Tumor-Homing Peptides as Crucial Component of Magnetic-Based Delivery Systems: Recent Developments and Pharmacoeconomical Perspective.

According to data from the World Health Organization (WHO), cancer is considered to be one of the leading causes of death worldwide, and new therapeutic approaches, especially improved novel cancer treatment regimens, are in high demand. Considering that many chemotherapeutic drugs tend to have poor pharmacokinetic profiles, including rapid clearance and limited on-site accumulation, a combined approach with tumor-homing peptide (THP)-functionalized magnetic nanoparticles could lead to remarkable improvements. This is confirmed by an increasing number of papers in this field, showing that the on-target peptide functionalization of magnetic nanoparticles improves their penetration properties and ensures tumor-specific binding, which results in an increased clinical response. This review aims to highlight the potential applications of THPs in combination with magnetic carriers across various fields, including a pharmacoeconomic perspective.

Membrane-Active Thermoresponsive Block Copolymers Containing a Diacylglycerol-Based Segment: RAFT Synthesis, Doxorubicin Encapsulation, and Evaluation of Cytotoxicity against Breast Cancer Cells.

Herein, we report the formation of drug delivery systems from original thermoresponsive block copolymers containing lipid-based segments. Two acrylate monomers derived from palmitic- or oleic-acid-based diacylglycerols (DAGs) were synthesized and polymerized by the reversible addition-fragmentation chain transfer (RAFT) method. Well-defined DAG-based polymers with targeted molar masses and narrow molar mass distributions were next used as macro-chain transfer agents (macro-CTAs) for the polymerization of N-isopropylacrylamide (NIPAAm) or N-vinylcaprolactam (NVCL). The obtained amphiphilic block copolymers were formed into polymeric nanoparticles (PNPs) with and without encapsulated doxorubicin and characterized. Their biological assessment indicated appropriate cytocompatibility with the representatives of normal cells. Furthermore, compared to the free drug, increased cytotoxicity and apoptosis or necrosis induction in breast cancer cells was documented, including a highly aggressive and invasive triple-negative MDA-MB-231 cell line.

Folic-Acid-Conjugated Thermoresponsive Polymeric Particles for Targeted Delivery of 5-Fluorouracil to CRC Cells.

Colorectal cancer is the fourth most common cancer worldwide and the third most frequently diagnosed form of cancer associated with high mortality rates. Recently, targeted drug delivery systems have been under increasing attention owing to advantages such as high therapeutic effectiveness with a significant depletion in adverse events. In this report, we describe the biocompatible and thermoresponsive FA-conjugated PHEA-b-PNIPAAm copolymers as nanocarriers for the delivery of 5-FU. The block copolymers were obtained using RAFT (Reversible Addition-Fragmentation chain Transfer) polymerization and were characterized by methods such as SEC (Size Exclusion Chromatography), NMR (Nuclear Magnetic Resonance), UV-Vis (Ultraviolet-Visible), FT-IR (Fourier Transform Infrared) spectroscopy, and TGA (Thermogravimetric Analysis). Nanoparticles were formed from polymers with and without the drug-5-fluorouracil, which was confirmed using DLS (Dynamic Light Scattering), zeta potential measurements, and TEM (Transmission Electron Microscopy) imaging. The cloud points of the polymers were found to be close to the temperature of the human body. Eventually, polymeric carriers were tested as drug delivery systems for the safety, compatibility, and targeting of colorectal cancer cells (CRC). The biological evaluation indicated high compatibility with the representative host cells. Furthermore, it showed that proposed nanosystems might have therapeutic potential as mitigators for 5-FU-induced monocytopenia, cardiotoxicity, and other chemotherapy-associated disorders. Moreover, results show increased cytotoxicity against cancer cells compared to the drug, including a line with a drug resistance phenotype. Additionally, the ability of synthesized carriers to induce apoptosis and necrosis in treated CRC cells has been confirmed. Undoubtedly, the presented aspects of colorectal cancer therapy promise future solutions to overcome the conventional limitations of current treatment regimens for this type of cancer and to improve the quality of life of the patients.

Probing E/Z Isomerism Using Pillar[4]pyridinium/Gold Nanoparticle Ensembles and Their Photoresponsive Behavior.

Despite the fundamental importance and broad applicability of E/Z dicarboxylic acids, their discrimination remains challenging and greatly unexplored. Herein, we present a general approach for the recognition of E/Z diacids using supramolecular interactions coupled with plasmonic response. The method allows detecting both single isomers and their light-induced interconversion, which ultimately entails multiple reversible nanoparticle aggregations. Such a molecular recognition-coupled responsive nanoscale self-assembly resembles natural mechanisms and can be a versatile means of building artificial complexity.

Magnetic Particles with Polymeric Shells Bearing Cholesterol Moieties Sensitize Breast Cancer Cells to Low Doses of Doxorubicin.

One of the promising strategies for improvement of cancer treatment is application of a combination therapy. The aim of this study was to investigate the anticancer activity of nanoformulations containing doxorubicin and iron oxide particles covered with polymeric shells bearing cholesterol moieties. It was postulated that due to high affinity to cell membranes, particles comprising poly(cholesteryl acrylate) can sensitize cancer cells to doxorubicin chemotherapy. The performed analyses revealed that the developed systems are effective against the human breast cancer cell lines MCF-7 and MDA-MB-231 even at low doses of the active compound applied (0.5 µM). Additionally, high compatibility and lack of toxicity of the tested materials against human red blood cells, immune (monocytic THP-1) cells, and cardiomyocyte H9C2(2-1) cells was demonstrated. Synergistic effects observed upon administration of doxorubicin with polymer-iron oxide hybrids comprising poly(cholesteryl acrylate) may provide an opportunity to limit toxicity of the drug and to improve its therapeutic efficiency at the same time.

Antimicrobial and Physicochemical Properties of Artificial Saliva Formulations Supplemented with Core-Shell Magnetic Nanoparticles.

Saliva plays a crucial role in oral cavity. In addition to its buffering and moisturizing properties, saliva fulfills many biofunctional requirements, including antibacterial activity that is essential to assure proper oral microbiota growth. Due to numerous extra- and intra-systemic factors, there are many disorders of its secretion, leading to oral dryness. Saliva substitutes used in such situations must meet many demands. This study was design to evaluate the effect of core-shell magnetic nanoparticles (MNPs) adding (gold-coated and aminosilane-coated nanoparticles NPs) on antimicrobial (microorganism adhesion, biofilm formation), rheological (viscosity, viscoelasticity) and physicochemical (pH, surface tension, conductivity) properties of three commercially available saliva formulations. Upon the addition of NPs (20 µg/mL), antibacterial activity of artificial saliva was found to increase against tested microorganisms by 20% to 50%. NPs, especially gold-coated ones, decrease the adhesion of Gram-positive and fungal cells by 65% and Gram-negative bacteria cells by 45%. Moreover, the addition of NPs strengthened the antimicrobial properties of tested artificial saliva, without influencing their rheological and physicochemical properties, which stay within the range characterizing the natural saliva collected from healthy subjects.

Inhibition of inflammatory response in human keratinocytes by magnetic nanoparticles functionalized with PBP10 peptide derived from the PIP2-binding site of human plasma gelsolin.

BACKGROUND: Human plasma gelsolin (pGSN) is a multifunctional actin-binding protein involved in a variety of biological processes, including neutralization of pro-inflammatory molecules such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and modulation of host inflammatory response. It was found that PBP10, a synthetic rhodamine B-conjugated peptide, based on the phosphoinositide-binding site of pGSN, exerts bactericidal activity against Gram-positive and Gram-negative bacteria, interacts specifically with LPS and LTA, and limits microbial-induced inflammatory effects. The therapeutic efficiency of PBP10 when immobilized on the surface of iron oxide-based magnetic nanoparticles was not evaluated, to date. RESULTS: Using the human keratinocyte cell line HaCaT stimulated by bacterially-derived LPS and LTA as an in vitro model of bacterial infection, we examined the anti-inflammatory effects of nanosystems consisting of iron oxide-based magnetic nanoparticles with aminosilane (MNP@NH2) or gold shells (MNP@Au) functionalized by a set of peptides, derived from the phosphatidylinositol 4,5-bisphosphate (PIP2)-binding site of the human plasma protein gelsolin, which also binds LPS and LTA. Our results indicate that these nanosystems can kill both Gram-positive and Gram-negative bacteria and limit the production of inflammatory mediators, including nitric oxide (NO), reactive oxygen species (ROS), and interleukin-8 (IL-8) in the response to heat-killed microbes or extracted bacterial cell wall components. The nanoparticles possess the potential to improve therapeutic efficacy and are characterized by lower toxicity and improved hemocompatibility when compared to free peptides. Atomic force microscopy (AFM) showed that these PBP10-based nanosystems prevented changes in nanomechanical properties of cells that were otherwise stimulated by LPS. CONCLUSIONS: Neutralization of endotoxemia-mediated cellular effects by gelsolin-derived peptides and PBP10-containing nanosystems might be considered as potent therapeutic agents in the improved therapy of bacterial infections and microbial-induced inflammation.

Mucoadhesive Alginate/Pectin Films Crosslinked by Calcium Carbonate as Carriers of a Model Antifungal Drug-Posaconazole.

The mucosal membrane of the oral cavity, due to its unique structure and availability, constitutes an appropriate site for the delivery of drugs, both with local and systemic effects. Mucoadhesive buccal films are drug dosage forms that due to their convenience of application, flexibility and size, are characterized by patients' compliance. Sodium alginate and pectin are natural polymers from the polysaccharides group, with mucoadhesive properties, that are widely applied to obtain buccal films. However, their hydrophilic nature and poor water resistance limit their application in sustained drug release formulations. Hence, the aim of this investigation was to design alginate/pectin buccal films by a one-step crosslinking technique-with the application of calcium carbonate. This technique was applied to prepare crosslinked alginate and alginate/pectin mucoadhesive films with a model antifungal drug-posaconazole. The obtained formulations were evaluated for the impact of crosslinking and pectin's presence on their pharmaceutical, mucoadhesive, mechanical and physicochemical properties. Additionally, the antifungal activity of the prepared films against Candida spp. was evaluated. It was shown that pectin's presence in the formulations improved flexibility, mucoadhesion and antifungal activity. The crosslinking process reduced mucoadhesiveness and antifungal activity but significantly enhanced the mechanical properties and stability and enabled prolonged drug release.

Doxorubicin delivery systems with an acetylacetone-based block in cholesterol-terminated copolymers: Diverse activity against estrogen-dependent and estrogen-independent breast cancer cells.

The study presents the synthesis of original cholesterol-terminated copolymers comprising acetylacetone-based (AcacI) and N-isopropylacrylamide (NIPAAm) units with a varied arrangement (block and random copolymers). The nanoprecipitation method was used to form empty and doxorubicin-loaded polymeric nanoparticles (PNPs) from these copolymers, which were further studied in terms of their physicochemical and biological properties. Unexpectedly, it was revealed that even empty PNPs are effective against breast cancer cells, specifically towards estrogen-dependent MCF-7 cell line. The anti-cancer efficacy was further improved when a low dose of doxorubicin was introduced to the tested systems. It was shown that the proposed carriers modulate doxorubicin (DOX) compatibility with representatives of normal cells, including immune cells, cardiomyocyte cells, and fibroblasts, and reduce side effects associated with standard chemotherapy. The use of these carriers might be a strategy leading to enhancement of DOX activity in cancer cells which develop resistance through decreased drug penetration or drug efflux.

Visual discrimination of aromatic acid substitution patterns by supramolecular nanocooperativity.

Physicochemical and, in particular, visual recognition of positional isomers, due to their similar appearance and properties, is an extremely challenging task. Here we present an easy-to-prepare assay for the naked-eye differentiation of all possible isomers of phthalic acids. The desired optical response is attained through specific non-covalent interactions between the acids and a cationic macrocyclic host. These interactions are then translated to and amplified by gold nanoparticles which subsequently aggregate to various extents producing a color palette.

Evaluation of Cytotoxic Effect of Cholesterol End-Capped Poly(N-Isopropylacrylamide)s on Selected Normal and Neoplastic Cells.

PURPOSE: Efficient intracellular delivery of a therapeutic compound is an important feature of smart drug delivery systems (SDDS). Modification of a carrier structure with a cell-penetrating ligand, ie, cholesterol moiety, is a strategy to improve cellular uptake. Cholesterol end-capped poly(N-isopropylacrylamide)s offer a promising foundation for the design of efficient thermoresponsive drug delivery systems. METHODS: A series of cholesterol end-capped poly(N-isopropylacrylamide)s (PNIPAAm) with number-average molar masses ranging from 3200 to 11000 g·mol-1 were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization from original xanthate-functionalized cholesterol and self-assembled into micelles. The physicochemical characteristics and cytotoxicity of cholesterol end-capped poly(N-isopropylacrylamide)s have been thoroughly investigated. RESULTS: Phase transition temperature dependence on the molecular weight and hydrophilic/hydrophobic ratio in the polymers were observed in water. Biological test results showed that the obtained materials, both in disordered and micellar form, are non-hemolytic, highly compatible with fibroblasts, and toxic to glioblastoma cells. It was found that the polymer termini dictates the mode of action of the system. CONCLUSION: The cholesteryl moiety acts as a cell-penetrating agent, which enables disruption of the plasma membrane and in effect leads to the restriction of the tumor growth. Cholesterol end-capped PNIPAAm showing in vitro anticancer efficacy can be developed not only as drug carriers but also as components of combined/synergistic therapy.