Incorporation Of Targeting Ligands Research Articles

Quaternization drives spleen-to-lung tropism conversion for mRNA-loaded lipid-like nanoassemblies.

Background: As the overwhelming majority of advanced mRNA delivery systems are preferentially accumulated in the liver, there is an accelerating growth in the demand for the development of non-liver mRNA delivery platforms. Methods: In this study, we prepared cationic lipid-like nanoassemblies through a N-quaternizing strategy. Their physicochemical properties, in vitro mRNA delivery efficiency, and organ tropism in mice were investigated. Results: Introduction of quaternary ammonium groups onto lipid-like nanoassemblies not only enhances their mRNA delivery performance in vitro, but also completely alters their tropism from the spleen to the lung after intravenous administration in mice. Quaternized lipid-like nanoassemblies exhibit ultra-high specificity to the lung and are predominantly taken up by pulmonary immune cells, leading to over 95% of exogenous mRNA translation in the lungs. Such mRNA delivery carriers are stable even after more than one-year storage at ambient temperature. Conclusions: Quaternization provides an alternative method for design of new lung-targeted mRNA delivery systems without incorporation of targeting ligands, which should extend the therapeutic applicability of mRNA to lung diseases.

Targeted Polymeric Nanoparticles as a Strategy for the Treatment of Glioblastoma: A Review.

Glioblastoma multiforme is the most common and aggressive malignant tumor that affects the central nervous system, with high mortality and low survival. Glioblastoma multiforme treatment includes resection tumor surgery, followed by radiotherapy and chemotherapy adjuvants. However, the drugs used in chemotherapy present some limitations, such as the difficulty of crossing the bloodbrain barrier and resisting the cellular mechanisms of drug efflux. The use of polymeric nanoparticles has proven to be an effective alternative to circumvent such limitations, as it allows the exploration of a range of polymeric structures that can be modified in order to control the biodistribution and cytotoxic effect of the drug delivery systems. Nanoparticles are nanometric in size and allow the incorporation of targeting ligands on their surface, favoring the transposition of the blood-brain barrier and the delivery of the drug to specific sites, increasing the selectivity and safety of chemotherapy. The present review has described the characteristics of chitosan, poly(vinyl alcohol), poly(lactic-coglycolic acid), poly(ethylene glycol), poly(β-amino ester), and poly(ε-caprolactone), which are some of the most commonly used polymers in the manufacture of nanoparticles for the treatment of glioblastoma multiforme. In addition, some of the main targeting ligands used in these nanosystems are presented, such as transferrin, chlorotoxin, albumin, epidermal growth factor, and epidermal growth factor receptor blockers, explored for the active targeting of antiglioblastoma agents.

A short appraisal of nanodiamonds in drug delivery and targeting: recent advancements

Nanodiamonds have emerged as a powerful tool in the field of drug delivery, offering exciting recent advancements and promising future prospects. Recent research has focused on enhancing drug loading efficiency, targeted delivery, and precision medicine using nanodiamonds. Strategies such as surface functionalization, polymer coatings, and encapsulation techniques have been optimized to improve drug loading, stability, and controlled release. Nanodiamonds have shown potential in targeted drug delivery through the incorporation of targeting ligands, enabling site-specific drug delivery and improved therapeutic outcomes. Additionally, nanodiamonds allow for combination therapy by carrying multiple drugs simultaneously, opening avenues for synergistic treatments. Stimuli-responsive nanodiamonds have been developed for precise and controlled drug release. Overcoming biological barriers, such as the blood-brain barrier, has been investigated by modifying nanodiamonds’ surfaces. Recent studies have highlighted innovative strategies for loading a variety of therapeutic cargoes onto nanodiamond platforms, including small molecules, proteins, nucleic acids, and even gene-editing tools. Future prospects include the integration of nanodiamonds with emerging technologies and addressing biocompatibility and safety concerns. Despite the need for further research and clinical studies, the recent advancements and future prospects of nanodiamonds in drug delivery suggest their potential to revolutionize the field and enhance patient care.

Coencapsulation of Gemcitabine and Thymoquinone in Citrem-Phosphatidylcholine Hexosome Nanocarriers Improves In Vitro Cellular Uptake in Breast Cancer Cells.

Lyotropic liquid crystalline nanoassemblies (LLCNs) are internally self-assembled (ISA)-somes formed by amphiphilic molecules in a mixture comprising a lipid, stabilizer, and/or surfactant and aqueous media/dispersant. LLCNs are unique nanoassemblies with versatile applications in a wide range of biomedical functions. However, they comprise a nanosystem that is yet to be fully explored for targeted systemic treatment of breast cancer. In this study, LLCNs proposed for gemcitabine and thymoquinone (Gem-TQ) co-delivery were prepared from soy phosphatidylcholine (SPC), phytantriol (PHYT), or glycerol monostearate (MYVR) in optimized ratios containing a component of citric and fatty acid ester-based emulsifier (Grinsted citrem) or a triblock copolymer, Pluronic F127 (F127). Hydrodynamic particle sizes determined were below 400 nm (ranged between 96 and 365 nm), and the series of nanoformulations displayed negative surface charge. Nonlamellar phases identified by small-angle X-ray scattering (SAXS) profiles comprise the hexagonal, cubic, and micellar phases. In addition, high entrapment efficiency that accounted for 98.3 ± 0.1% of Gem and 99.5 ± 0.1% of TQ encapsulated was demonstrated by the coloaded nanocarrier system, SPC/citrem/Gem-TQ hexosomes. Low cytotoxicity of SPC-citrem hexosomes was demonstrated in MCF10A cells consistent with hemo- and biocompatibility observed in zebrafish (Danio rerio) embryos for up to 96 h postfertilization (hpf). SPC/citrem/Gem-TQ hexosomes demonstrated IC50 of 24.7 ± 4.2 μM in MCF7 breast cancer cells following a 24 h treatment period with the moderately synergistic interaction between Gem and TQ retained (CI = 0.84). Taken together, biocompatible SPC/citrem/Gem-TQ hexosomes can be further developed as a multifunctional therapeutic nanodelivery approach, plausible for targeting breast cancer cells by incorporation of targeting ligands.

Progress of albumin-polymer conjugates as efficient drug carriers

Abstract Albumin is a protein that has garnered wide attention in nanoparticle-based drug delivery of cancer therapeutics due to its natural abundance and unique cancer-targeting ability. The propensity of albumin to naturally accumulate in tumours, further augmented by the incorporation of targeting ligands, has made the field of albumin-polymer conjugate development a much pursued one. Polymerization techniques such as RAFT and ATRP have paved the path to incorporate various polymers in the design of albumin-polymer hybrids, indicating the advancement of the field since the first instance of PEGylated albumin in 1977. The synergistic combination of albumin and polymer endows manifold features to these macromolecular hybrids to evolve as next generation therapeutics. The current review is successive to our previously published review on drug delivery vehicles based on albumin-polymer conjugates and aims to provide an update on the progress of albumin-polymer conjugates. This review also highlights the alternative of exploring albumin-polymer conjugates formed via supramolecular, non-covalent interactions. Albumin-based supramolecular polymer systems provide a versatile platform for functionalization, thereby, holding great potential in enhancing cytotoxicity and controlled delivery of therapeutic agents.

Tumor-mesoporous silica nanoparticle interactions following intraperitoneal delivery for targeting peritoneal metastasis

The use of intraperitoneal administration of nanoparticles has been reported to facilitate higher concentrations of nanoparticles in metastatic peritoneal tumors. While this strategy is appealing for limiting systemic exposure of nanocarrier delivered toxic cargoes and increasing nanoparticle concentrations in avascular peritoneal tumors, little is known about the mechanism of nanoparticle accumulation on tumor tissues and currently, no nanoparticle-based product has been approved for intraperitoneal delivery. Here, we investigated the nanoparticle-specific characteristics that led to increased peritoneal tumor accumulation using MCM-41 type mesoporous silica nanoparticles as our model system. We also investigated the components of the peritoneal tumor stroma that facilitated nanoparticle-tumor interaction. The tumor extracellular matrix is the main factor driving these interactions, specifically the interaction of nanoparticles with collagen. Upon disruption of the collagen matrix, nanoparticle accumulation was reduced by 50%. It is also notable that the incorporation of targeting ligands did not increase overall tumor accumulation in vivo while it significantly increased nanoparticle accumulation in vitro. The use of other particle chemistries did not grossly affect the tumor targetability, but additional concerns arose when those tested particles exhibited significant systemic exposure. Mesoporous silica nanoparticles are advantageous for intraperitoneal administration for the treatment of peritoneal metastasis due to their physical stability, tumor targetability, strong interaction with the collagen matrix, and extended peritoneal residence time. Maximizing nanoparticle interaction with the tumor extracellular matrix is critical for developing strategies to deliver emerging therapeutics for peritoneal cancer treatment using nanocarriers.

An optimized mesoporous silica nanosphere-based carrier system with chemically removable Au nanoparticle caps for redox-stimulated and targeted drug delivery

To date, numerous drug delivery systems based on mesoporous silica nanoparticles (MSNs) have been explored, but little has been done on optimizing the structure and composition of MSNs to achieve effective drug delivery for cancer cells. Ideal mesoporous drug carriers should incorporate drugs in a way that prevents pre-release in biological surroundings before reaching the targeted area, which usually requires the capping of the open ends on the surface and the incorporation of targeting ligands on the exterior of nanocarriers. In this study, an MSN-based drug carrier system was synthesized with biocompatible Au nanoparticles (NPs) as the ‘hard caps’, and folic acid conjugated to the surface for targeting folate receptor-overexpressed cancer cells. Disulfide bonds linking Au and MSN NPs were introduced to the MSN surface as the redox-sensitive and chemically removable components. To study the effect of structures of MSNs in drug release, three types of MSNs were compared, including hollow mesoporous silica NPs, large-pore hollow mesoporous silica NPs and typical nano-sized pores on the surface (MSN). To achieve optimal coverage of thiol groups, two methods of functionalization were compared in effecting drug loading and release in vitro. Finally, the effect of residual surfactant was also discussed in anticancer studies. Therefore, the appropriate MSN nanostructure for redox-sensitive and targeted drug delivery was optimized.

Graphene-based nanovehicles for photodynamic medical therapy.

Graphene and its derivatives such as graphene oxide (GO) have been widely explored as promising drug delivery vehicles for improved cancer treatment. In this review, we focus on their applications in photodynamic therapy. The large specific surface area of GO facilitates efficient loading of the photosensitizers and biological molecules via various surface functional groups. By incorporation of targeting ligands or activatable agents responsive to specific biological stimulations, smart nanovehicles are established, enabling tumor-triggering release or tumor-selective accumulation of photosensitizer for effective therapy with minimum side effects. Graphene-based nanosystems have been shown to improve the stability, bioavailability, and photodynamic efficiency of organic photosensitizer molecules. They have also been shown to behave as electron sinks for enhanced visible-light photodynamic activities. Owing to its intrinsic near infrared absorption properties, GO can be designed to combine both photodynamic and photothermal hyperthermia for optimum therapeutic efficiency. Critical issues and future aspects of photodynamic therapy research are addressed in this review.

Development of delivery, targeting, and imaging strategies to improve oncolytic vesicular stomatitis virus therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a disease with rising incidence, limited treatment options and poor prognosis, representing a major worldwide health concern. Due to the vast deficit of viable treatment options, oncolytic viruses have emerged as promising alternative therapies to specifically target and lyse tumor cells. We have previously demonstrated the safety and efficacy of oncolytic vesicular stomatitis virus (VSV) applied via hepatic arterial infusion to treat orthotopic HCC in immune-competent rats, and based on encouraging data such as these, a recombinant VSV vector has recently entered the clinic in phase I trials for HCC in patients. Although systemic administration of oncolytic viral therapies is ideal for targeting metastatic disease, the efficacy of such an approach is extremely compromised due to rapid clearance from circulation as a result of neutralizing blood components and non-specific uptake by liver and spleen. Furthermore, the complex microenvironment in the liver poses a unique set of challenges to the fate of oncolytic viral therapies directed at hepatic tumors. Although attempts to shield viruses from adverse interactions have led to increased circulation times in vivo, they are also associated with decreased infectivity of the target cells. We have therefore developed several strategies, including novel cell carrier and synthetic shielding approaches, to simultaneously protect VSV from nonspecific interactions and deliver it specifically to the tumor target, where it can exert its oncolytic effect. Because a variety of immune cells possess the inherent ability to take up oncolytic virus and subsequently home to tumor beds, they offer the unique dual benefit of delivering viruses in stealth, while contributing to antitumor immune responses. Alternatively, synthetic polymers can provide highly effective shielding through surface modification of oncolytic viruses and have the advantage of being adaptable to optimize the shielding effect. Through the incorporation of targeting ligands or selectively cleavable linkers, the ability of the virus to infect is then rescued locally and specifically at the tumor site. Furthermore, advancement of imaging technologies allows us the possibility to monitor the biodistribution of these shielded viruses to observe the circulation time and replication kinetics noninvasively and in real-time, which will further facilitate the clinical translation of oncolytic virus therapies. A summary of these novel approaches to enhance oncolytic VSV accumulation within orthotopic HCC tumors and improve the therapy outcome, as well as virus imaging strategies, will be presented.

Polymers for nucleic acid transfer-an overview.

For the last five decades cationic polymers have been used for nucleic acids transfection. Our understanding of polymer-nucleic acid interactions and their rational use in delivery has continuously increased. The great improvements in macromolecular chemistry and the recognition of distinct biological extra- and intracellular delivery hurdles triggered several breakthrough developments, including the discovery of natural and synthetic polycations for compaction of nucleic acids into stable nanoparticles termed polyplexes; the incorporation of targeting ligands and surface-shielding of polyplexes to enable receptor-mediated gene delivery into defined target tissues; and strongly improved intracellular transfer efficacy by better endosomal escape of vesicle-trapped polyplexes into the cytosol. These experiences triggered the development of second-generation polymers with more dynamic properties, such as endosomal pH-responsive release mechanisms, or biodegradable units for improved biocompatibility and intracellular release of the nucleic acid pay load. Despite a better biological understanding, significant challenges such as efficient nuclear delivery and persistence of gene expression persist. The therapeutic perspectives widened from pDNA-based gene therapy to application of novel therapeutic nucleic acids including mRNA, siRNA, and microRNA. The finding that different therapeutic pay loads require different tailor-made carriers complicates preclinical developments. Convincing evidence of medical efficacy still remains to be demonstrated. Bioinspired multifunctional polyplexes resembling "synthetic viruses" appear as attractive opportunity, but provide additional challenges: how to identify optimum combinations of functional delivery units, and how to prepare such polyplexes reproducibly in precise form? Design of sequence-defined polymers, screening of combinatorial polymer and polyplex libraries are tools for further chemical evolution of polyplexes.

Coating of adeno‐associated virus with reactive polymers can ablate virus tropism, enable retargeting and provide resistance to neutralising antisera

Copolymers based on poly-[N-(2-hydroxypropyl) methacrylamide] (HPMA) have been used previously to enable targeted delivery of adenovirus. Here we demonstrate polymer-coating techniques can also be used to modify and retarget adeno-associated virus (AAV) types 5 and 8. Three strategies for modifying transductional targeting of AAV were employed. The first involved direct reaction of AAV5 or AAV8 with amino-reactive HPMA copolymer. The second approach used carbodiimide (EDC) chemistry to increase the number of surface amino groups on the AAV5 capsid, thereby improving coating efficiency. In the third approach, the AAV5 genome was isolated from capsid proteins and delivered in a synthetic polyplex consisting of polyethylenimine (PEI) and HPMA. Efficient covalent attachment of HPMA copolymer to AAV5 could only be achieved following modification of the virus with EDC. Coating inhibited sialic acid dependent infection and provided a platform for retargeting via new ligands, including basic fibroblast growth factor. Retargeted infection was shown to be partially resistant to neutralising antisera. Delivery of AAV5 genomes using PEI and HPMA was efficient and provided absolute control of tropism and protection from antisera. In contrast AAV8 could be reacted directly with HPMA copolymer and allowed specific retargeting via the epidermal growth factor receptor, but gave no protection against neutralising antisera. Reactive HPMA polymers can be used to ablate the natural tropism of both AAV8 and EDC-modified AAV5 and enable receptor-specific infection by incorporation of targeting ligands. These data show transductional targeting strategies can be used to improve the versatility of AAV vectors.

A versatile system for receptor-mediated gene delivery permits increased entry of DNA into target cells, enhanced delivery to the nucleus and elevated rates of transgene expression

We have developed a method for stabilisation of polyelectrolyte gene delivery vectors by crosslinking their surfaces with biodegradable multivalent copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA). The resulting nanoparticulate vectors resist attack by serum proteins and can be modified for cell-specific delivery by incorporation of targeting ligands onto the polymer coating. Here we show that vascular endothelial growth factor (VEGF), transferrin and basic fibroblast growth factor (bFGF) can each be linked to polyHPMA-coated poly(L-lysine)/DNA complexes. All ligand-targeted complexes demonstrated increased uptake into receptor-positive cells (measured using plasmids containing 32P-dCTP), that could be antagonised with excess free ligand. Targeted complexes also showed increased transfection, resistant to inhibition by serum, suggesting the possibility of effective application in vivo. Analysis using fluorescence microscopy confirmed enhanced uptake of ligand-targeted complexes (using Texas Red-labelled plasmid DNA), although VEGF- and transferrin-targeted complexes were restricted to cytoplasmic or perinuclear distributions. In contrast, bFGF-targeted complexes showed efficient delivery into the nucleus, with accumulation of more than 100000 plasmids per cell within distinct intranuclear compartments. This method permits versatile targeting of genes to selected cells and may also permit manipulation of intracellular trafficking. It should find several important applications in gene delivery systems both in vitro and in vivo.