic resonance (MR), and upconversion luminescence (UCL) tri-modality imaging and near-infrared (NIR) light-activated drug/gene on-demand delivery. The photoactivatable platinum(IV) (Pt(IV))-backbone polymers (PPt) and the siRNA targeting polo-like kinase 1 (Plk1) are loaded on the surface of polyethyleneimine (PEI)-coated UCNPs (PUCNP) to obtain the multifunctional polyprodrug/siRNA loaded UCNPs (PUCNP@Pt@siPlk1). The PUCNP@Pt@siPlk1 can be served as a “nanotransducer” to convert NIR light (980 nm) into local ultraviolet (UV) to visible light for the cleavage of photosensitive PPt, resulting in the simultaneous on-demand release of high toxic platinum(II) (Pt(II)) and siPlk1. Meanwhile, the PUCNP@Pt@siPlk1 has CT, T 1 -weighted MR, and UCL tri-modality imaging abilities. Based on these merits, PUCNP@Pt@siPlk1 displayed excellent synergistic therapeutic efficacy via image-guided and NIR light-activated platinum-based chemotherapy and RNA interfering in vitro and in vivo. Thus, this developed nanosystem with NIR light-controlled drug/gene delivery and multi-modality imaging abilities, will display great potential in combining chemotherapy and gene therapy.
研究领域:
纳米技术
·
癌症治疗
·
药物递送系统
·
医学成像
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2025
·
IF 5.5
Suixin Xing,Xu Zhang,Haizhen Guo,Shitian Jia,Shujing Xu,Yongxin Liu,Xue Li,Yuewei Li,Sheng Wang
Ferroptosis has become an emerging paradigm in tumor therapy characterized by the accumulation of lipid peroxides (LPO). However, intracellular glutathione peroxidase 4 (GPX4) will lead to the clearance of LPO, weakening the therapeutic effect based on ferroptosis. Herein, the integration of the Fenton reaction amplifier and GPX4-targeted siRNA (si-GPX4) was proposed. A polyprodrug-siGPX4 nanoparticle (denoted as si-PDAFH NP) was prepared. On one hand, the si-PDAFH NP can respond to tumor microenvironment, leading to structural degradation of the NPs and release of therapeutic components. The released cinnamaldehyde and ferrocene can amplify the Fenton reaction to produce •OH, oxidizing unsaturated fatty acids to generate LPO. On the other hand, the expression of the GPX4 protein can be knocked down by si-GPX4, preventing the clearance of LPO. The results showed that the si-PDAFH NPs can significantly affect the tumor redox status related to ferroptosis and suppress tumor growth. Therefore, this study provides a new avenue to enhance ferroptosis for cancer treatment.
研究领域:
生物化学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Hongjie Zhang,Jing Wang,Ruiying Wu,Benyan Zheng,Yanxiang Sang,Bibo Wang,Lei Song,Yuan Hu,Xiaopeng Ma
Currently, the secondary development and modification of clinical drugs has become one of the research priorities. Researchers have developed a variety of TME-responsive nanomedicine carriers to solve certain clinical problems. Unfortunately, endogenous stimuli such as reactive oxygen species (ROS), as an important prerequisite for effective therapeutic efficacy, are not enough to achieve the expected drug release process, therefore, it is difficult to achieve a continuous and efficient treatment process. Herein, a self-supply ROS-responsive cascade polyprodrug (PMTO) was designed. The encapsulation of the chemotherapy drug mitoxantrone (MTO) in a polymer backbone could effectively reduce systemic toxicity when transported in vivo. After PMTO was degraded by endogenous ROS of the TME, another part of the polyprodrug backbone became cinnamaldehyde (CA), which can further enhance intracellular ROS, thereby achieving a sustained drug release process. Meanwhile, due to the disruption of the intracellular redox environment, the efficacy of chemotherapy drugs is enhanced. Finally, the anticancer treatment efficacy was further enhanced due to the mild hyperthermia effect of PMTO. In conclusion, the designed PMTO demonstrated remarkable antitumor efficacy, effectively addressing the limitations associated with MTO. This article is protected by copyright. All rights reserved
研究领域:
药理学
·
纳米技术
·
肿瘤学
·
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）