Spotlight on Photoactivatable Liposomes beyond Drug Delivery: An Enabler of Multitargeting of Molecular Pathways

Abstract

The potential of photoactivating certain molecules, photosensitizers (PS), resulting in photochemical processes, has long been realized in the form of photodynamic therapy (PDT) for the management of several cancerous and noncancerous pathologies. With an improved understanding of the photoactivation process and its broader implications, efforts are being made to exploit the various facets of photoactivation, PDT, and the associated phenomenon of photodynamic priming in enhancing treatment outcomes, specifically in cancer therapeutics. The parallel emergence of nanomedicine, specifically liposome-based nanoformulations, and the convergence of the two fields of liposome-based drug delivery and PDT have led to the development of unique hybrid systems, which combine the exciting features of liposomes with adequate complementation through the photoactivation process. While initially liposomes carrying photosensitizers (PSs) were developed for enhancing the pharmacokinetics and the general applicability of PSs, more recently, PS-loaded liposomes, apart from their utility in PDT, have found several applications including enhanced targeting of drugs, coloading multiple therapeutic agents to enhance synergistic effects, imaging, priming, triggering drug release, and facilitating the escape of therapeutic agents from the endolysosomal complex. This review discusses the design strategies, potential, and unique attributes of these hybrid systems, with not only photoactivation as an attribute but also the ability to encapsulate multiple agents for imaging, biomodulation, priming, and therapy referred to as photoactivatable multiagent/inhibitor liposomes (PMILS) and their targeted versions�targeted PMILS (TPMILS). While liposomes have formed their own niche in nanotechnology and nanomedicine with several clinically approved formulations, we try to highlight how using PS-loaded liposomes could address some of the limitations and concerns usually associated with liposomes to overcome them and enhance their preclinical and clinical utility in the future.

Light-Activated siRNA Endosomal Release (LASER) by Porphyrin Lipid Nanoparticles

“…To alleviate the twostep requirement, a few exploratory studies have applied PS-siRNA conjugates, 17−19 polymeric and liposome-based siRNA carriers to improve siRNA endosomal escape via PCI. 20−22 Nevertheless, such systems are still limited by (1) the synthetic and scalable challenges to chemically link PS and siRNA; 23 (2) the premature leakage of small-molecule PS from siRNA nanocarriers; 24 (3) the poor biocompatibilities of cationic siRNA carriers; 25 and last (4) the lack of direct evidence supporting proposed PCI mechanisms (e.g., PS localization on endocytic membranes, changes in membrane integrity). Given the great clinical successes already achieved by LNPs in delivering siRNA and mRNA, PCI systems built upon LNPs will be highly translatable by addressing the unmet RNA endosomal escape challenge.…”

“…The resulting inconsistent distribution of PS and macromolecules to target cells largely hinders its applications in vivo . To alleviate the two-step requirement, a few exploratory studies have applied PS-siRNA conjugates, − polymeric and liposome-based siRNA carriers to improve siRNA endosomal escape via PCI. − Nevertheless, such systems are still limited by (1) the synthetic and scalable challenges to chemically link PS and siRNA; (2) the premature leakage of small-molecule PS from siRNA nanocarriers; (3) the poor biocompatibilities of cationic siRNA carriers; and last (4) the lack of direct evidence supporting proposed PCI mechanisms ( e.g. , PS localization on endocytic membranes, changes in membrane integrity).…”

Dual-Function Antibody Conjugate-Enabled Photoimmunotherapy Complements Fluorescence and Photoacoustic Imaging of Head and Neck Cancer Spheroids

“…Recent advances in tumor-targeted imaging have seen several antibody fluorophore conjugates being tested in clinical trials for guiding resection surgeries. , In this context, the use of photosensitizers provides an advantage where the photoactive molecule can be used for fluorescence imaging and treatment of the target lesions through photodynamic therapy. This has been shown in several studies from our lab and others. ,− Although photoimmunotherapy (PIT) was developed three decades ago, it has recently gained popularity with clinical approval in Japan for head and neck cancers. Ongoing phase III clinical trials are evaluating the efficacy of PIT for head and neck cancers in USA. − , The efficacy of photodynamic therapy (PDT), however, largely depends on the tumor size and oxygenation.…”

Recent Advances in Intranasal Liposomes for Drug, Gene, and Vaccine Delivery

“…Nanoparticles (typically <1000 nm) loaded with drug or gene molecules have many advantages, such as their high surface area and improved solubility, absorption, and stability [ 4 , 5 ]. Many studies have focused on liposomes, which are spherical nanosized vesicles similar to biological membranes that are produced from cholesterol and phospholipids [ 6 , 7 ]. Liposomes are highly safe, biocompatible, and biodegradable; thus, they are ideal carriers for various drug delivery routes [ 8 ].…”