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Design of Polymeric Gene Carriers for Effective Intracellular Delivery
Polymeric carriers have emerged as major non-viral alternatives for gene delivery due to their lower immunogenicity and pathogenicity. However, during intracellular delivery of these carriers, multiple barriers have to be overcome or the efficiency of gene delivery will be impeded. A thorough understanding of these cellular impediments is pivotal to optimizing the efficiency of polymer-based gene delivery. This review delineates the major barriers encountered during intracellular delivery of polyplexes and discusses possible molecular designs to overcome these barriers. Based on a review of the latest strategies to enhance the intracellular delivery process, we provide insights into the further development of polymeric carriers with enhanced efficiency in transfection.
Use of polymers as alternatives to viral vectors imposes fewer safety concerns and enables larger payloads to be carried.
Cellular internalization, endosomal escape, and nuclear translocation are three major barriers to intracellular gene delivery mediated by polymeric carriers.
The performance of polymeric carriers can be improved by both chemical and engineering strategies.
The incorporation of optically active agents into carrier design enables spatiotemporal control of transgene expression.
Journal Article
Biomimetic Anti‐PD‐1 Peptide‐Loaded 2D FePSe3 Nanosheets for Efficient Photothermal and Enhanced Immune Therapy with Multimodal MR/PA/Thermal Imaging
Metal phosphorous trichalcogenides (MPX3) are novel 2D nanomaterials that have recently been exploited as efficient photothermal–chemodynamic agents for cancer therapy. As a representative MPX3, FePSe3 has the potential to be developed as magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) agents due to the composition of Fe and the previously revealed PA signal. Here, a FePSe3‐based theranostic agent, FePSe3@APP@CCM, loaded with anti‐PD‐1 peptide (APP) as the inner component and CT26 cancer cell membrane (CCM) as the outer shell is reported, which acts as a multifunctional agent for MR and PA imaging and photothermal and immunotherapy against cancer. FePSe3@APP@CCM induces highly efficient tumor ablation and suppresses tumor growth by photothermal therapy under near‐infrared laser excitation, which further activates immune responses. Moreover, APP blocks the PD‐1/PD‐L1 pathway to activate cytotoxic T cells, causing strong anticancer immunity. The combined therapy significantly prolongs the lifespan of experimental mice. The multimodal imaging and synergistic therapeutic effects of PTT and its triggered immune responses and APP‐related immunotherapy are clearly demonstrated by in vitro and in vivo experiments. This work demonstrates the potential of MPX3‐based biomaterials as novel theranostic agents. In this work, it is shown that the novel biomimetic nanosystem FePSe3@APP@CCM can be used for magnetic resonance/photoacoustic imaging‐guided synergistic anticancer photothermal therapy (PTT) and immunotherapy. The nanosheets (NSs) are decorated with cancer cell membranes and show immune escape and homologous targeting abilities. Under near‐infrared laser irradiation, these NSs provide direct PTT and multiple immunotherapies.
Journal Article
Chiral transcription in self-assembled tetrahedral Eu4L6 chiral cages displaying sizable circularly polarized luminescence
Predictable stereoselective formation of supramolecular assembly is generally believed to be an important but complicated process. Here, we show that point chirality of a ligand decisively influences its supramolecular assembly behavior. We designed three closely related chiral ligands with different point chiralities, and observe their self-assembly into europium (Eu) tetrametallic tetrahedral cages. One ligand exhibits a highly diastereoselective assembly into homochiral (either ΔΔΔΔ or ΛΛΛΛ) Eu tetrahedral cages whereas the two other ligands, with two different approaches of loosened point chirality, lead to a significant breakdown of the diastereoselectivity to generate a mixture of (ΔΔΔΔ and ΛΛΛΛ) isomers. The cages are highly emissive (luminescence quantum yields of 16(1) to 18(1)%) and exhibit impressive circularly polarized luminescence properties (|
g
lum
|: up to 0.16). With in-depth studies, we present an example that correlates the nonlinear enhancement of the chiroptical response to the nonlinearity dependence on point chirality.
Controlling the chirality of self-assembled polyhedra is a synthetic challenge. Here, the authors stereoselectively form emissive lanthanide tetrahedral cages from a series of chiral ligands, and use their circularly polarized luminescence to explore the effect of ligand point chirality on supramolecular architecture.
Journal Article
Scalable synthesis enabling multilevel bio-evaluations of natural products for discovery of lead compounds
Challenges in the development of anti-cancer chemotherapeutics continue to exist, particularly with respect to adverse effects and development of resistance, underlining the need for novel drugs with good safety profiles. Natural products have proven to be a fertile ground for exploitation, and development of anti-cancer drugs from structurally complex natural products holds promise. Unfortunately, this approach is often hindered by low isolation yields and limited information from preliminary cell-based assays. Here we report a concise and scalable synthesis of a series of low-abundance
Isodon
diterpenoids (a large class of natural products with over 1000 members isolated from the herbs of genus
Isodon
, which are well-known folk medicines for the treatment of inflammation and cancer), including eriocalyxin B, neolaxiflorin L and xerophilusin I. These scalable syntheses enable multilevel bio-evaluation of the natural products, in which we identify neolaxiflorin L as a promising anti-cancer drug candidate.
Isodon
diterpenoids, promising anti-cancer agents found in certain tropical plants, are difficult to obtain. Here, the authors developed a synthetic strategy to synthesise several different members of this group, including neolaxiflorin L which emerged from this study as a promising drug candidate.
Journal Article
Sustainability of Green Tourism among International Tourists and Its Influence on the Achievement of Green Environment: Evidence from North Cyprus
Sustainability of green tourism is gaining more attention from different stakeholders due to its environmental benefits. However, empirical studies on the behavioral aspect of the tourists towards sustainability of green tourism and its influence on the achievement of the green environment have not been exhaustively researched, most especially in a small island state like North Cyprus. In this paper, we investigate the behavioral aspects of international tourists towards the sustainability of green tourism employing an extended framework of the theory of planned behavior (TPB). A sample of 395 questionnaires was administered to the tourists that lodged at the 20 randomly selected five-star hotels in North Cyprus, while the study model was examined through structural equation modelling (SEM). Our study findings indicated that tourists’ perceptions of the sustainability of green tourism and their environmental concerns had a significantly positive impact on their attitudes. In addition, our results revealed that subjective norms had a significantly negative impact on intentions of the tourists to participate in sustainability of green tourism, while attitude was found to have a significantly positive impact on the tourists’ intentions to participate in the sustainability of green tourism. Moreover, we found that both environmental concerns and the intention of the tourists to participate in the sustainability of green tourism had a significantly positive impact on environmentally responsible tourism behavior. Lastly, our study contributes to enhancing the understanding of the perception of tourists on the green environment as it affects their behavior and subsequent influence on their intention to participate in the sustainability of green tourism with the attendant impact on the achievement of environmental degradation reduction.
Journal Article
AAV5–Factor VIII Gene Transfer in Severe Hemophilia A
An AAV5 vector with a functional factor VIII gene was tested in men with hemophilia A. Men receiving the high dose had a factor VIII level above 5 IU per deciliter at 1 year; most had a normal level. Toxic effects were minimal, and bleeding episodes nearly eliminated.
Journal Article
Progress and trends in the development of therapies for Hutchinson–Gilford progeria syndrome
Hutchinson–Gilford progeria syndrome (HGPS) is an autosomal‐dominant genetic disease that leads to accelerated aging and often premature death caused by cardiovascular complications. Till now clinical management of HGPS has largely relied on the treatment of manifestations and on the prevention of secondary complications, cure for the disease has not yet been established. Addressing this need cannot only benefit progeria patients but may also provide insights into intervention design for combating physiological aging. By using the systematic review approach, this article revisits the overall progress in the development of strategies for HGPS treatment over the last ten years, from 2010 to 2019. In total, 1,906 articles have been retrieved, of which 56 studies have been included for further analysis. Based on the articles analyzed, the trends in the use of different HGPS models, along with the prevalence, efficiency, and limitations of different reported treatment strategies, have been examined. Emerging strategies for preclinical studies, and possible targets for intervention development, have also been presented as avenues for future research. Hutchinson–Gilford progeria syndrome is an autosomal‐dominant genetic disease which has no cure right now. Development of therapies has clinical importance and may provide a window into the mechanism and treatment of physiological aging.
Journal Article
Deterministic evolution and stringent selection during preneoplasia
The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention
1
. Here we model occult preneoplasia by biallelic inactivation of
TP53
, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years.
TP53
loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of
TP53-
deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours.
We model occult preneoplasia by biallelic inactivation of
TP53
, a common early event in gastric cancer, in human gastric organoids, the results implying predictability in the earliest stages of tumorigenesis.
Journal Article
Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A
In 15 participants with hemophilia A treated with a single infusion of AAV5 vector containing the factor VIII gene, 7 who received 6×10
13
vector genomes per kilogram had a median factor VIII level of 20 IU per deciliter, and 6 who received 4×10
13
vg per kilogram had a median level of 13 IU per deciliter. Factor VIII levels decreased in years 2 and 3 of follow-up, but the median annualized rate of bleeding events among these 13 participants remained zero.
Journal Article