Physical stimuli-responsive vesicles in drug delivery: Beyond liposomes and polymersomes

Over the past few decades, a range of vesicle-based drug delivery systems have entered clinical practice and several others are in various stages of clinical translation. While most of these vesicle constructs are lipid-based (liposomes), or polymer-based (polymersomes), recently new classes of vesicles have emerged that defy easy classification. Examples include assemblies with small molecule amphiphiles, biologically derived membranes, hybrid vesicles with two or more classes of amphiphiles, or more complex hierarchical structures such as vesicles incorporating gas bubbles or nanoparticulates in the lumen or membrane. In this review, we explore these recent advances and emerging trends at the edge and just beyond the research fields of conventional liposomes and polymersomes. A focus of this review is the distinct behaviors observed for these classes of vesicles when exposed to physical stimuli - such as ultrasound, heat, light and mechanical triggers - and we discuss the resulting potential for new types of drug delivery, with a special emphasis on current challenges and opportunities

Advanced Rose Bengal Delivery Systems for the local and systemic management of cancer.

Rose Bengal is a promising anticancer agent with proven cytotoxicity against several cell lines. Still, its high water solubility and poor lipophilic tendency hinder its therapeutic efficiency. Thus, the current PhD thesis focused on the project, development and characterisation of advanced Rose Bengal delivery systems for local and systemic cancer therapy. Rose Bengal was mainly investigated to manage melanoma cancer following skin administration routes. Rose Bengal was formulated in liposome-like vesicles, and their permeation through the skin was enhanced by the mean of the microneedle technique. Lastly, Rose Bengal was included in a 3D-printed implantable device to provide a long-term delivery for in situ cancer therapyRose Bengal is a promising anticancer agent with proven cytotoxicity against several cell lines. Still, its high water solubility and poor lipophilic tendency hinder its therapeutic efficiency. Thus, the current PhD thesis focused on the project, development and characterisation of advanced Rose Bengal delivery systems for local and systemic cancer therapy. Rose Bengal was mainly investigated to manage melanoma cancer following skin administration routes. Rose Bengal was formulated in liposome-like vesicles, and their permeation through the skin was enhanced by the mean of the microneedle technique. Lastly, Rose Bengal was included in a 3D-printed implantable device to provide a long-term delivery for in situ cancer therapy

Microneedles for painless transdermal immunotherapeutic applications

Immunotherapy has recently garnered plenty of attention to improve the clinical outcomes in the treatment of various diseases. However, owing to the dynamic nature of the immune system, this approach has often been challenged by concerns regarding the lack of adequate long-term responses in patients. The development of microneedles (MNs) has resulted in the improvement and expansion of immuno-reprogramming strategies due to the housing of high accumulation of dendritic cells, macrophages, lymphocytes, and mast cells in the dermis layer of the skin. In addition, MNs possess many outstanding properties, such as the ability for the painless traverse of the stratum corneum, minimal invasiveness, facile fabrication, excellent biocompatibility, convenient administration, and bypassing the first pass metabolism that allows direct translocation of therapeutics into the systematic circulation. These advantages make MNs excellent candidates for the delivery of immunological biomolecules to the dermal antigen-presenting cells in the skin with the aim of vaccinating or treating different diseases, such as cancer and autoimmune disorders, with minimal invasiveness and side effects. This review discusses the recent advances in engineered MNs and tackles limitations relevant to traditional immunotherapy of various hard-to-treat diseases.Peer reviewe

Hybrid antibacterial microneedle patches against skin infections

Skin and soft tissue infections (SSTIs) are a major healthcare burden that has increased in incidence since the beginning of the 21st century resulting in an annual spending of approximately 15 b$ in 2012 in the United States (US).1 Treatment of SSTIs is complex and typically involves the administration of antibiotics. However, the antibiotic therapy of SSTIs has multiple obstacles interfering with an efficient treatment outcome such as (i) limited local antibiotic penetration into the skin and (ii) rising antibiotic resistant SSTIs. The limitation of local drug penetration is associated with the route of administration. On the one hand, antibiotics can be given topically; however, the protective function of the skin limits the types of drugs that can efficiently be given via this route. On the other hand, systemic administration of the antibiotic parenterally or intravenously (IV) shows low local skin absorption while suffering from side effects associated with the systemic exposure of the body to the antibiotic. Furthermore, the rise in antibiotic resistance urgently calls for the development of novel antibacterial treatment options to optimize the antibacterial effect of current antibiotics and reduce further resistance development. A potential to improve the antibacterial effect of antibiotics is through multimodal therapies and as such the incorporation of heat from photothermal therapy (PTT) has been reported as a promising avenue to improve antibiotic efficiency. In the scope of this thesis, microneedle (MN) arrays were developed to address the problems faced in the treatment of bacterial SSTIs. In the first part of this thesis, dissolvable MN arrays loaded with the antibiotic vancomycin (VAN) were developed and tested in ex vivo porcine infection models of methicillin-resistant Staphylococcus aureus (MRSA), a strain commonly found in SSTIs. The MN arrays allowed the delivery of high concentrations of VAN locally in the skin where it remained active to inhibit the growth of MRSA after only two applications for 10 minutes. The second part of this thesis describes the development of photothermal MN arrays with plasmonic Au/SiO2 and Ag/SiO2 nanoaggregates. Four different fabrication methods following traditional mold-and-casting methods using Au/SiO2 revealed that the rational selection of the fabrication method allows for a control over the MN morphology, photothermal effect, and a reduction of nanoparticle (NP) deposition into the skin. Additionally, Ag/SiO2 nanoaggregates were employed in nanocomposites of ultraviolet (UV)-curable resin to be used for the 3D printing of photothermal MN arrays. Such 3Dprinted photothermal MN arrays allowed for the in vitro killing of the SSTI-associated bacterial species S. aureus and Pseudomonas aeruginosa by heat. However, final temperature of the planktonic samples reached >60 ºC limiting the clinical potential of such photothermal MNs as monotherapies since such high temperatures may cause damage to healthy cells. Therefore, hybrid MN arrays were developed that incorporate both VAN and photothermal nanoaggregates to reduce the needed antibiotic and temperature dose through synergistic interactions. Such hybrid MNs were fabricated employing an outer, dissolvable, drug-loaded layer and an inner, non-dissolvable, photothermal core aiming to combine the advantages of (i) high local VAN delivery and (ii) intradermal PTT. We showed the successful synergistic growth inhibition of MRSA in vitro of such hybrid MN arrays. Overall, the work in this thesis introduces a potential novel treatment option for bacterial SSTIs

Microneedles for painless transdermal immunotherapeutic applications

Immunotherapy has recently garnered plenty of attention to improve the clinical outcomes in the treatment of various diseases. However, owing to the dynamic nature of the immune system, this approach has often been challenged by concerns regarding the lack of adequate long-term responses in patients. The development of microneedles (MNs) has resulted in the improvement and expansion of immuno-reprogramming strategies due to the housing of high accumulation of dendritic cells, macrophages, lymphocytes, and mast cells in the dermis layer of the skin. In addition, MNs possess many outstanding properties, such as the ability for the painless traverse of the stratum corneum, minimal invasiveness, facile fabrication, excellent biocompatibility, convenient administration, and bypassing the first pass metabolism that allows direct translocation of therapeutics into the systematic circulation. These advantages make MNs excellent candidates for the delivery of immunological biomolecules to the dermal antigen-presenting cells in the skin with the aim of vaccinating or treating different diseases, such as cancer and autoimmune disorders, with minimal invasiveness and side effects. This review discusses the recent advances in engineered MNs and tackles limitations relevant to traditional immunotherapy of various hard-to-treat diseases. © 2020 Elsevier B.V

Drug Delivery Technology Development in Canada

Canada continues to have a rich history of ground-breaking research in drug delivery within academic institutions, pharmaceutical industry and the biotechnology community

Sonosensitive cavitation nuclei-a customisable platform technology for enhanced therapeutic delivery

Ultrasound-mediated cavitation shows great promise for improving targeted drug delivery across a range of clinical applications. Cavitation nuclei-sound-sensitive constructs that enhance cavitation activity at lower pressures-have become a powerful adjuvant to ultrasound-based treatments, and more recently emerged as a drug delivery vehicle in their own right. The unique combination of physical, biological, and chemical effects that occur around these structures, as well as their varied compositions and morphologies, make cavitation nuclei an attractive platform for creating delivery systems tuned to particular therapeutics. In this review, we describe the structure and function of cavitation nuclei, approaches to their functionalization and customization, various clinical applications, progress toward real-world translation, and future directions for the field

Needle-free jet injector-assisted dermal delivery of bleomycin:Paving the way to effective and minimal invasive treatment of keloidal scars

In this thesis, we explored electronically-controlled needle-free jet injection-assisted dermal drug delivery of bleomycin as a novel treatment for keloid scars that could potentially lead to a high skin bioavailability, better patient satisfaction, and, ultimately, in higher clinical effectiveness compared to conventional hypodermic needle injections