Stable Loading and Delivery of Melittin with Lipid-Coated Polymeric Nanoparticles for Effective Tumor Therapy with Negligible Systemic Toxicity

ABSTRACTFor decades, cationic polymer nanoparticles have been investigated for nucleic acid delivery. Despite promising in vitro transfection results, most formulations have failed to translate into the clinic due to significant in vivo toxicity – especially when delivered intravenously. To address this significant problem, we investigated the detailed mechanisms that govern the complex in vivo systemic toxicity response to common polymeric nanoparticles. We determined that the toxicity response is material dependent. For branched polyethylenimine (bPEI) nanoparticles – toxicity is a function of multiple pathophysiological responses – triggering of innate immune sensors, induction of hepatic toxicity, and significant alteration of hematological properties. In contrast, for chitosan-based nanoparticles – systemic toxicity is primarily driven through innate immune activation. We further identified that modification of primary amines to secondary and tertiary amines using the small molecule imidazole-acetic-acid (IAA) ameliorates in vivo toxicity from both nanocarriers by different, material-specific mechanisms related to Toll-like receptor 4 activation (for bPEI) and complement activation driven neutrophil infiltration (for chitosan), respectively. Our results provide a detailed roadmap for evaluating in vivo toxicity of nanocarriers and identifies potential opportunities to reduce toxicity for eventual clinical translation.Graphical Abstract

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The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy

Biomolecules ◽

10.3390/biom9020060 ◽

2019 ◽

Vol 9 (2) ◽

pp. 60 ◽

Cited By ~ 6

Author(s):

Philippe Bertrand ◽

Christophe Blanquart ◽

Valérie Héroguez

Keyword(s):

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Tumor Therapy ◽

Systemic Toxicity ◽

Oxide Shell ◽

Cancer Drugs ◽

Native Form ◽

In Vivo Models ◽

Anti Cancer

Fast clearance, metabolism, and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects, despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo models of cancer. The specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. This paper deals with the synthesis of the polymeric nanoparticle platform, which was produced by Ring-Opening Metathesis Polymerization (ROMP), able to release anti-cancer drugs in dispersion, such as histone deacetylase inhibitors, into mesothelioma tumors. The core-shell nanoparticles (NPs) have stealth properties due to their poly(ethylene oxide) shell and can be viewed as universal nano-carriers on which any alkyne-modified anti-cancer molecule can be grafted by click chemistry. A cleavage reaction of the chemical bond between NPs and drugs through the contact of NPs with a medium presenting an acidic pH, which is typically a cancer tumor environment or an acidic intracellular compartment, induces a controlled release of the bioactive molecule in its native form. In our in vivo syngeneic model of mesothelioma, a highly selective accumulation of the particles in the tumor was obtained. The release of the drugs led to an 80% reduction of tumor weight for the best compound without toxicity. Our work demonstrates that the use of theranostic nanovectors leads to an optimized delivery of epigenetic inhibitors in tumors, which improves their anti-tumor properties in vivo.

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Polysaccharides-Based Polymeric Nanoparticles for Drug Delivery and Tumor Therapy

Frontiers in Nanobiomedical Research - The World Scientific Encyclopedia of Nanomedicine and Bioengineering II ◽

10.1142/9789813205566_0008 ◽

2017 ◽

pp. 195-223

Author(s):

Jing Yao ◽

Fatima Zohra Dahmani ◽

Hui Xiong ◽

Yan Xiao ◽

Yuanke Li ◽

...

Keyword(s):

Drug Delivery ◽

Polymeric Nanoparticles ◽

Tumor Therapy

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Novel CD44-Targeting and pH/redox Dual-Stimuli Responsive Core-Shell Nanoparticles Loading Triptolide to Combat Breast Cancer Growth and Lung Metastasis

10.21203/rs.3.rs-295313/v1 ◽

2021 ◽

Author(s):

Jinfeng Shi ◽

Yali Ren ◽

Jiaqi Ma ◽

Xi Luo ◽

Jiaxin Li ◽

...

Keyword(s):

Breast Cancer ◽

Drug Release ◽

Lung Metastasis ◽

Cancer Progression ◽

Drug Loading ◽

Tumor Therapy ◽

Systemic Toxicity ◽

Migration And Invasion ◽

Drug Release Profile ◽

Cd44 Targeting

Abstract BackgroundThe toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited its clinical application. Therefore, we fabricated a CD44-targeting and tumor-microenvironment pH/redox sensitive nanosystem, composed by hyaluronic acid-Vitamin E succinate (HA-VE) and Poly (β-Amino Esters) (PBAEss) polymers, to enhance the suppression of breast cancer proliferation and lung metastasis of TPL. ResultsThe generated TPL/NPs had the high drug loading efficiency (94.93 ± 2.1%) and a desirable average size (191 nm). Mediated by PBAEss core, TPL/NPs displayed a pH/redox dual stimuli drug release profile in vitro. Based on HA coating, TPL/NPs exhibited selective tumor-cellular uptake and high tumor-tissue accumulation capacity via targeting CD44. As a consequence, TPL/NPs showed higher cell proliferation suppression, pro-apoptosis and cell cycle arrest activities, and stronger inhibitory effects on cell migration and invasion than free TPL in MCF-7 and MDA-MB-231 cells. Importantly, TPL/NPs also showed higher efficacy in shrinking tumor size and block lung metastasis in a 4T1 breast cancer mice model at equivalent or lower TPL dosage compared to free TPL, with the decreased systemic toxicity. Histological immunofluorescence and immunohistochemical analyses in tumor and lung tissue revealed that TPL/NPs induced a high level of apoptosis, suppressed expression of matrix metalloproteinases, which all these contributed to inhibit tumor growth and pulmonary metastasis. ConclusionCollectively, our results demonstrate that TPL/NPs, which integrates tumor active-targeting and pH/redox responsive drug release, pro-apoptosis, and anti-mobility, represent a promising candidate in halting breast cancer progression and metastasis while minimizing systemic toxicity.

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5-Boronopicolinic acid-functionalized polymeric nanoparticles for targeting drug delivery and enhanced tumor therapy

Materials Science and Engineering C ◽

10.1016/j.msec.2020.111553 ◽

2021 ◽

Vol 119 ◽

pp. 111553

Author(s):

Xuefang Hao ◽

Weiwei Gai ◽

Lina Wang ◽

Jiadi Zhao ◽

Dandan Sun ◽

...

Keyword(s):

Drug Delivery ◽

Polymeric Nanoparticles ◽

Tumor Therapy

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Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis

Journal of Nanobiotechnology ◽

10.1186/s12951-021-00934-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jinfeng Shi ◽

Yali Ren ◽

Jiaqi Ma ◽

Xi Luo ◽

Jiaxin Li ◽

...

Keyword(s):

Breast Cancer ◽

Hyaluronic Acid ◽

Drug Release ◽

Lung Metastasis ◽

Drug Loading ◽

Tumor Therapy ◽

Systemic Toxicity ◽

Migration And Invasion ◽

Stimuli Responsive ◽

Cd44 Targeting

Abstract Background The toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited the clinical application. Thus, we fabricated a CD44-targeting and tumor microenvironment pH/redox-sensitive nanosystem composed of hyaluronic acid-vitamin E succinate and poly (β-amino esters) (PBAEss) polymers to enhance the TPL-mediated suppression of breast cancer proliferation and lung metastasis. Results The generated TPL nanoparticles (NPs) had high drug loading efficiency (94.93% ± 2.1%) and a desirable average size (191 nm). Mediated by the PBAEss core, TPL/NPs displayed a pH/redox-dual-stimuli-responsive drug release profile in vitro. Based on the hyaluronic acid coating, TPL/NPs exhibited selective tumor cellular uptake and high tumor tissue accumulation capacity by targeting CD44. Consequently, TPL/NPs induced higher suppression of cell proliferation, blockage of proapoptotic and cell cycle activities, and strong inhibition of cell migration and invasion than that induced by free TPL in MCF-7 and MDA-MB-231 cells. Importantly, TPL/NPs also showed higher efficacy in shrinking tumor size and blocking lung metastasis with decreased systemic toxicity in a 4T1 breast cancer mouse model at an equivalent or lower TPL dosage compared with that of free TPL. Histological immunofluorescence and immunohistochemical analyses in tumor and lung tissue revealed that TPL/NPs induced a high level of apoptosis and suppressed expression of matrix metalloproteinases, which contributed to inhibiting tumor growth and pulmonary metastasis. Conclusion Collectively, our results demonstrate that TPL/NPs, which combine tumor active targeting and pH/redox-responsive drug release with proapoptotic and antimobility effects, represent a promising candidate in halting breast cancer progression and metastasis while minimizing systemic toxicity. Graphic Abstract

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Nanomaterials as Promising Theranostic Tools in Nanomedicine and Their Applications in Clinical Disease Diagnosis and Treatment

Nanomaterials ◽

10.3390/nano11123346 ◽

2021 ◽

Vol 11 (12) ◽

pp. 3346

Author(s):

Wei Zhu ◽

Zhanqi Wei ◽

Chang Han ◽

Xisheng Weng

Keyword(s):

Cardiovascular Diseases ◽

Polymeric Nanoparticles ◽

Human Life ◽

Rapid Development ◽

Tumor Therapy ◽

Chemical Properties ◽

Surface Characteristics ◽

Disease Diagnosis ◽

Diagnosis And Treatment ◽

Low Sensitivity

In recent decades, with the rapid development of nanotechnology, nanomaterials have been widely used in the medical field, showing great potential due to their unique physical and chemical properties including minimal size and functionalized surface characteristics. Nanomaterials such as metal nanoparticles and polymeric nanoparticles have been extensively studied in the diagnosis and treatment of diseases that seriously threaten human life and health, and are regarded to significantly improve the disadvantages of traditional diagnosis and treatment platforms, such as poor effectiveness, low sensitivity, weak security and low economy. In this review, we report and discuss the development and application of nanomaterials in the diagnosis and treatment of diseases based mainly on published research in the last five years. We first briefly introduce the improvement of several nanomaterials in imaging diagnosis and genomic sequencing. We then focus on the application of nanomaterials in the treatment of diseases, and select three diseases that people are most concerned about and that do the most harm: tumor, COVID-19 and cardiovascular diseases. First, we introduce the characteristics of nanoparticles according to the excellent effect of nanoparticles as delivery carriers of anti-tumor drugs. We then review the application of various nanoparticles in tumor therapy according to the classification of nanoparticles, and emphasize the importance of functionalization of nanomaterials. Second, COVID-19 has been the hottest issue in the health field in the past two years, and nanomaterials have also appeared in the relevant treatment. We enumerate the application of nanomaterials in various stages of viral pathogenesis according to the molecular mechanism of the complete pathway of viral infection, pathogenesis and transmission, and predict the application prospect of nanomaterials in the treatment of COVID-19. Third, aiming at the most important causes of human death, we focus on atherosclerosis, aneurysms and myocardial infarction, three of the most common and most harmful cardiovascular diseases, and prove that nanomaterials could be involved in a variety of therapeutic approaches and significantly improve the therapeutic effect in cardiovascular diseases. Therefore, we believe nanotechnology will become more widely involved in the diagnosis and treatment of diseases in the future, potentially helping to overcome bottlenecks under existing medical methods.

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Intracellular tracking of drug release from pH-sensitive polymeric nanoparticles via FRET for synergistic chemo-photodynamic therapy

Journal of Nanobiotechnology ◽

10.1186/s12951-019-0547-2 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 7

Author(s):

Chen Du ◽

Yan Liang ◽

Qingming Ma ◽

Qianwen Sun ◽

Jinghui Qi ◽

...

Keyword(s):

Photodynamic Therapy ◽

Drug Release ◽

Real Time ◽

Polymeric Nanoparticles ◽

Drug Loading ◽

Tumor Therapy ◽

Resonance Energy Transfer ◽

Resonance Energy

Abstract Background Synergistic therapy of tumor is a promising way in curing cancer and in order to achieve effective tumor therapy with real-time drug release monitoring, dynamic cellular imaging and antitumor activity. Results In this work, a polymeric nanoparticle with Forster resonance energy transfer (FRET) effect and chemo-photodynamic properties was fabricated as the drug vehicle. An amphiphilic polymer of cyclo(RGDfCSH) (cRGD)-poly(ethylene glycol) (PEG)-Poly(l-histidine) (PH)-poly(ε-caprolactone) (PCL)-Protoporphyrin (Por)-acting as both a photosensitizer for photodynamic therapy (PDT) and absorption of acceptor in FRET was synthesized and self-assembled into polymeric nanoparticles with epirubicin (EPI)-acting as an antitumor drug for chemotherapy and fluorescence of donor in FRET. Spherical EPI-loaded nanoparticles with the average size of 150 ± 2.4 nm was procured with negatively charged surface, pH sensitivity and high drug loading content (14.9 ± 1.5%). The cellular uptake of EPI-loaded cRGD-PEG-PH-PCL-Por was monitored in real time by the FRET effect between EPI and cRGD-PEG-PH-PCL-Por. The polymeric nanoparticles combined PDT and chemotherapy showed significant anticancer activity both in vitro (IC50 = 0.47 μg/mL) and better therapeutic efficacy than that of free EPI in vivo. Conclusions This work provided a versatile strategy to fabricate nanoassemblies for intracellular tracking of drug release and synergistic chemo-photodynamic therapy.

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