Ultrasmall-in-Nano Approach: Enabling the Translation of Metal Nanomaterials to Clinics

Currently, nanomaterials are of widespread use in daily commercial products. However, the most-promising and potentially impacting application is in the medical field. In particular, nanosized noble metals hold the promise of shifting the current medical paradigms for the detection and therapy of neoplasms thanks to the: (i) localized surface plasmon resonances (LSPRs), (ii) high electron density, and (iii) suitability for straightforward development of all-in-one nanoplatforms. Nonetheless, there is still no clinically approved noble metal nanomaterial for cancer therapy and diagnostics. The clinical translation of noble metal nanoparticles (NPs) is mainly prevented by the issue of persistence in organism after the medical action. Such persistence increases the likelihood of toxicity and the interference with common medical diagnoses. Size reduction to ultrasmall nanoparticles (USNPs) is a suitable approach to promoting metal excretion by the renal pathway. However, most of the functionalities of NPs are lost or severely altered in USNPs, jeopardizing clinical applications. A ground-breaking advance to jointly combine the appealing behaviors of NPs with metal excretion relies on the ultrasmall-in-nano approach for the design of all-in-one degradable nanoplatforms composed of USNPs. Such nanoarchitectures might lead to the delivery of a novel paradigm for nanotechnology, enabling the translation of noble metal nanomaterials to clinics to treat carcinomas in a less-invasive and more-efficient manner. This Review covers the recent progresses related to this exciting approach. The most-significant nanoarchitectures designed with the ultrasmall-in-nano approach are discussed, and perspectives on these nanoarchitectures are provided

Light-triggered liposomal cargo delivery platform incorporating photosensitizers and gold nanoparticles for enhanced singlet oxygen generation and increased cytotoxicity.

We developed light-triggered liposomes incorporating 3-5 nm hydrophobic gold nanoparticles and Rose Bengal (RB), a well-known photosensitizer used for photodynamic therapy. Singlet oxygen generated by these liposomes with 532 nm light illumination was characterized for varying the molar ratio of lipids and gold nanoparticles while keeping the amount of RB constant. Gold nanoparticles were found to enhance the singlet oxygen generation rate, with a maximum enhancement factor of 1.75 obtained for the molar ratio of hydrogenated soy l-α-phosphatidylcholine:1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(hexanoylamine):gold of 57:5:17 compared with liposomes loaded with RB alone. The experimental results could be explained by the local electric field enhancement caused by gold nanoparticles. We further assessed cellular cytotoxicity of gold-loaded liposomes by encapsulating an antitumor drug, doxorubicin (Dox); such Dox-loaded liposomes were applied to human colorectal cancer cells (HCT116) and exposed to light. Gold-loaded liposomes containing RB and Dox where Dox release was triggered by light were found to exhibit higher cytotoxicity compared with the liposomes loaded with RB and Dox alone. Our results indicate that gold-loaded liposomes incorporating photosensitizers may serve as improved agents in photodynamic therapy and chemotherapy

Local Enhancement of Lipid Membrane Permeability Induced by Irradiated Gold Nanoparticles

Photothermal therapies are based on the optical excitation of plasmonic nanoparticles in the biological environment. The effects of the irradiation on the biological medium depend critically on the heat transfer process at the nanoparticle interface, on the temperature reached by the tissues, as well as on the spatial extent of temperature gradients. Unfortunately, both the temperature and its biological effects are difficult to be probed experimentally at the molecular scale. Here, we approach this problem using nonequilibrium molecular dynamics simulations. We focus on photoporation, a photothermal application based on the irradiation of gold nanoparticles by single, short-duration laser pulses. The nanoparticles, stably bound to cell membranes, convert the radiation into heat, inducing transient changes of membrane permeability. We make a quantitative prediction of the temperature gradient around the nanoparticle upon irradiation by typical experimental laser fluences. Water permeability is locally enhanced around the nanoparticle, in an annular region that extends only a few nanometers from the nanoparticle interface. We correlate the local enhancement of permeability at the nanoparticle-lipid interface to the temperature inhomogeneities of the membrane and to the consequent availability of free volume pockets within the membrane core

A Snapshot of photoresponsive liposomes in cancer chemotherapy and immunotherapy: opportunities and challenges

© 2023 The Authors. Published by American Chemical Society. This is an open access article under the Creative Commons Attribution-NonCommercial-NoDerivatives CC BY-NC-ND licence, https://creativecommons.org/licenses/by-nc-nd/4.0To provide precise medical regimens, photonics technologies have been involved in the field of nanomedicine. Phototriggered liposomes have been cast as promising nanosystems that achieve controlled release of payloads in several pathological conditions such as cancer, autoimmune, and infectious diseases. In contrast to the conventional liposomes, this photoresponsive element greatly improves therapeutic efficacy and reduces the adverse effects of gene/drug therapy during treatment. Recently, cancer immunotherpay has been one of the hot topics in the field of oncology due to the great success and therapeutic benefits that were well-recognized by the patients. However, several side effects have been encountered due to the unmonitored augmentation of the immune system. This Review highlights the most recent advancements in the development of photoresponsive liposome nanosystems in the field of oncology, with a specific emphasis on challenges and opportunities in the field of cancer immunotherapy.Peer reviewe

Toxicity and cellular uptake of gold nanoparticles: what we have learned so far?

Gold nanoparticles have attracted enormous scientific and technological interest due to their ease of synthesis, chemical stability, and unique optical properties. Proof-of-concept studies demonstrate their biomedical applications in chemical sensing, biological imaging, drug delivery, and cancer treatment. Knowledge about their potential toxicity and health impact is essential before these nanomaterials can be used in real clinical settings. Furthermore, the underlying interactions of these nanomaterials with physiological fluids is a key feature of understanding their biological impact, and these interactions can perhaps be exploited to mitigate unwanted toxic effects. In this Perspective we discuss recent results that address the toxicity of gold nanoparticles both in vitro and in vivo, and we provide some experimental recommendations for future research at the interface of nanotechnology and biological systems

Interfacing Zwitterionic Liposomes with Inorganic Nanomaterials: Surface Forces, Membrane Integrity, and Applications

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Langmuir, © 2016 American Chemical Society after peer review and technical editing by publisher. To access the final edited and published work see Liu, J. (2016). Interfacing Zwitterionic Liposomes with Inorganic Nanomaterials: Surface Forces, Membrane Integrity, and Applications. Langmuir, 32(18), 4393–4404. https://doi.org/10.1021/acs.langmuir.6b00493Zwitterionic phosphocholine (PC) lipids are the main constituent of the mammalian cell membrane. PC bilayers are known for their antifouling properties, yet they are adsorbed by all tested inorganic nanoparticles. This feature article is focused on the developments in my laboratory in the past few years on this topic. The main experimental techniques include fluorescence-based liposome leakage assays, adsorption and desorption, and cryo-TEM. Different materials interact with PC liposomes differently. PC liposomes adsorb on SiO2, followed by membrane fusion with the surface forming supported lipid bilayers. TiO2 and other metal oxides adsorb only intact PC liposomes via lipid phosphate bonding; the steric effect from the choline group hinders subsequent liposome fusion onto the particles. Citrate-capped AuNPs are adsorbed very strongly via van der Wags forces, inducing local gelation. The result is transient liposome leakage upon AuNP adsorption or desorption and AuNP aggregation on the liposome surface. All carbon-based nanomaterials (graphene oxides, carbon nanotubes, and nanodiamond) are adsorbed mainly via hydrogen bonding. The oxidation level of graphene oxide strongly influences the outcome of the final hybrid material. In the context of inorganic nanoparticle adsorption, insights are given regarding the lack of protein adsorption by PC bilayers. These inorganic/lipid hybrid materials can be used for controlled release, drug delivery, and fundamental studies. A few examples of application are covered toward the end, and future perspectives are given.University of Waterloo; Canada Foundation for Innovation (CFI),; Natural Sciences and Engineering Research Council of Canada (NSERC

Liposomal discovery of diacylglycerol (DAG)-binding proteins and the use of signaling lipids to improve nanodrug delivery

The protein signaling activities of the glycerolipid diacylglycerol (DAG) form the impetus for the projects described herein. DAG’s governance of cellular functions involves activation of peripheral membrane proteins (PMPs) at bilayer surfaces, which includes the activation of protein kinase C (PKC) to regulate oncogenesis. In addition to enzymatic signal transduction, DAG influences membrane mechanics and is a central lipid metabolite. Relatively little is known about DAG when compared to more common signaling lipids such as phosphatidylinositol polyphosphates (PIPns). This is due in part to the surreptitious nature of PMP operation and the complexity of natural bilayers. We developed a liposomal platform to identify PMP binding as a function of specific lipids. Synthetic, photocrosslinking lipids with clickable tags are incorporated into liposomes to capture and enrich proteins. Affinity-based protein profiling (AfBPP) experiments initially demonstrated proteome-wide increases in affinity when using DAG or phosphatidic acid (PA) as chase lipids. With the aid of collaborators at The Scripps Research Institute (TSRI), we optimized our AfBPP protocol to label select proteins as a function of liposomal DAG content when a generic lipid probe was also present in the membrane. The generic probe strategy varies natural lipid content with consistent probe concentration between liposomal treatments, this is called the lipomimetic approach. Lipid specific probes have also been applied to liposomal AfBPP, which is termed the lipospecific approach.In a separate project, we tested to see if DAG could potentiate the cell-association of a liposomal delivery system (LDS). LDSs are a rapidly expanding field; most existing nanodrugs are liposomal. Strategies for increasing LDS efficacies often undermine clinical translatability. Incorporating natural signaling lipids into nanodrugs architectures is a clinically viable targeting strategy. A polyethylene glycol (PEG) decorated (PEGylated) liposome bearing a cell penetrating peptide (CPP) was doped with DAG and/or PS and significant, dose-dependent increases in association to target cells were observed. We also advanced LDSs with new technologies for controlling vesicle release and fusion. Liposomes have limitless utility as theranostic tools and platforms for biochemical investigations. Herein, we bring liposomal technologies closer to their scientific and clinical potentials