25 research outputs found
Editorial: Synthesis, Functionalization, and Clinical Translation of Pharmaceutical Biomaterials
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Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure
Highlights
This review focuses on the therapeutic mechanisms, targeting strategies of various nanomaterials in acute liver failure, and recent advances of diverse nanomaterials for acute liver failure therapy, diagnosis, and imaging.
This review provides an outlook on the applications of nanomaterials, especially on the new horizons in acute liver failure therapy, and inspires broader interests across various disciplines.
Acute liver failure (ALF), a fatal clinical disease featured with overwhelming hepatocyte necrosis, is a grand challenge in global health. However, a satisfactory therapeutic option for curing ALF is still absent, other than liver transplantation. Nanobiomaterials are currently being developed for the diagnosis and treatment of ALF. The liver can sequester most of nanoparticles from blood circulation, which becomes an intrinsic superiority for nanobiomaterials targeting hepatic diseases. Nanobiomaterials can enhance the bioavailability of free drugs, thereby significantly improving the therapeutic effects in ALF. Nanobiomaterials can also increase the liver accumulation of therapeutic agents and enable more effective targeting of the liver or specific liver cells. In addition, stimuli-responsive, optical, or magnetic nanomaterials exhibit great potential in the therapeutical, diagnostic, and imaging applications in ALF. Therefore, therapeutic agents in combination with nanobiomaterials increase the specificity of ALF therapy, diminish adverse systemic effects, and offer a multifunctional theranostic platform. Nanobiomaterial holds excellent significance and prospects in ALF theranostics. In this review, we summarize the therapeutic mechanisms and targeting strategies of various nanobiomaterials in ALF. We highlight recent developments of diverse nanomedicines for ALF therapy, diagnosis, and imaging. Furthermore, the challenges and future perspectives in the theranostics of ALF are also discussed
Age at menarche and risk of major cardiovascular diseases: Evidence of birth cohort effects from a prospective study of 300,000 Chinese women
AbstractBackgroundPrevious studies of mostly Western women have reported inconsistent findings on the association between age at menarche and risk of cardiovascular disease (CVD). Little is known about the association in China where there has been a large intergenerational decrease in women's mean age at menarche.MethodsThe China Kadoorie Biobank recruited 302,632 women aged 30–79 (mean 50.5)years in 2004–8 from 10 diverse regional sites across China. During 7years follow-up, 14,111 incident cases of stroke, 14,093 of coronary heart disease (CHD), and 3200 CVD deaths were reported among 281,491 women who had no prior history of CVD at baseline. Cox regression yielded adjusted hazard ratios (HRs) relating age at menarche to CVD risks.ResultsThe mean (SD) age of menarche was 15.4 (1.9)years, decreasing from 16.2 (2.0) among women born before 1940 to 14.7 (1.6) for those born during the 1960s–1970s. The patterns of association between age at menarche and CVD risk appeared to differ between different birth cohorts, with null associations in older generations but U-shaped or weak positive associations in younger women, especially those born after the 1960s. After minimizing the potential confounding effects from major CVD risk factors, both early and late menarche, compared with menarche at age 13years, were associated with increased risk of CVD morbidity and mortality, which was more pronounced in younger generations.ConclusionAmong Chinese women the associations between age at menarche and risk of CVD differed by birth cohort, suggesting other factors may underpin the association
Vitamin D and cause-specific vascular disease and mortality:a Mendelian randomisation study involving 99,012 Chinese and 106,911 European adults
Synergistic treatment of triple-negative breast cancer by doxorubicin and thioridazine and its nano-formulation
Photodynamic therapy-triggered on-demand drug release from ROS-responsive core-cross-linked micelles toward synergistic anti-cancer treatment
Polymeric micelles have demonstrated wide utility for chemodrug delivery, which however, still suffer from shortcomings such as undesired drug loading, disassembly upon dilution, pre-leakage of drug cargoes during systemic circulation, and lack of cancer-selective drug release. Herein, a poly(ethylene glycol) (PEG)-polyphosphoester-based, reactive oxygen species (ROS)-responsive, core-cross-linked (CCL) micellar system was developed to encapsulate both chemodrug (doxorubicin, Dox) and photosensitizer (chlorin e6, Ce6). The hydrophobic core of the micelles was cross-linked via a thioketal (TK)-containing linker, which notably enhanced the drug loading and micelle stability. In tumor cells, far-red light irradiation of Ce6 generated ROS to cleave the TK linkers and disrupt the micelle cores. As such, micelles were destabilized and Dox release was promoted, which thereafter imparted synergistic anti-cancer effect with ROS-mediated photodynamic therapy. This study provides an effective approach to realize the precise control over drug loading, formulation stability, and cancer-selective drug release using polymeric micelles, and would render promising utilities for the programmed anti-cancer combination therapy
Engineering the Aromaticity of Cationic Helical Polypeptides toward “Self-Activated” DNA/siRNA Delivery
The development of
potent yet nontoxic membrane-penetrating materials is in high demand
for effective intracellular gene delivery. We have recently developed
α-helical polypeptides which afford potent membrane activities
to facilitate intracellular DNA delivery via both endocytosis and
the nonendocytic “pore formation” mechanism. Endocytosis
will cause endosomal entrapment of the DNA cargo, while excessive
“pore formation” would cause appreciable cytotoxicity.
Additionally, helical polypeptides with stiff, rodlike structure suffer
from low siRNA binding affinity. To address such critical issues,
we herein incorporated various aromatic domains (benzyl, naphthyl,
biphenyl, anthryl, and pyrenyl) into the side-chain terminals of guanidine-rich,
helical polypeptides, wherein the flat-rigid shape, π-electronic
structures of aromatic motifs “self-activated” the membrane-penetrating
capabilities of polypeptides to promote intracellular gene delivery.
Benzyl (Bn)- and naphthyl (Naph)-modified polypeptides demonstrated
the highest DNA uptake level that outperformed the unmodified polypeptide,
P2, by ∼4 fold. More importantly, compared with P2, Bn- and
Naph-modified polypeptides allowed more DNA cargos to be internalized
via the nonendocytic pathway, which significantly bypassed the endosomal
entrapment and accordingly enhanced the transfection efficiency by
up to 42 fold, outperforming PEI 25k as the commercial reagent by
3–4 orders of magnitude. The aromatic modification also improved
the siRNA condensation capability of polypeptides, achieving notably
enhanced gene-silencing efficiency against tumor necrosis factor-α
to treat acute hepatic inflammation. Furthermore, we revealed that
aromaticity-augmented membrane activity was accompanied by comparable
or even significantly reduced “pore formation” capability,
thus leading to diminished cytotoxicity at high concentrations. This
study therefore provides a promising approach to manipulate the membrane
activities and penetration mechanisms of polycations, which overcomes
the multiple critical barriers preventing effective and safe gene
delivery
High Drug Loading and Sub-Quantitative Loading Efficiency of Polymeric Micelles Driven by Donor–Receptor Coordination Interactions
Polymeric micelles
are extensively used for the delivery of hydrophobic
drugs, which, however, suffer from unsatisfactory drug loading, colloidal
uniformity, formulation stability, and drug release. Herein, we demonstrate
a convenient strategy to prepare micelles with ultrahigh drug loading
via the incorporation of polymer–drug coordination interactions.
An amphiphilic copolymer containing pendant phenylboronic acid as
electron acceptor unit was synthesized, which afforded donor–acceptor
coordination with doxorubicin to obtain micelles with ultrahigh drug
loading (∼50%), nearly quantitative loading efficiency (>95%),
uniform size, and colloidal stability. Besides, the encapsulated drug
can be effectively and selectively released in response to the high
reactive oxygen species levels in cancer cells, which potentiated
the anticancer efficacy and reduced systemic toxicity. Apart from
doxorubicin, the current platform could be extended to other drugs
with electron-donating groups (e.g., epirubicin and irinotecan), rendering
a simple and robust strategy for enabling high drug loading in polymeric
micelles and cancer-specific drug release
Nanoscaled Poly(l‑glutamic acid)/Doxorubicin-Amphiphile Complex as pH-responsive Drug Delivery System for Effective Treatment of Nonsmall Cell Lung Cancer
Nonsmall cell lung cancer (NSCLC)
is the leading cause of cancer-related death worldwide. Herein, we
develop a polypeptide-based block ionomer complex formed by anionic
methoxy poly(ethylene glycol)-<i>b</i>-poly(l-glutamic
acid) (mPEG-<i>b</i>-PLG) and cationic anticancer drug doxorubicin
hydrochloride (DOX·HCl) for NSCLC treatment. This complex spontaneously
self-assembled into spherical nanoparticles (NPs) in aqueous solutions
via electrostatic interaction and hydrophobic stack, with a high loading
efficiency (almost 100%) and negative surface charge. DOX·HCl
release from the drug-loaded micellar nanoparticles (mPEG-<i>b</i>-PLG-DOX·HCl) was slow at physiological pH, but obviously
increased at the acidic pH mimicking the endosomal/lysosomal environment.
In vitro cytotoxicity and hemolysis assays demonstrated that the block
copolypeptide was cytocompatible and hemocompatible, and the presence
of copolypeptide carrier could reduce the hemolysis ratio of DOX·HCl
significantly. Cellular uptake and cytotoxicity studies suggested
that mPEG-<i>b</i>-PLG-DOX·HCl was taken up by A549
cells via endocytosis, with a slightly slower cellular internalization
and lower cytotoxicity compared with free DOX·HCl. The pharmacokinetics
study in rats showed that DOX·HCl-loaded micellar NPs significantly
prolonged the blood circulation time. Moreover, mPEG-<i>b</i>-PLG-DOX·HCl exhibited enhanced therapeutic efficacy, increased
apoptosis in tumor tissues, and reduced systemic toxicity in nude
mice bearing A549 lung cancer xenograft compared with free DOX·HCl,
which were further confirmed by histological and immunohistochemical
analyses. The results demonstrated that mPEG-<i>b</i>-PLG
was a promising vector to deliver DOX·HCl into tumors and achieve
improved pharmacokinetics, biodistribution and efficacy of DOX·HCl
with reduced toxicity. These features strongly supported the interest
of developing mPEG-<i>b</i>-PLG-DOX·HCl as a valid
therapeutic modality in the therapy of human NSCLC and other solid
tumors