Targeted Delivery Systems Research Articles

Abstract 828: DNA origami nanostructures as a targeted payload delivery system

Abstract DNA origami is a platform nanotechnology allows for the generation of nanostructures with precisely defined geometric shape that may be easily functionalized with a variety of payloads for therapeutic delivery. These payloads include nucleic acids (miRNA, siRNA, gene sequences), associated Cas protein molecules, therapeutic small molecules drugs, functional peptides (adjuvants or cell penetrating peptides), and incorporated targeting and/or therapeutic antibodies. Hence, DNA origami is a highly promising vehicle to deliver targeted therapeutic payloads to cancer cells or other diseases. Previous studies by our laboratory and others revealed DNA origami mediated drug delivery efficiently delivered daunorubicin or doxorubicin to cancer cells while outperforming free drug in both solid and liquid tumor model systems in vitro and in vivo. Our recent findings showed significant survival advantage by doxorubicin-loaded DNA origami over delivery of free doxorubicin in an aggressive, acute monocytic leukemia model. We also showed antibody-directed drug delivery by DNA origami may be directly targeted to monocytic leukemia cells expressing the target surface antigen, and superior efficacy in vitro against acute myeloid leukemia cells when loaded with daunorubicin relative to free drug at low concentrations. Thus, antibody targeted drug loaded DNA origami represent a promising novel precision medicine approach. Additionally, recent findings by our laboratory in vivo determined that DNA origami nanostructures alone administered at high dose (12.0mg/kg) distribute well, are non-toxic, and illicit mild immunogenicity, making them an attractive candidate for further development towards therapeutic applications. We recently developed a DNA origami structure functionalized at a high density with adjuvant (CpG) and antigenic peptides (OVA) to stimulate a directed antigen-specific immune response. We have shown this DNA origami vaccine platform displays significant improvement in efficacy by an OVA-pulsed antigen-killing assay in vivo relative to alum and CFA standard adjuvant formulations. Thus, our DNA origami vaccine platform represents a promising novel approach to optimize an anti-cancer immune response, a finding also shown by other laboratories.Collectively, DNA Nanobot technology offers 1) a promising a cancer drug delivery system that can deliver a high number of therapeutic drugs (100s of drug molecules per targeted delivery system) utilizing existing ADC conjugation methods; 2) An optimal vaccine delivery method to enhance efficacy; and 3) cell specific targeted delivery of therapeutic nucleic acids and genes to modify oncogene and/or tumor suppressor gene expression. Citation Format: Patrick Halley, Niksa Roki, Nicholas Vantangoli, Tom Zupancic, Jeff Spitzner, Meixiao Long, Karilyn Karilyn Larkin, John Byrd, Carlos Castro, Chris R. Lucas. DNA origami nanostructures as a targeted payload delivery system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 828.

Genetically engineered CXCR4-modified exosomes for delivery of miR-126 mimics to macrophages alleviate periodontitis

Biofilm-related diseases are a group of diseases that tolerate antimicrobial chemotherapies and therefore are refractory to treatment. Periodontitis, a non-device chronic biofilm disease induced by dental plaque, can serve as an excellent in vivo model to study the important effects of host factors on the biofilm microenvironment. Macrophage activity is one of the key factors that modulate the progression of inflammation-driven destruction in periodontitis; therefore it is an important host immunomodulatory factor. In this study, the reduction of microRNA-126 (miR-126) with the recruitment of macrophages in periodontitis was confirmed in clinical samples, and a strategy for targeted delivery of miR-126 to macrophages was explored. Exosomes overexpressing the C-X-C motif chemokine receptor 4 (CXCR4) loaded with miR-126 (CXCR4-miR126-Exo) was successfully constructed, which reduced off-target delivery to macrophages and regulated macrophages toward the anti-inflammatory phenotype. In vivo local injection of CXCR4-miR126-Exo into sites of periodontitis in rats effectively reduced bone resorption and osteoclastogenesis and inhibited the progression of periodontitis. These results provide new insights for designing novel immunomodulatory factor targeted delivery systems to treat periodontitis and other biofilm-related diseases.

In Vivo RNA Delivery to Hematopoietic Stem and Progenitor Cells via Targeted Lipid Nanoparticles.

Ex vivo autologous hematopoietic stem cell (HSC) gene therapy has provided new therapies for the treatment of hematological disorders. However, these therapies have several limitations owing to the manufacturing complexities and toxicity resulting from required conditioning regimens. Here, we developed a c-kit (CD117) antibody-targeted lipid nanoparticle (LNP) that, following a single intravenous injection, can deliver RNA (both siRNA and mRNA) to HSCs in vivo in rodents. This targeted delivery system does not require stem cell harvest, culture, or mobilization of HSCs to facilitate delivery. We also show that delivery of Cre recombinase mRNA at a dose of 1 mg kg-1 can facilitate gene editing to almost all (∼90%) hematopoietic stem and progenitor cells (HSPCs) in vivo, and edited cells retain their stemness and functionality to generate high levels of edited mature immune cells.

Evolution, Stability, and Applicability of Surfactant Aggregates in Targeted Delivery.

Self-assembly/self-aggregation of surfactant molecules in bulk and the vicinity of a surface has been a topic of interest for decades because of its utilization in numerous modern technical applications. In this article, the results of molecular dynamics simulations are reported to investigate the self-aggregation of sodium dodecyl sulfate (SDS) at an interface of mica and water. SDS molecules starting from lower to higher surface concentrations tend to create distinct aggregated structures in the vicinity of a mica surface. The structural properties, such as density profiles, radial distribution functions, and thermodynamic properties like excess entropy and second virial coefficient, are calculated to address the bits and pieces of the self-aggregation. The change in the free energy for aggregates of varied sizes approaching the surface from the bulk aqueous solution, along with the change in their shapes during the process in terms of change in the radius of gyration and its components, is reported respectively to model a generic pathway for a surfactant-based targeted delivery system.

Synthesis, characterization, and in vitro anti-tumor activity studies of the hyaluronic acid-mangiferin-methotrexate nanodrug targeted delivery system

In this study, to increase the accumulation of MTX in the tumor site and reduce the toxicity to normal tissues by MA, a novel nano-drug delivery system comprised of hyaluronic acid (HA)-mangiferin (MA)-methotrexate (MTX) (HA-MA-MTX) was developed by a self-assembly strategy. The advantage of the nano-drug delivery system is that MTX can be used as a tumor-targeting ligand of the folate receptor (FA), HA can be used as another tumor-targeting ligand of the CD44 receptor, and MA serves as an anti-inflammatory agent. 1HNMR and FT-IR results confirmed that HA, MA, and MTX were well coupled together by the ester bond. DLS and AFM images revealed that the size of HA-MA-MTX nanoparticles was about ~138 nm. In vitro cell experiments proved that HA-MA-MTX nanoparticles have a positive effect on inhibiting K7 cancer cells while having relatively lower toxicity to normal MC3T3-E1 cells than MTX does. All these results indicated that the prepared HA-MA-MTX nanoparticles can be selectively ingested by K7 tumor cells through FA and CD44 receptor-mediated endocytosis, thus inhibiting the growth of tumor tissues and reducing the nonspecific uptake toxicity caused by chemotherapy. Therefore, these self-assembled HA-MA-MTX NPs could be a potential anti-tumor drug delivery system.

Dual-Ligand-Functionalized Liposomes Based on Glycyrrhetinic Acid and cRGD for Hepatocellular Carcinoma Targeting and Therapy.

Hepatocellular carcinoma (HCC) is one of the most common cancers, with high mortality. Chemotherapy is one of the main treatment options for HCC. However, the high toxicity and poor specificity of chemotherapeutic drugs have limited their clinical application. In this study, dual-ligand liposomes modified with glycyrrhetinic acid (GA) and cyclic arginine-glycine-aspartic acid (cRGD) (GA/cRGD-LP) were designed to target the GA receptor and αvβ3 integrin, respectively. The aim was to develop a highly selective targeted drug delivery system and further enhance the antitumor efficiency of drugs by targeting both hepatic tumor cells and vasculature. A novel lipid conjugate (mGA-DOPE) by coupling dioleoylphosphatidyl ethanolamine (DOPE) with methyl glycyrrhetinic acid (mGA) was synthesized, and its structure was confirmed. The targeting efficiency of GA/cRGD-LP by in vitro cellular uptake and ex vivo imaging was assessed. GA- and cRGD-modified doxorubicin-loaded liposomes (GA/cRGD-LP-DOX) were prepared, and their cytotoxicity in HepG2 and antitumor activity were evaluated. The results showed that the average particle size of the GA/cRGD-LP-DOX was 114 ± 4.3 nm, and the zeta potential was -32.9 ± 2.0 mV. The transmission electron microscopy images showed that the shapes of our liposomes were spherical. cGA/cRGD-LP-DOX displayed an excellent cellular uptake in both HepG2 and human umbilical vein endothelial cells. In the in vivo study, pharmacokinetic parameters indicated that cGA/cRGD-LP can prolong the circulation time of DOX in the blood. GA/cRGD-LP-DOX showed greater inhibition of tumor growth for HepG2-bearing mice than either the single-ligand-modified liposomes or nontargeted liposomes. GA/cRGD-LP-DOX displayed higher liver tumor localization than that of single-ligand-modified liposomes or free DOX. GA/cRGD-LP is a promising drug delivery system for liver cancer targeting and therapy and is worthy of further study.

Three-dimensional-cultured MSC-derived exosome with hydrogel for cerebral ischemia repair

Microglia-mediated neuroinflammatory response, one of the most essential pathological processes of cerebral ischemia-reperfusion (I/R) injury, is acknowledged as the main factors leading to poor prognosis of cerebral ischemia. Exosome derived from mesenchymal stem cell (MSC-Exo) exhibits neuroprotective functions by reducing cerebral ischemia-induced neuroinflammatory response and promoting angiogenesis. However, MSC-Exo has disadvantages such as insufficient targeting capability and low production, which limits their clinical applications. Here, we fabricated gelatin methacryloyl (GelMA) hydrogel for three-dimensional (3D) culture of MSCs. It is indicated that 3D environment could simulate the biological niches of MSCs, thereby significantly increasing the cell stemness of MSCs and improving the yield of MSCs-derived exosomes (3D-Exo). In this study, we utilized the modified Longa method to induce middle cerebral artery occlusion (MCAO) model. Additionally, in vitro and in vivo studies were conducted to interrogate the mechanism of the stronger neuroprotective effect of 3D-Exo. Furthermore, the administration of 3D-Exo in MCAO model could promote neovascularization in infarct region and result in a significant suppression of inflammatory response. This study proposed an exosome-based targeting delivery system for cerebral ischemia and provided a promising strategy for efficient and large-scale production of MSC-Exo.

Pathogen Recognition-Driven Dendritic Cell-Specific Gene Silencing and Editing

Dendritic cells (DCs) play an essential role in both the induction of the immune response and the maintenance of immune tolerance, with any malfunction of DCs potentially causing several diseases. While gene-based therapy for DC manipulation is a promising approach, it remains challenging due to the lack of efficient delivery systems for DC targeting. Herein, we describe a novel bacterial nanomedicine (BNM) system for pathogen recognition-mediated DCs-specific gene silencing and gene editing. BNMs contain components from bacterial outer membranes and achieve efficient DC targeting through the recognition of pathogen-associated molecular patterns by pattern recognition receptors on DCs. The targeting efficiency of BNMs is reduced in DCs lacking toll-like receptor 4, which is responsible for recognizing lipopolysaccharide, a major component of the bacterial outer membrane. As a proof-of-concept demonstration, we present gene-based therapy mediated by BNMs for enhancing antigen cross-presentation in DCs, which generates a remarkable antitumor effect.

SOLID LIPID NANOPARTICLES: A REVIEW ON DIFFERENT TECHNIQUES AND APPROACHES TO TREAT BREAST CANCER

Breast cancer, the most common malignancy among women, is also the second-leading cause of cancer deaths all over the world. As commonly used chemotherapy drugs, which are given systematically, causes toxicity not only to cancerous cells but also to proliferating normal cells. Similarly, drug resistance leads to drastic side effects and treatment failure. Thus arises the need for improving the therapeutic index of anticancer drugs. Owing to these failures, nanotechnology holds significant promises. Using keywords like multi-drug resistance, effective targeting, therapeutics, intracellular pathways, efficacy, and breast cancer, references were looked up from specialised databases including Elsevier, Pubmed, and Cambridge from the year 1994 to 2023. This review was supplemented by a few references from Springer Nature and pertinent data from an online source. Along with online articles from Medscape, StatPearls, and The Lancet Respiratory Medicine, it was excellent. Supported literature was used to overcome these challenges; therapeutic drugs are encapsulated in nanoparticles. Concurrently, solid lipid nanoparticles (SLN), with their few merits, like enhancing the therapeutic profile, overcoming multidrug resistance, providing a targeted approach, and serving as a controlled release, have gained the attention of researchers. SLNs confine significant promises, overcome these challenges, and help to possibly deliver the drug to a specific part of the body, particular organ, or tissue by an actively or passively targeted delivery system, which will be beneficial in the diagnosis and treatment of breast cancer. The objective of this article is to highlight the factors that influence the targeted drug delivery system and resultant bioavailability and also provide updates on recent research and various approaches used for breast drug delivery systems.

Control release of α-mangostin by a novel dual-polysaccharides delivery system for colitis treatment under simulated gastrointestinal conditions

The poor hydrophilia and strong cytotoxicity of α-mangostin, a major component of xanthones from pericarps of mangosteen (Garcinia Mangostana L.), restrict its application in functional food. To overcome its shortage, a series of alginate/xanthan gum or alginate/κ-carrageenan hydrogels loaded with α-mangostin were fabricated and their anti-inflammatory effects were investigated under gastrointestinal tract (GIT). With the increased concentration of polysaccharides, the release of α-mangostin was slower due to denser microstructure and hardness. The digestive profile suggested that the release of α-mangostin in 0.3% alginate/0.15% xanthan gum (0.15%X-αM), 0.3% alginate/0.2% xanthan gum (0.25%X-αM) and 0.3% alginate/0.3% κ-carrageenan (0.3%C-αM) hydrogels were faster than the others. The cytotoxicity of α-mangostin loaded in hydrogels was dramatically reduced. However, the anti-inflammatory effect of the three intestinal digestive fluids was still maintained at 71.9% ± 1.2%, 83.1% ± 2.0%, and 70.6% ± 3.3% in LPS-induced Raw246.7 cells. In addition, the three intestinal digestive fluids (50 μM of α-mangostin) showed good inhibition of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and the expression of iNos and Cox-2 respectively. Given these data, xanthan gum/κ-carrageenan-alginate composite hydrogels can be a good colonic target delivery system for bioactive compounds, which can be applied in functional foods to improve human health and wellness.

Protein-Precoated Surface of Metal-Organic Framework Nanoparticles for Targeted Delivery.

Metal-organic framework (MOF) nanoparticles have recently emerged as a promising vehicle for drug delivery with high porosity and feasibility. However, employing a MOF-based drug delivery system remains a challenge due to the difficulty in controlling interfaces of particles in a biological environment. In this paper, protein corona-blocked Zr6 -based MOF (PCN-224) nanoparticles are presented for targeted cancer therapy with high efficiency. The unmodified PCN-224 surface is precoated with glutathione transferase (GST)-fused targetable affibody (GST-Afb) proteins via simple mixing conjugations instead of chemical modifications that can induce the impairment of proteins. GST-Afb proteins are shown to stably protect the surface of PCN-224 particles in a specific orientation with GST adsorbed onto the porous surface and the GST-linked Afb posed outward, minimizing the unwanted interfacial interactions of particles with external biological proteins. The Afb-directed cell-specific targeting ability of particles and consequent induction of cell death is demonstrated both in vitro and in vivo by using two kinds of Afb, which targets the surface membrane receptor, human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR). This study provides insight into the way of regulating the protein-adhesive surface of MOF nanoparticles and designing a more effective MOF-hosted targeted delivery system.

Colon cancer and their targeting approaches through nanocarriers

Colon cancer is the fifth most common type of cancer in the world. Colon cancer develops when healthy cells in the lining of the colon or rectum alter and grow uncontrollably to form a mass known as a tumor. Despite major medical improvements, colon cancer is still one of the leading causes of cancer-related mortality globally. One of the main issues of chemotherapy is toxicity related to conventional medicines. The targeted delivery systems are considered the safest and most effective by increasing the concentration of a therapeutic substance at the tumor site while decreasing it at other organs. Therefore, these delivery systems required lower doses for high therapeutic value with minimum side effects. The current review focuses on targeting therapeutic substances at the desired site using nanocarriers. Additionally, the diagnostic applications of nanocarriers in colorectal cancer are also discussed.

Transcytosable Peptide-Paclitaxel Prodrug Nanoparticle for Targeted Treatment of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an extremely aggressive subtype associated with a poor prognosis. At present, the treatment for TNBC mainly relies on surgery and traditional chemotherapy. As a key component in the standard treatment of TNBC, paclitaxel (PTX) effectively inhibits the growth and proliferation of tumor cells. However, the application of PTX in clinical treatment is limited due to its inherent hydrophobicity, weak penetrability, nonspecific accumulation, and side effects. To counter these problems, we constructed a novel PTX conjugate based on the peptide-drug conjugates (PDCs) strategy. In this PTX conjugate, a novel fused peptide TAR consisting of a tumor-targeting peptide, A7R, and a cell-penetrating peptide, TAT, is used to modify PTX. After modification, this conjugate is named PTX-SM-TAR, which is expected to improve the specificity and penetrability of PTX at the tumor site. Depending on hydrophilic TAR peptide and hydrophobic PTX, PTX-SM-TAR can self-assemble into nanoparticles and improve the water solubility of PTX. In terms of linkage, the acid- and esterase-sensitive ester bond was used as the linking bond, with which PTX-SM-TAR NPs could remain stable in the physiological environment, whereas PTX-SM-TAR NPs could be broken and PTX be released at the tumor site. A cell uptake assay showed that PTX-SM-TAR NPs were receptor-targeting and could mediate endocytosis by binding to NRP-1. The vascular barrier, transcellular migration, and tumor spheroids experiments showed that PTX-SM-TAR NPs exhibit great transvascular transport and tumor penetration ability. In vivo experiments, PTX-SM-TAR NPs showed higher antitumor effects than PTX. As a result, PTX-SM-TAR NPs may overcome the shortcomings of PTX and present a new transcytosable and targeted delivery system for PTX in TNBC treatment.

Preclinical and Clinical Trials of New Treatment Strategies Targeting Cancer Stem Cells in Subtypes of Breast Cancer.

Breast cancer (BC) can be classified into various histological subtypes, each associated with different prognoses and treatment options, including surgery, radiation, chemotherapy, and endocrine therapy. Despite advances in this area, many patients still face treatment failure, the risk of metastasis, and disease recurrence, which can ultimately lead to death. Mammary tumors, like other solid tumors, contain a population of small cells known as cancer stem-like cells (CSCs) that have high tumorigenic potential and are involved in cancer initiation, progression, metastasis, tumor recurrence, and resistance to therapy. Therefore, designing therapies specifically targeting at CSCs could help to control the growth of this cell population, leading to increased survival rates for BC patients. In this review, we discuss the characteristics of CSCs, their surface biomarkers, and the active signaling pathways associated with the acquisition of stemness in BC. We also cover preclinical and clinical studies that focus on evaluating new therapy systems targeted at CSCs in BC through various combinations of treatments, targeted delivery systems, and potential new drugs that inhibit the properties that allow these cells to survive and proliferate.

Polyelectrolyte Microcapsules-A Promising Target Delivery System of Amiodarone with the Possibility of Prolonged Release.

Atrial fibrillation is one of the most common cardiac arrhythmias. Pharmacological preparations are used for treatment to control heart rate and rhythm. Amiodarone is one of these highly effective preparations, but, at the same time, it has significant toxicity and nonspecific accumulation in tissues. The drug delivery system based on polyelectrolyte microcapsules is one of the solutions. For this purpose, we compared different encapsulation methods of amiodaron: monoammonium salt of glycyrrhizic acid (Am:MASGA) complex (molar ratio 1:8). The concentration of amiodarone was determined by spectrophotometric methods at 251 nm. It has been shown that the co-precipitation method allows capturing 8% of Am:MASGA by CaCO3 microspherulites, which is not sufficient for the long-acting drug. The adsorption method allows encapsulating more than 30% of Am:MASGA into CaCO3 microspherulites and polyelectrolyte microcapsules CaCO3(PAH/PSS)3, but, at the same time, an insignificant amount of substance is released into the incubation medium. The development of delivery and long-acting drug system based on such methods are not inexpedient. The most appropriate encapsulation method of Am:MASGA is the adsorption method into polyelectrolyte microcapsules with complex interpolyelectrolyte structure (PAH/PSS)3. Such a type of PMC adsorbed about 50% of the initial amount of the substance and 25-30% of Am:MASGA was released into the medium after 115 h of incubation. The adsorption of Am:MASGA by polyelectrolyte microcapsules has electrostatic nature as evidenced by the acceleration of the release by 1.8 times as ionic strength increases.

Recent updates in click and computational chemistry for drug discovery and development.

Drug discovery is a costly and time-consuming process with a very high failure rate. Recently, click chemistry and computer-aided drug design (CADD) represent popular areas for new drug development. Herein, we summarized the recent updates in click and computational chemistry for drug discovery and development including clicking to effectively synthesize druggable candidates, synthesis and modification of natural products, targeted delivery systems, and computer-aided drug discovery for target identification, seeking out and optimizing lead compounds, ADMET prediction as well as compounds synthesis, hopefully, inspires new ideas for novel drug development in the future.

Hybrid Nanosystems of Antibiotics with Metal Nanoparticles-Novel Antibacterial Agents.

The appearance and increasing number of microorganisms resistant to the action of antibiotics is one of the global problems of the 21st century. Already, the duration of therapeutic treatment and mortality from infectious diseases caused by pathogenic microorganisms have increased significantly over the last few decades. Nanoscale inorganic materials (metals and metal oxides) with antimicrobial potential are a promising solution to this problem. Here we discuss possible mechanisms of pathogenic microorganisms' resistance to antibiotics, proposed mechanisms of action of inorganic nanoparticles on bacterial cells, and the possibilities and benefits of their combined use with antibacterial drugs. The prospects of using metal and metal oxide nanoparticles as carriers in targeted delivery systems for antibacterial compositions are also discussed.

The Contest of Nanoparticles: Searching for the Most Effective Topical Delivery of Corticosteroids.

Owing to their complicated pathophysiology, the treatment of skin diseases necessitates a complex approach. Conventional treatment using topical corticosteroids often results in low effectiveness and the incidence of local or even systemic side effects. Nanoformulation of potent anti-inflammatory drugs has been selected as an optimal strategy for enhanced topical delivery of corticosteroids. In order to assess the efficiency of various nanoformulations, we formulated hydrocortisone (HC) and hydrocortisone-17-butyrate (HCB) into three different systems: lipid nanocapsules (LNC), polymeric nanoparticles (PNP), and ethosomes (ETZ). The systems were characterized using dynamic light scattering for their particle size and uniformity and the morphology of nanoparticles was observed by transmission electron microscopy. The nanosystems were tested using ex vivo full thickness porcine and human skin for the delivery of HC and HCB. The skin penetration was observed by confocal microscopy of fluorescently labelled nanosystems. ETZ were proposed as the most effective delivery system for both transdermal and dermal drug targeting but were also found to have a profound effect on the skin barrier with limited restoration. LNC and PNP were found to have significant effects in the dermal delivery of the actives with only minimal transdermal penetration, especially in case of HCB administration.

Cationic lipid-conjugated bis-arylidene oxindole derivatives as broad-spectrum breast cancer-selective therapeutics

Breast cancer is a heterogeneous malignancy with wide-ranging variations in therapeutic responses, overall survival etc. Major challenges for available chemotherapeutic agents in achieving clinical success are in maintaining systemic bio-distribution and avoiding non-specific adverse effects. Bis-arylidene oxindoles are estrogen receptor (ER)-selective bioactive molecules with moderate potency. In here, we have designed, synthesized and evaluated a series of twin aliphatic chain cationic lipid-conjugated bis-arylidene oxindole molecules with variations in nature of linker, lengths of carbon spacer and hydrophobic twin chains. We observed that among the various structural analogues, C8 twin-chain containing molecules, PGC8, S2C8 and S3C8 showed effective cancer cell-selective cytotoxicity in different cancer cell lines with an IC50 ranging from 4 to 7 µM. These molecules selectively induced apoptosis, ROS production and cell cycle inhibition at G1/S phase in ER + breast cancer cells but not in non-cancer cells. Additionally, these molecules formed homogenous self-assemblies exhibiting effective hydrodynamic diameter with positive surface charge. The self-assemblies also showed prominent cancer cell-selective uptake and DNA-binding abilities. Hence, we have shown successful incorporation of dexamethasone to the self-assemblies, and its enhanced cytotoxicity even in ER-negative breast cancer cells. All these results indicate that PGC8, S2C8 and S3C8 molecules, albeit their potent and selective ER-positive anti-breast cancer activity, can be repurposed as targeted delivery systems and hold promise as unique, broader spectrum breast cancer cell-selective therapeutic payloads.

Nano-Sized Fucoidan Interpolyelectrolyte Complexes: Recent Advances in Design and Prospects for Biomedical Applications.

The marine polysaccharide fucoidan (FUC) is a promising polymer for pharmaceutical research and development of novel drug delivery systems with modified release and targeted delivery. The presence of a sulfate group in the polysaccharide makes FUC an excellent candidate for the formation of interpolyelectrolyte complexes (PECs) with various polycations. However, due to the structural diversity of FUC, the design of FUC-based nanoformulations is challenging. This review describes the main strategies for the use of FUC-based PECs to develop drug delivery systems with improved biopharmaceutical properties, including nanocarriers in the form of FUC-chitosan PECs for pH-sensitive oral delivery, targeted delivery systems, and polymeric nanoparticles for improved hydrophobic drug delivery (e.g., FUC-zein PECs, core-shell structures obtained by the layer-by-layer self-assembly method, and self-assembled hydrophobically modified FUC particles). The importance of a complex study of the FUC structure, and the formation process of PECs based on it for obtaining reproducible polymeric nanoformulations with the desired properties, is also discussed.