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The concept of nanoparticle transport through gaps between endothelial cells (inter-endothelial gaps) in the tumour blood vessel is a central paradigm in cancer nanomedicine. The size of these gaps was found to be up to 2,000 nm. This justified the development of nanoparticles to treat solid tumours as their size is small enough to extravasate and access the tumour microenvironment. Here we show that these inter-endothelial gaps are not responsible for the transport of nanoparticles into solid tumours. Instead, we found that up to 97% of nanoparticles enter tumours using an active process through endothelial cells. This result is derived from analysis of four different mouse models, three different types of human tumours, mathematical simulation and modelling, and two different types of imaging techniques. These results challenge our current rationale for developing cancer nanomedicine and suggest that understanding these active pathways will unlock strategies to enhance tumour accumulation. The dominant mechanism of nanoparticle entry into solid tumours has now been shown to be an active trans-endothelial pathway rather than the currently established passive transport via inter-endothelial gaps.

Metastasis of solid tumors is a key determinant of cancer patient survival. Targeting micrometastases using nanoparticles could offer a way to stop metastatic tumor growth before it causes excessive patient morbidity. However, nanoparticle delivery to micrometastases is difficult to investigate because micrometastases are small in size and lie deep within tissues. Here, we developed an imaging and image analysis workflow to analyze nanoparticle–cell interactions in metastatic tumors. This technique combines tissue clearing and 3D microscopy with machine learning-based image analysis to assess the physiology of micrometastases with single-cell resolution and quantify the delivery of nanoparticles within them. We show that nanoparticles access a higher proportion of cells in micrometastases (50% nanoparticle-positive cells) compared with primary tumors (17% nanoparticle-positive cells) because they reside close to blood vessels and require a small diffusion distance to reach all tumor cells. Furthermore, the high-throughput nature of our image analysis workflow allowed us to profile the physiology and nanoparticle delivery of 1,301 micrometastases. This enabled us to use machine learning-based modeling to predict nanoparticle delivery to individual micrometastases based on their physiology. Our imaging method allows researchers to measure nanoparticle delivery to micrometastases and highlights an opportunity to target micrometastases with nanoparticles. The development of models to predict nanoparticle delivery based on micrometastasis physiology could enable personalized treatments based on the specific physiology of a patient’s micrometastases.

Cancer nanomedicine offers promising characteristics such as protecting small molecules from early degradation, reducing systemic toxicity and prolonging blood circulation to increase drug accumulation in the tumour. The majority of clinically-approved anti-cancer nanomedicines are lipid-based nanoparticles. Studies have used animal survival graphs and tumour growth curves to identify potential candidates, but it is not obvious which cells within the tumour microenvironment contribute towards their therapeutic effect. The incomplete understanding of lipid nanoparticle behaviour at the cellular-level may have contributed towards the limited number of nanotherapeutic translations into the clinic. In my thesis, I focus on two aspects of nano-bio interaction to better understand how liposomes interact within the tumour microenvironment. First, I conducted an in-depth investigation into how a therapeutic lipid nanoparticle affects the cytodistribution within the tumour microenvironment. This revealed intrinsic properties unique to lipid nanoparticles and the cell types it predominantly impacted. Flow cytometry revealed that Doxil, a liposomal formulation of Doxorubicin, preferentially killed cancer cells, macrophages and neutrophils within a breast cancer tumour model. Immunofluorescent imaging of apoptotic cells, pharmacokinetic study and uptake and cell viability experiments further supported the findings to explain the delay exhibited by Doxil-treated tumours. By identifying cells predominantly killed by Doxil, we can better explain how and why liposomes uniquely cause a tumour growth delay and may guide the design of future nanocarriers against those predominant cell types and prolong the therapeutic effect. Second, I developed a simple tag for the three-dimensional (3D) mapping of liposomes in intact tissues. Prior to this tag, it was not possible to image liposomes in optically-cleared tissues because the typical processing step of rendering tissues transparent removed lipids. This will provide a means to visualize where liposomes distribute, how stable they are and how fast they degrade in vivo within a tumour using 3D imaging. Knowledge established from this thesis has the potential to optimize the design and selection of future formulations to obtain a longer and more responsive therapeutic effect.

Lumbar disc herniation is a common cause for lower back pain and reason for spinal surgery. Inevitably, patients will feel acute post-operative pain following surgery, thus local analgesics are given to patients after the surgery to alleviate pain. Existing drug delivery methods are limited by large doses, quick clearance rate from the injury site, short pain-relief period and multiple injections. As a result, there is an unmet need for a local, controlled and sustained drug delivery system following spine surgery. We propose to investigate a novel biomaterial to prolong the delivery of drugs to the local injury site. The drug-loaded hydrogel was characterized in terms of its release profile (where different factors were considered to prolong the release of the drug), storage modulus and swelling ratio. Behavioural tests and a pharmacokinetic study were conducted to determine the effects of the drug-loaded hydrogel in vivo.

AbstractAlthough researchers widely use the Parental Bonding Instrument (PBI) to measure parenting behaviour in terms of parental care and overprotection, its development using Western samples has cast doubt on its applicability among non-Western ones. In response, we examined psychometric properties of the Chinese version of the PBI by using survey data collected from a sample of 1997 Chinese adolescents in Hong Kong, whose mean age was 14.6 years and 50.3% of whom were girls. Our results supported a 4-factor structure representing caring, indifferent, overprotective, and autonomous parenting behaviours that we confirmed to be applicable to paternal and maternal parenting behaviours. Results of Cronbach’s alpha tests indicated that the measure is of good reliability, and correlations between the PBI and character strengths confirmed the scale’s good concurrent validity. Parental care and autonomy positively correlated with bravery, honesty, perseverance, kindness, love, self-regulation, social intelligence, and fairness, whereas indifference and overprotection negatively correlated with those eight character strengths. Parenting differences emerged regarding parental and children’s gender. In all, the Chinese version of the PBI proved to be a psychometrically robust measure for capturing adolescents’ perceptions of parenting behaviours in Hong Kong, which we discuss in terms of implications for future research.

There is concern that the time taken to publish academic papers in microbiological science has significantly increased in recent years. While the data do not specifically support this, evidence suggests that editors are having to invite more and more reviewers to identify those willing to perform peer review.

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) signals an urgent need for an expansion in treatment options. In this study, we investigated the anti-SARS-CoV-2 activities of 22 antiviral agents with known broad-spectrum antiviral activities against coronaviruses and/or other viruses. They were first evaluated in our primary screening in VeroE6 cells and then the most potent anti-SARS-CoV-2 antiviral agents were further evaluated using viral antigen expression, viral load reduction, and plaque reduction assays. In addition to remdesivir, lopinavir, and chloroquine, our primary screening additionally identified types I and II recombinant interferons, 25-hydroxycholesterol, and AM580 as the most potent anti-SARS-CoV-2 agents among the 22 antiviral agents. Betaferon (interferon-β1b) exhibited the most potent anti-SARS-CoV-2 activity in viral antigen expression, viral load reduction, and plaque reduction assays among the recombinant interferons. The lipogenesis modulators 25-hydroxycholesterol and AM580 exhibited EC50 at low micromolar levels and selectivity indices of >10.0. Combinational use of these host-based antiviral agents with virus-based antivirals to target different processes of the SARS-CoV-2 replication cycle should be evaluated in animal models and/or clinical trials.

We obtained 24 air samples in 8 general wards temporarily converted into negative-pressure wards admitting coronavirus disease 2019 (COVID-19) patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant BA.2.2 in Hong Kong. SARS-CoV-2 RNA was detected in 19 (79.2%) of 24 samples despite enhanced indoor air dilution. It is difficult to prevent airborne transmission of SARS-CoV-2 in hospitals.