Advanced Technologies for Developing the State-of-the-Art Nanomedicines

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: closed (20 November 2022) | Viewed by 22631

Special Issue Editors

CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics and University of Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Beijing 100049, China
Interests: nanomedicines; peptide self-assembly; mitochondria
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Multidisciplinary Research Division, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China
Interests: nanomedicines; biomaterials; drug delivery
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Special Issue Information

Dear Colleagues,

The past two decades have witnessed the rapid development of nanomedicines for antitumor therapy. In addition to antitumor therapy, nanomedicines also emerge as promising drugs for other devastating diseases including cerebro-cardiovascular diseases, central nervous system (CNS) disorders, infectious diseases, etc. As compared with small-molecule drugs, nanomedicines have unique physicochemical properties and can be used for diverse therapeutic purposes. State-of-the-art technologies provide new tools for the development of nanomedicines with enhanced efficacy and safety. For instance, advances in material sciences offer versatile nanomaterials for developing multifunctional nanomedicines. These nanomedicines can be spatiotemporally controlled for extended blood circulation, sustained release, immune evasion, tissue penetration, sub-organelle targeting, and imaging. Moreover, the nanomedicines that integrate different therapeutic modalities, such as photodynamic therapy (PDT) and chemodynamic therapy (CDT), typically show enhanced therapeutic effects.

This Special Issue aims to highlight recent advances in the development of nanomedicines. Nanomedicines with novel strategies, novel materials, and/or novel therapeutic targets will be well illustrated by eminent scientists, as well as several emerging young scientists, in the field of nanomedicines.

We welcome contributions in the form of reviews or original research articles on the topics of nanomedicines, including, but not limited to, the following fields: 

  • Nanomedicines beyond the enhanced permeability and retention (EPR) effect
  • Nanomedicines for targeted drug delivery
  • Stimuli-responsive nanomedicines
  • Bio-inspired nanomaterials
  • Organic-inorganic nanomaterials
  • Peptide self-assembly
  • Analytic techniques for characterizing nanomedicines
  • Nanovaccine

Dr. Yi Hu
Dr. Jun Chen
Guest Editors

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Keywords

  • nanomedicines
  • nanocarriers
  • drug delivery
  • peptide self-assembly
  • analytic techniques
  • vaccine
  • inorganic nanomaterials
  • mitochondria

Published Papers (11 papers)

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Editorial

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3 pages, 171 KiB  
Editorial
Editorial for Special Issue: Advanced Technologies for Developing the State-of-the-Art Nanomedicines
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Pharmaceutics 2023, 15(7), 1954; https://doi.org/10.3390/pharmaceutics15071954 - 15 Jul 2023
Viewed by 730
Abstract
This Special Issue aims to introduce advanced technologies that promote the development of nanomedicines [...] Full article

Research

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16 pages, 2527 KiB  
Article
Identification of Nanoparticle Properties for Optimal Drug Delivery across a Physiological Cell Barrier
Pharmaceutics 2023, 15(1), 200; https://doi.org/10.3390/pharmaceutics15010200 - 06 Jan 2023
Cited by 2 | Viewed by 1679
Abstract
Nanoparticles (NPs) represent an attractive strategy to overcome difficulties associated with the delivery of therapeutics. Knowing the optimal properties of NPs to address these issues could allow for improved in vivo responses. This work investigated NPs prepared from 5 materials of 3 sizes [...] Read more.
Nanoparticles (NPs) represent an attractive strategy to overcome difficulties associated with the delivery of therapeutics. Knowing the optimal properties of NPs to address these issues could allow for improved in vivo responses. This work investigated NPs prepared from 5 materials of 3 sizes and 3 concentrations applied to a cell barrier model. The NPs permeability across a cell barrier and their effects on cell barrier integrity and cell viability were evaluated. The properties of these NPs, as determined in water (traditional) vs. media (realistic), were compared to cell responses. It was found that for all cellular activities, NP properties determined in media was the best predictor of the cell response. Notably, ZnO NPs caused significant alterations to cell viability across all 3 cell lines tested. Importantly, we report that the zeta potential of NPs correlates significantly with NP permeability and NP-induced changes in cell viability. NPs with physiological-based zeta potential of −12 mV result in good cell barrier penetration without considerable changes in cell viability. Full article
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18 pages, 10729 KiB  
Article
PEG-Bottlebrush Stabilizer-Based Worm-like Nanocrystal Micelles with Long-Circulating and Controlled Release for Delivery of a BCR-ABL Inhibitor against Chronic Myeloid Leukemia (CML)
Pharmaceutics 2022, 14(8), 1662; https://doi.org/10.3390/pharmaceutics14081662 - 10 Aug 2022
Cited by 3 | Viewed by 1681
Abstract
Drug nanocrystals, one of most common drug delivery systems, enable the delivery of poorly water-soluble drugs with high drug loading and enhanced dissolution. The rapid clearance and uncontrolled drug release of drug nanocrystals limit their delivery efficiency and clinical application. Herein, an amphiphilic [...] Read more.
Drug nanocrystals, one of most common drug delivery systems, enable the delivery of poorly water-soluble drugs with high drug loading and enhanced dissolution. The rapid clearance and uncontrolled drug release of drug nanocrystals limit their delivery efficiency and clinical application. Herein, an amphiphilic co-polymer, poly oligo(ethylene glycol) methacrylate-b-poly(styrene–co-4-formylphenyl methacrylate) (POEGMA-b-P (St-co-FPMA), PPP), characterized by a hydrophilic part with bottlebrush-like oligo(ethylene glycol) methacrylate (OEGMA) side chains, was synthesized as stabilizers to fabricate a high-drug-loading nanocrystal micelle (053-PPP NC micelle) using the chronic myeloid leukemia (CML) drug candidate N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-4-(methylamino)pyrimidine-5-carboxamide (CHMFL-ABL-053 or 053) as a model drug. The 053-PPP NC micelle was characterized and subjected to in vitro and in vivo studies. It featured a worm-like shape of small size, high drug loading (~50%), high colloidal stability, and controlled release in vitro. The presence of the 053-PPP NC micelle resulted in a long-circulation property and a much higher AUC. The 053-PPP NC micelle induced higher accumulation in the tumor tissues under multiple continuous administration. For in vivo efficacy, the 053-PPP NC micelle with a longer dosing interval (96 h), beneficial for improving patient adherence, demonstrated superiority to the 053-F127 NC. The proposed stabilizer PPP and the 053-PPP NC micelle with high drug loading enables drug delivery with long circulation and controlled release of drugs. It is also promising for the development of more efficient nanocrystal-based intravenous injection formulations for poorly water-soluble drugs. It might also offer new possibilities for potential clinical application of the CML candidate drug 053. Full article
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15 pages, 4331 KiB  
Article
Codelivery of HBx-siRNA and Plasmid Encoding IL-12 for Inhibition of Hepatitis B Virus and Reactivation of Antiviral Immunity
Pharmaceutics 2022, 14(7), 1439; https://doi.org/10.3390/pharmaceutics14071439 - 09 Jul 2022
Cited by 3 | Viewed by 2299
Abstract
Chronic hepatitis B is a critical cause of many serious liver diseases such as hepatocellular carcinoma (HCC). The main challenges in hepatitis B treatment include the rebound of hepatitis B virus (HBV)-related antigen levels after drug withdrawal and the immunosuppression caused by the [...] Read more.
Chronic hepatitis B is a critical cause of many serious liver diseases such as hepatocellular carcinoma (HCC). The main challenges in hepatitis B treatment include the rebound of hepatitis B virus (HBV)-related antigen levels after drug withdrawal and the immunosuppression caused by the virus. Herein, we demonstrate that the HBV-related antigen can be effectively inhibited and antiviral immunity can be successfully reactivated through codelivery of the small interfering RNA (siRNA) targeting HBV X protein (HBx) and the plasmid encoding interleukin 12 (pIL-12) to hepatocytes and immune cells. After being treated by the siRNA/pIL-12 codelivery system, HBx mRNA and hepatitis B surface antigen (HBsAg) are dramatically reduced in HepG2.215 cells. More importantly, the downregulated CD47 and programmed death ligand 1 (PD-L1) and the upregulated interferon-β promoter stimulator-1 (IPS-1), retinoic acid-inducible gene-1 (RIG-1), CD80, and human leukocyte antigen-1 (HLA-1) in treated HepG2.215 cells indicate that the immunosuppression is reversed by the codelivery system. Furthermore, the codelivery system results in inhibition of extracellular regulated protein kinases (ERK) and phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pathways, as well as downregulation of B-cell lymphoma-2 (Bcl-2) and upregulation of p53, implying its potential in preventing the progression of HBV-induced HCC. In addition, J774A.1 macrophages treated by the codelivery system were successfully differentiated into the M1 phenotype and expressed enhanced cytokines with anti-hepatitis B effects such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α). Therefore, we believe that codelivery of siRNA and pIL-12 can effectively inhibit hepatitis B virus, reverse virus-induced immunosuppression, reactivate antiviral immunity, and hinder the progression of HBV-induced hepatocellular carcinoma. This investigation provides a promising approach for the synergistic treatment of HBV infection. Full article
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10 pages, 1532 KiB  
Article
Mg2+ Ions Regulating 3WJ-PRNA to Construct Controllable RNA Nanoparticle Drug Delivery Platforms
Pharmaceutics 2022, 14(7), 1413; https://doi.org/10.3390/pharmaceutics14071413 - 06 Jul 2022
Cited by 1 | Viewed by 1279
Abstract
RNA nanotechnology has shown great progress over the past decade. Diverse controllable and multifunctional RNA nanoparticles have been developed for various applications in many areas. For example, RNA nanoparticles can participate in the construction of drug delivery nanoplatforms. Recently, a three-way junction packaging [...] Read more.
RNA nanotechnology has shown great progress over the past decade. Diverse controllable and multifunctional RNA nanoparticles have been developed for various applications in many areas. For example, RNA nanoparticles can participate in the construction of drug delivery nanoplatforms. Recently, a three-way junction packaging RNA (3WJ-pRNA) has been exploited for its characteristics of self-assembly and ultrahigh stability in many aspects. 3WJ-pRNA is the 3WJ part of bacteriophage φ29 pRNA and joins different components of φ29 as a linker element. In this work, we used all-atom MD simulation to study the thermal stability of 3WJ-pRNA and the underlying mechanisms. While 3WJ-pRNA can remain in its original structure without Mg2+ ions at room temperature, only Mg-bound 3WJ-pRNA still maintains its initial three-way junction structure at a higher temperature (T = 400 K). The Mg-free 3WJ-pRNA undergoes dramatic deformation under high temperature condition. The contribution of Mg ions can be largely attributed to the protective effect of two Mg clamps on the hydrogen bond and base stacking interactions in helices. Taken together, our results reveal the extraordinary thermal stability of 3WJ-pRNA, which can be regulated by Mg2+ ions. Comprehensive depictions of thermal stability of pRNA and the regulation mechanism are helpful for the further development of controllable RNA nanoparticle drug delivery platforms. Full article
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11 pages, 2386 KiB  
Article
Synthesis of Aliphatic Polyanhydrides with Controllable and Reproducible Molecular Weight
Pharmaceutics 2022, 14(7), 1403; https://doi.org/10.3390/pharmaceutics14071403 - 04 Jul 2022
Cited by 6 | Viewed by 1712
Abstract
Polyanhydrides have been synthesized for decades by melt-polycondensation of diacid monomers and 5 to >10 times mole excess acetic anhydride to diacid monomers to form polymers with a polydispersity ranging from 2.5 to 6 and low reproducibility. Hydrophobic segments in polyanhydrides are beneficial [...] Read more.
Polyanhydrides have been synthesized for decades by melt-polycondensation of diacid monomers and 5 to >10 times mole excess acetic anhydride to diacid monomers to form polymers with a polydispersity ranging from 2.5 to 6 and low reproducibility. Hydrophobic segments in polyanhydrides are beneficial to hinder the characteristic hydrolytic cleavage of an anhydride bond that provides stable polyanhydrides at room temperature. The objective of this work is to synthesize aliphatic polyanhydrides with various hydrophobic segments, controllable and reproducible molecular weight, and low polydispersity that are essential for potential use as drug carriers. A series of polyanhydrides of suberic, azelaic, sebacic, and dodecanedioic acids with controlled molecular weight, reduced polydispersity, and standard deviation of molecular weights, have been synthesized. All synthesized polyanhydrides were thoroughly characterized by NMR, Fourier transform infrared spectroscopy, and gel permeation chromatography. Molecular weights of the synthesized polyanhydrides are highly controllable, depending on the degree of activation of the dicarboxylic acid monomers, i.e., the amount of acetic anhydride used during synthesis. Polyanhydrides have been synthesized in triplicate by melt-polycondensation, using various mole ratios of acetic anhydride to diacids. The standard deviation of the molecular weights of the polyanhydrides is minute when using 1 equivalent of acetic anhydride during the activation of dicarboxylic acids, whereas if excess acetic anhydride is used, the standard deviation is very high. The effect of safe and natural inorganic catalysts, Calcium oxide, Zinc oxide, and Calcium carbonate on polymerization is also studied. As-synthesized poly(sebacic acid) can offer convenience to use in controlled drug delivery applications. In vitro drug release study using Temozolamide (TMZ), a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma, shows 14% TMZ release after the first hour and 70% release over one day from the poly(sebacic acid) wafers. Full article
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17 pages, 3781 KiB  
Article
Vehicle-Free Nanotheranostic Self-Assembled from Clinically Approved Dyes for Cancer Fluorescence Imaging and Photothermal/Photodynamic Combinational Therapy
Pharmaceutics 2022, 14(5), 1074; https://doi.org/10.3390/pharmaceutics14051074 - 17 May 2022
Cited by 6 | Viewed by 1706
Abstract
Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT) has attracted growing attention as a noninvasive option for cancer treatment. At present, researchers have developed various “all-in-one” nanoplatforms for cancer imaging and PTT/PDT combinational therapy. However, the complex structure, tedious preparation procedures, overuse [...] Read more.
Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT) has attracted growing attention as a noninvasive option for cancer treatment. At present, researchers have developed various “all-in-one” nanoplatforms for cancer imaging and PTT/PDT combinational therapy. However, the complex structure, tedious preparation procedures, overuse of extra carriers and severe side effects hinder their biomedical applications. In this work, we reported a nanoplatform (designated as ICG-MB) self-assembly from two different FDA-approved dyes of indocyanine green (ICG) and methylene blue (MB) without any additional excipients for cancer fluorescence imaging and combinational PTT/PDT. ICG-MB was found to exhibit good dispersion in the aqueous phase and improve the photostability and cellular uptake of free ICG and MB, thus exhibiting enhanced photothermal conversion and singlet oxygen (1O2) generation abilities to robustly ablate cancer cells under 808 nm and 670 nm laser irradiation. After intravenous injection, ICG-MB effectively accumulated at tumor sites with a near-infrared (NIR) fluorescence signal, which helped to delineate the targeted area for NIR laser-triggered phototoxicity. As a consequence, ICG-MB displayed a combinational PTT/PDT effect to potently inhibit tumor growth without causing any system toxicities in vivo. In conclusion, this minimalist, effective and biocompatible nanotheranostic would provide a promising candidate for cancer phototherapy based on current available dyes in clinic. Full article
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17 pages, 3644 KiB  
Article
Extracellular Vesicles from M1-Polarized Macrophages Combined with Hyaluronic Acid and a β-Blocker Potentiate Doxorubicin’s Antitumor Activity by Downregulating Tumor-Associated Macrophages in Breast Cancer
Pharmaceutics 2022, 14(5), 1068; https://doi.org/10.3390/pharmaceutics14051068 - 17 May 2022
Cited by 9 | Viewed by 2702
Abstract
One of the main reasons for cancer’s low clinical response to chemotherapeutics is the highly immunosuppressive tumor microenvironment (TME). Tumor-ass ociated M2 macrophages (M2-TAMs) orchestrate the immunosuppression, which favors tumor progression. Extracellular vesicles (EVs) have shown great potential for targeted therapies as, depending [...] Read more.
One of the main reasons for cancer’s low clinical response to chemotherapeutics is the highly immunosuppressive tumor microenvironment (TME). Tumor-ass ociated M2 macrophages (M2-TAMs) orchestrate the immunosuppression, which favors tumor progression. Extracellular vesicles (EVs) have shown great potential for targeted therapies as, depending on their biological origin, they can present different therapeutic properties, such as enhanced accumulation in the target tissue or modulation of the immune system. In the current study, EVs were isolated from M1-macrophages (M1-EVs) pre-treated with hyaluronic acid (HA) and the β-blocker carvedilol (CV). The resulting modulated-M1 EVs (MM1-EVs) were further loaded with doxorubicin (MM1-DOX) to assess their effect in a mouse model of metastatic tumor growth. The cell death and cell migration profile were evaluated in vitro in 4T1 cells. The polarization of the RAW 264.7 murine macrophage cell line was also analyzed to evaluate the effects on the TME. Tumors were investigated by qRT-PCR and immunohistochemistry. MM1-DOX reduced the primary tumor size and metastases. NF-κB was the major gene downregulated by MM1-DOX. Furthermore, MM1-DOX reduced the expression of M2-TAM (CD-163) in tumors, which resulted in increased apoptosis (FADD) as well as decreased expression of MMP-2 and TGF-β. These results suggest a direct effect in tumors and an upregulation in the TME immunomodulation, which corroborate with our in vitro data that showed increased apoptosis, modulation of macrophage polarization, and reduced cell migration after treatment with M1-EVs combined with HA and CV. Our results indicate that the M1-EVs enhanced the antitumor effects of DOX, especially if combined with HA and CV in an animal model of metastatic cancer. Full article
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Review

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24 pages, 3970 KiB  
Review
Cationic Polymers as Transfection Reagents for Nucleic Acid Delivery
Pharmaceutics 2023, 15(5), 1502; https://doi.org/10.3390/pharmaceutics15051502 - 15 May 2023
Cited by 18 | Viewed by 2533
Abstract
Nucleic acid therapy can achieve lasting and even curative effects through gene augmentation, gene suppression, and genome editing. However, it is difficult for naked nucleic acid molecules to enter cells. As a result, the key to nucleic acid therapy is the introduction of [...] Read more.
Nucleic acid therapy can achieve lasting and even curative effects through gene augmentation, gene suppression, and genome editing. However, it is difficult for naked nucleic acid molecules to enter cells. As a result, the key to nucleic acid therapy is the introduction of nucleic acid molecules into cells. Cationic polymers are non-viral nucleic acid delivery systems with positively charged groups on their molecules that concentrate nucleic acid molecules to form nanoparticles, which help nucleic acids cross barriers to express proteins in cells or inhibit target gene expression. Cationic polymers are easy to synthesize, modify, and structurally control, making them a promising class of nucleic acid delivery systems. In this manuscript, we describe several representative cationic polymers, especially biodegradable cationic polymers, and provide an outlook on cationic polymers as nucleic acid delivery vehicles. Full article
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18 pages, 6664 KiB  
Review
Chiral Biomaterials for Nanomedicines: From Molecules to Supraparticles
Pharmaceutics 2022, 14(9), 1951; https://doi.org/10.3390/pharmaceutics14091951 - 15 Sep 2022
Cited by 5 | Viewed by 2025
Abstract
Chirality, the property whereby an object or a system cannot be superimposed on its mirror image, prevails amongst nature over various scales. Especially in biology, numerous chiral building blocks and chiral-specific interactions are involved in many essential biological activities. Despite the prevalence of [...] Read more.
Chirality, the property whereby an object or a system cannot be superimposed on its mirror image, prevails amongst nature over various scales. Especially in biology, numerous chiral building blocks and chiral-specific interactions are involved in many essential biological activities. Despite the prevalence of chirality in nature, it has been no longer than 70 years since the mechanisms of chiral-specific interactions drew scientific attention and began to be studied. Owing to the advent of chiral-sensitive equipment such as circular dichroism spectrometers or chiral liquid columns for chromatography, it has recently been possible to achieve a deeper understanding of the chiral-specific interactions and consequential impacts on the functionality and efficiency of nanomedicine. From this point of view, it is worthwhile to examine previously reported chiral biomaterials with their compositions and possible applications to achieve new paradigms of biomaterials. This review discusses chiral materials on various scales and their biological applications. Full article
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18 pages, 1138 KiB  
Review
Nanocarrier-Based Targeted Therapies for Myocardial Infarction
Pharmaceutics 2022, 14(5), 930; https://doi.org/10.3390/pharmaceutics14050930 - 25 Apr 2022
Cited by 14 | Viewed by 3000
Abstract
Myocardial infarction is a major cause of morbidity and mortality worldwide. Due to poor inherent regeneration of the adult mammalian myocardium and challenges with effective drug delivery, there has been little progress in regenerative therapies. Nanocarriers, including liposomes, nanoparticles, and exosomes, offer many [...] Read more.
Myocardial infarction is a major cause of morbidity and mortality worldwide. Due to poor inherent regeneration of the adult mammalian myocardium and challenges with effective drug delivery, there has been little progress in regenerative therapies. Nanocarriers, including liposomes, nanoparticles, and exosomes, offer many potential advantages for the therapy of myocardial infarction, including improved delivery, retention, and prolonged activity of therapeutics. However, there are many challenges that have prevented the widespread clinical use of these technologies. This review aims to summarize significant principles and developments in the field, with a focus on nanocarriers using ligand-based or cell mimicry-based targeting. Lastly, a discussion of limitations and potential future direction is provided. Full article
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