Drug Targeting Applications Research Articles

Synthesis of Poly(2-Hydroxyethyl Methacrylate) (PHEMA)-Based Superparamagnetic Nanoparticles for Biomedical and Pharmaceutical Applications.

The performance of polymeric nanomaterials relies greatly upon their properties which are intimately related to the methods of fabrication of their materials. Among various synthetic polymers the polymers of 2-hydroxyethyl methacrylate (PHEMA) maintains a prime position in the biomedical field due to their useful physicochemical properties and suitability for controlled drug delivery applications. Furthermore, the addition of iron oxide to PHEMA nanoparticles imparts superparamagnetism to the nanoparticles and expands the range of their uses to include magnetic drug targeting applications. Here we focus on three methods for preparation of PHEMA nanoparticles, one by suspension polymerization, a second by emulsion polymerization without the use of any surfactants, and the final one with the incorporation of iron oxide into PHEMA nanoparticles.

Abstract A097: Tubulysin ADC payloads: An antimitotic drug class that retains activity in multidrug resistant models

Abstract As antibody-drug conjugates (ADCs) find increasing clinical application, treatment-related resistance mechanisms may eventually impact efficacy. One resistance mechanism that emerges following prolonged exposure to auristatin-based ADCs such as brentuximab vedotin and polatuzumab vedotin involves upregulation of efflux pumps that confer the multidrug resistance positive (MDR+) phenotype. New payload technologies that retain activity in this context may be important for next-generation anti-tubulin ADCs. The tubulysins are a potent class of tubulin binders consisting of natural products and designed analogues which have become a compelling cytotoxic payload for drug targeting applications. This is due in large part to their high cytotoxic potency on cancer cells, including those that express MDR-conferring transporters. Recently, we developed the quaternary ammonium linker system to conjugate tertiary amine-containing payloads and applied it to the tubulysins. In this work, β-glucuronidase-cleavable quaternary ammonium linkers of tubulysin M were evaluated as ADC payloads for activity in MDR+ models. The resulting conjugates displayed high potency in multiple MDR+ models at well-tolerated doses, including those resistant to MMAE-based ADCs. In addition to potency in resistant models, the tubulysin conjugates also retained bystander activity - a property in common with vedotin-based conjugates and important for indications characterized by heterogeneous antigen expression. Thus, the glucuronide-tubulysin M linker could enable future ADC programs designed for the treatment of resistant tumors due to emergence of MDR transporters. Citation Format: Patrick J Burke, Joseph Z Hamilton, Thomas A Pires, Kim K Emmerton, Peter D Senter, Scott C Jeffrey. Tubulysin ADC payloads: An antimitotic drug class that retains activity in multidrug resistant models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A097. doi:10.1158/1535-7163.TARG-19-A097

Guiding and Accumulation of Magnetic Nanoparticles Employing High Intensity Focused Ultrasound for Drug Targeting Applications

Abstract Magnetic Drug Targeting (MDT) is a cancer treatment technique that enables a local chemotherapy. In MDT, chemotherapeutic drugs are bound to magnetic nanoparticles and are accumulated in the tumor area by means of an external magnetic field. Unfortunately, a single magnet can only generate a pulling magnetic force. However, in some applications a pushing force on the nanoparticles could be advantageous. One way to realize pushing forces is to exploit the acoustic radiation force based on the nonlinearity of sound propagation in fluid media generated by a high intensity focused ultrasonic transducer. In this context, we built a test setup was built to investigate the utility of High Intensity Focused Ultrasound (HIFU) to generate a pushing force on the magnetic nanoparticles. The results show that the acoustic radiation force can be employed for particle guidance to achieve concentration differences similar to those obtained by using an electromagnet.

Functionalized mesoporous silica nanoparticles in anticancer therapeutics.

The application of nanomedicines in tumor targeting and attaining meaningful therapeutic benefits for the treatment of cancers has been going on for almost two decades. Beyond the lipidic and polymeric nanomedicines-based passive and active targeting, the quest for inventing the new generation of carriers has no end. This has lead to the evolution of some of the unique carrier systems with supramolecular assembly structures. Mesoporous nanoparticulate systems (MSNPs) are the recently explored substances with favorable potential for drug delivery and drug targeting applications especially in cancer chemotherapeutics. Notwithstanding their physical properties that makes them a suitable carrier for cancer treatment, but their outstanding ability towards chemical functionalization helps in delivering the imaging agents for diagnostic applications. MSNPs can improve the dissolution rate and systemic availability of the poorly water soluble drugs due to their mesoporous structures. Besides, guest molecules including targeting ligands, biomimetic agents, fluorescent dyes, and biocompatible polymers can be efficiently encapsulated in their tunable porous structure for targeting purpose. Some special features of the MSNPs which make them one of the highly effective nanocarrier systems include their ability to encapsulate non-crystalline drugs in their mesopores, high dispersion ability as a function of large surface area and wetting properties. For anticancer drug delivery, MSNPs are worthful to provide excellent drug loading capacity and endocytotic behavior. Moreover, the external surface of MSNPs can be precisely modified for tumor-recognition and developing sensitivity of the antitumor agents towards the cancer cells. Owing to the innumerable applications of MSNPs till now in cancer treatment, the present article particularly focuses to provide an overview account with complete details on the topic to make the readers abreast with details on physiochemical and material properties of MSNPs, their applications and current innovations for the purpose.

Controlled morphological transition of ABC triblock copolymer aided by oleic acid via hydrogen bonding

A facile method is introduced to tune the aggregate morphologies of ABC triblock copolymer in selective media by combining the self-assembly and hydrogen bonding. Poly(styrene)-block-poly(1,4-butadiene)-block-poly(2-vinyl pyridine), abbreviated for PS-b-PBd-b-P2VP and used as an ABC triblock copolymer, self-assembles in toluene and methanol mixture to form discoid micelles with PBd as the disk containing part of PS domains in the core, other PS as bumps and P2VP as corona, respectively. When oleic acid (OA) is added in the assembly system, supramolecular polymer PS-b-PBd-b-P2VP(OA) is prepared by the hydrogen bonding between OA and P2VP of triblock copolymer. As a result, biscuit-like and mushroom-like micelles are formed with assistance of hydrogen bonding. Interestingly, the biscuit-like and mushroom-like micelles can transform reciprocally by fission and fusion mechanism through varying the volume ratio of toluene and methanol. Thus, it provides a simple and convenient approach to control the aggregate morphologies of block copolymers by tuning the hydrogen bonding and selective solvent content. The multicompartment micelles from ABC triblock copolymer may present potential applications in drug delivery, targeting, catalysis and others.

Positive and negative effects of nanoparticles on plants and their applications in agriculture

Nanotechnology is the promising field with its wide applications in biotechnology, pharmaceutical science, drug targeting, nano-medicine and other research areas. This review highlights the positive and negative impact of nanoparticles on plants and its wide applications in agricultural sciences. Effect of NPs in terms of seed germination, growth promotion and enhancement of metabolic rate has been evaluated by several scientific researches. However, NPs also exert their negative effects such as suppression of plant growth, inhibition of chlorophyll synthesis, photosynthetic efficiency etc. Effects of NPs can be either positive or negative it depending upon the plant species and type of nanoparticles used & its concentration. Modern nano-biotechnological tools have a great potential to increase food quality, global food production, plant protection, detection of plant and animal diseases, monitoring of plant growth nano-fertilizers, nano-pesticide, nano-herbicides and nano-fungicides.

Niosome-loaded antifungal drugs as an effective nanocarrier system: A mini review.

Skin is an important organ of the body due to offering an accessible and convenient site for drug administration. One of the disadvantages of transdermal drug delivery is the low penetration rate of drugs through the skin. Over the past decades, nanoparticles have been used as drug delivery systems to increase therapeutic effects or reduce toxicity. Encapsulation of drugs in nanoparticulate vesicles simplifies the transports of drugs into and across the skin. Niosome nanoparticles are among these drug delivery systems, which have numerous applications in drug delivery and targeting. Niosomes are frequently used for loading drugs serving different purposes (e.g., anticancer, antiviral, and antibacterial agents). In recent years, there has been much research on the use of niosomal systems for the delivery of fungal drugs. A review of the literature investigating the advantages of niosomes in antifungal drug delivery can elucidate the efficiency and superiority of this nanocarrier over other nanocarriers.

Multifunctional doxorubicin-loaded magnetoliposomes with active and magnetic targeting properties

Multifunctional magnetoliposomes (MLs) with active and magnetic targeting potential are evaluated as platform systems for drug targeting applications. USPIO-encapsulating MLs are prepared by freeze drying/extrusion, decorated with one or two ligands for brain or cancer targeting (t-MLs), and actively loaded with Doxorubicin (DOX). MLs have mean diameters between 117 and 171 nm. Ligand attachment yields and DOX-loading efficiency are sufficiently high, 78–95% and 89–92%, respectively, while DOX loading and retention is not affected by co-entrapment of USPIOs, and USPIO loading/retention is not modulated by DOX. Attachment of ligands, also does not affect DOX or USPIO loading. Interestingly, MLs have high magnetophoretic mobility (MM) compared to free USPIOs, which is not affected by surface coating with PEG (up to 8 mol%), but is slightly reduced by Chol incorporation in their membrane, or when functional groups are immobilized on their surface. ML size, (directly related to number of USPIOs entrapped per vesicle), is the most important MM-determining factor. MM increases by 570% when ML size increases from 69 to 348 nm. Targeting potential of t-MLs is verified by enhanced: (i) transport across a cellular model of the blood-brain-barrier, and (ii) anti-proliferative effect towards B16 melanoma cells. The potential of further enhancing t-ML targeting magnetically is verified by additional enhancements of (i) and (ii), when experiments are performed under a permanent magnetic field.

Abstract 1649: Impact of linker and conjugation site on tubulysin M ADC stability and in vivo activity

Abstract The tubulysins are a potent class of microtubule-disrupting agents consisting of natural products and designed analogues that have become a compelling cytotoxic payload for drug-targeting applications. This is due in large part to their high cytotoxic potency on cancer cells, including those that express transporters conferring the multidrug resistance (MDR+) phenotype. All potent tubulysin natural products contain an acetoxy group at the C11-position in the central tubuvaline residue. Deacetylation results in >100-fold loss of cellular and biochemical potency, underscoring the importance of this structural element. Recently, we developed quaternary ammonium linker systems to conjugate tertiary amine-containing payloads, and applied them to the tubulysins. In this work, protease- and β-glucuronidase-cleavable quaternary ammonium linkers of tubulysin M were evaluated as ADC payloads. In vitro, both dipeptide and glucuronide linker systems provided ADCs with comparable biologic properties. However, in vivo, linker chemistry and conjugation site were important parameters impacting acetate group stability. Higher degrees of stability translated to greater activity in xenograft models. ADCs were prepared with both dipeptide and glucuronide linkers as heterogeneous ADCs loaded at an average of 4-drugs/Ab (DAR 4), and as homogeneous ADCs loaded at 2-drugs/Ab (DAR 2) at the engineered S239C sites. Increased in vivo acetate stability was observed for glucuronide-based conjugates relative to the dipeptide analogue. Further stabilization was achieved by conjugating at the S239C sites (DAR 2) relative to native antibody cysteines (DAR 4). Tubulysin M acetate stabilization by both linker and conjugation site selection resulted in increased ADC potency in preclinical models and, combined, serves as an enabling strategy for antibody-mediated tubulysin M drug delivery. Citation Format: Patrick J. Burke, Joseph Z. Hamilton, Thomas A. Pires, Christopher I. Leiske, Julia H. Cochran, Jocelyn R. Setter, Kim K. Emmerton, Andrew B. Waight, Peter D. Senter, Robert P. Lyon, Scott C. Jeffrey. Impact of linker and conjugation site on tubulysin M ADC stability and in vivo activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1649.

Formulation and optimization of pH sensitive drug releasing O/W emulsions using Albizia lebbeck L. seed polysaccharide

Smart polymers, one of the class of polymers with extensive growth in the last few decades due to their wide applications in drug targeting and controlled delivery systems. With this in mind, the aim of the present study is to design and formulate smart releasing o/w emulsion by using Albizia lebbeck L. seed polysaccharide (ALPS). For this purpose, the physicochemical and drug release characteristics like emulsion capacity (EC), emulsion stability (ES), viscosity, microscopy, zeta potential, polydispersity index (PDI) and in-vitro drug release were performed. The EC and ES values were found to increase with an increased concentration of ALPS. The emulsion formulations were statistically designed by using 32 full factorial design. All the emulsions showed a shear-thinning behavior. The zeta potential and polydispersity index were found to be in the range of −35.83 mV to −19.00 mV and 0.232–1.000 respectively. Further, the percent cumulative drug release of the emulsions at 8 h was found to be in the range of 30.19–82.65%. The drug release profile exhibited zero order release kinetics. In conclusion, the ALPS can be used as a natural emulsifier and smart polymer for the preparation of pH sensitive emulsions in drug delivery systems.

Facile synthesis and characterization of iron oxide–egg albumin (IOEA) as core–shell nanoparticles and study of water intake potential

In the present study an in-situ chemical precipitation method was followed to design core–shell nanoparticles having iron oxide as the core and glutaraldehyde-crosslinked egg albumin as shell. The experimental conditions like the concentrations of Fe2+/Fe3+ ions, egg albumin, and glutaraldehyde, pH and temperature were optimized to achieve controllable and desired size of nanoparticles suitable for magnetic drug targeting applications. The nanoparticles were characterized by FTIR, XRD, TEM, DSC, DLS and surface charge measurements techniques. The prepared core–shell nanoparticles were also studied by vibrating sample magnetometer (VSM) method to seek information about their superparamagnetic nature. The suitability of nanoparticles to function as swelling controlled drug delivery system was also examined by conducting swelling experiments in PBS (pH 7.4) under varying experimental conditions and the results obtained were optimized to achieve the conditions at which an optimum swelling behavior was obtained.

Dendrimers: Nanosized Multifunctional Platform for Drug Delivery

Background: Dendrimers are nano-sized drug delivery systems that present significant advantages, including ease of construction, large number of polymers available for their synthesis and amenability to affix various types of ligands for targeting to specific site. The nanosystem with unique functional architecture and macromolecular characteristics has garnered considerable interest amongst researchers and various research reports and patents inputs can be found in literature. Objective: Till date more than ten families of dendrimers have been reported for their wide applications in medicine including diagnostic/clinical, and also in industrial arenas. Unlike traditional polymers, many dendrimers have remarkable features like improved aqueous solubility, biocompatibility, polyvalency and precise molecular weight. These features make dendrimers an ideal vehicle for drug delivery and targeting applications. Conclusion: The current review is an attempt to define types of dendrimers and their applications in drug delivery and cosmetics. The write up also highlights future perspectives of the multifunctional nanosystem. Keywords: Dendrimers, applications, cosmetics, biomedical, pharmaceutical, nanosized multifunctional platform.

Study on the formation and properties of red blood cell-like Fe3O4/TbLa3(Bim)12/PLGA composite particles.

Besides the particle size and surface performance, the shape also plays a key role in drug delivery systems. Red blood cells are the most abundant blood cells in the human body, and are excellent oxygen carriers, due to their unique biconcave discoid shape. In this study, red blood cell (RBC)-like Fe3O4/TbLa3(Bim)12/poly(lactic-co-glycolic acid) (PLGA) composite particles, with magnetic response and bioimaging functions, were prepared by electrospraying. Various electrospraying parameters, such as solvent, PLGA concentration, collecting distance and solution flow rate were investigated in detail to attempt to obtain RBC-like composite particles. The size distribution, morphology, structure, and hydrophobicity–hydrophilicity of particles were characterized. The results revealed the RBC-like Fe3O4/TbLa3(Bim)12/PLGA composite particles exhibited a strong green fluorescence and good magnetic behavior even when incubated with cells. Furthermore, the intensity of the magnetization and fluorescence can be adjusted by changing the contents of Fe3O4 and TbLa3(Bim)12. The effect on cell viability of the RBC-like Fe3O4/TbLa3(Bim)12/PLGA composite particles was evaluated in A549 cells and RBCs, and it was determined to have low cytotoxicity and excellent blood biocompatibility, suggesting that it is a promising candidate for application in drug delivery, targeting and tracking.

Clickable Cubosomes for Antibody-Free Drug Targeting and Imaging Applications.

The combination of copper-free click chemistry with metabolic labeling offers new opportunities in drug delivery. The objective of this study was to determine whether cubosomes functionalized with azide or dibenzocyclooctyne (DBCO) groups are able to undergo copper-free click chemistry with a strained cyclooctyne or azide, respectively. Phytantriol-based cubosomes were functionalized using phospholipids bearing an azide or DBCO group. The modified cubosome dispersions were characterized using dynamic light scattering, cryo-TEM, and small-angle X-ray scattering. The efficiency of "clickability" was assessed by reacting the cubosomes with a complementary dye and determining bound and unbound dye via size exclusion chromatography. The clickable cubosomes reacted specifically and efficiently with a click-Cy5 dye with minor changes to the size, shape, and structure of the cubosomes. This indicates that cubosomes can retain their unique internal structure while participating in copper-free click chemistry. This proof of concept study paves the way for the use of copper-free click chemistry and metabolic labeling with cubosomes for targeted drug delivery and imaging.

Monodisperse and mesoporous walnut kernel-like SiO2/γ-Fe2O3 nanocomposite: Synthesis, magnetic properties, and application in drug delivery

Mesoporous and magnetic nanomaterials have attracted great attention owing to their unique characteristics and promising applications in drug delivery. In this context, a novel method has been developed to engineer a nanostructure of unique walnut kernel-like SiO2/γ-Fe2O3 nanocomposite by incorporating magnetic γ-Fe2O3 crystallites into mesoporous SiO2 nanospheres to exert their synergistic properties. The as-obtained SiO2/γ-Fe2O3 nanospheres may be applied as a promising drug carrier due to suitable their advantages such as suitable particle size, mesoporous structure, large specific surface area, high biocompatibility, good loading capacity, and long efficiency time of the drug release behavior. In particular, the composite exhibits intense magnetic property, which may lead to the development of nanocomposite with great potential for applications in drug targeting and magnetic hyperthermia therapy.

Unique Roles of Gold Nanoparticles in Drug Delivery, Targeting and Imaging Applications.

Nanotechnology has become more and more potentially used in diagnosis or treatment of diseases. Advances in nanotechnology have led to new and improved nanomaterials in biomedical applications. Common nanomaterials applicable in biomedical applications include liposomes, polymeric micelles, graphene, carbon nanotubes, quantum dots, ferroferric oxide nanoparticles, gold nanoparticles (Au NPs), and so on. Among them, Au NPs have been considered as the most interesting nanomaterial because of its unique optical, electronic, sensing and biochemical properties. Au NPs have been potentially applied for medical imaging, drug delivery, and tumor therapy in the early detection, diagnosis, and treatment of diseases. This review focuses on some recent advances in the use of Au NPs as drug carriers for the intracellular delivery of therapeutics and as molecular nanoprobes for the detection and monitoring of target molecules.

Modeling Superparamagnetic Particles in Blood Flow for Applications in Magnetic Drug Targeting

Magnetic drug targeting is a technique that involves the binding of medicine to magnetizable particles to allow for more specific transport to the target location. This has recently come to light as a method of drug delivery that reduces the disadvantages of conventional, systemic treatments. This study developed a mathematical model for tracking individual superparamagnetic nanoparticles in blood flow in the presence of an externally applied magnetic field. The model considers the magnetic attraction between the particles and the external magnet, influence of power law flow, diffusive interaction between the particles and blood, and random collisions with red blood cells. A stochastic system of differential equations is presented and solved numerically to simulate the paths taken by particles in a blood vessel. This study specifically focused on localized cancer treatment, in which a surface tumor is accessed through smaller blood vessels, which are more conducive to this delivery method due to slower flow velocities and smaller diameters. The probability of the particles reaching the tumor location is found to be directly dependent on ambient factors; thus, diffusion through Brownian motion and red blood cell collisions, different magnetic field and force models, blood viscosities, and release points are considered.

Developing Polyamine-Based Peptide Amphiphiles with Tunable Morphology and Physicochemical Properties.

The ability to tune supramolecular properties such as size, morphology, or metabolic stability is of paramount importance in the field of supramolecular chemistry. Peptide amphiphiles (PAs) are a family of functional self-assembling biomaterials that have garnered widespread attention due to their broad applicability in medicine. PAs are generally comprised of an amino acid sequence connected to lipid tail(s) allowing them to self-assemble into supramolecular structures with diverse morphologies. Herein, this study describes the synthesis of a new class of polyamine-based "hybrid" PAs (PPAs) as novel self-assembling systems. The described molecules possess diverse polyamine head groups with the goal of tuning physicochemical properties. The findings indicate that small changes in the polyamine head groups result in altered PPA morphologies (nanofibers, micelles, nanoworms). The PPAs present a wide range of physicochemical characteristics, show superior resistance to aggregation, a diverse metabolic profile, and varied assembling kinetics. Most of the PPAs do not show toxicity in the human cells lines evaluated. The PPAs described herein hold promising potential as a safe and nontoxic option for drug delivery, targeting, and tissue engineering applications.

Zeolitic imidazolate framework-8 (ZIF-8) as a sacrificial template: one-pot synthesis of hollow poly(dopamine) nanocapsules and yolk-structured poly(dopamine) nanocomposites

Hollow poly(dopamine) (PDA) nanocapsules and yolk-structured PDA nanocomposites were prepared by an aqueous one-pot synthesis method utilizing zeolitic imidazolate framework-8 (ZIF-8) nanocrystals as a sacrificial template without any special etchant. The resulting PDA nanocapsules show negligible cytotoxicity in HeLa cells after incubation for 48 h at various doses, which implies their potential as candidates for practical applications in drug transport and targeting.

Layer-by-layer assembled magnetic prednisolone microcapsules (MPC) for controlled and targeted drug release at rheumatoid arthritic joints

We report here in about the formulation and evaluation of Magnetic Prednisolone Microcapsules (MPC) developed in order to improve the therapeutic efficacy relatively at a low dose than the conventional dosage formulations by means of magnetic drug targeting and thus enhancing bioavailability at the arthritic joints. Prednisolone was loaded to poly (sodium 4-styrenesulfonate) (PSS) doped calcium carbonate microspheres confirmed by the decrease in surface area from 97.48m2/g to 12.05 of m2/g by BET analysis. Adsorption with oppositely charged polyelectrolytes incorporated with iron oxide nanoparticles was confirmed through zeta analysis. Removal of calcium carbonate core yielded MPC with particle size of ~3.48µm, zeta potential of +29.7mV was evaluated for its magnetic properties. Functional integrity of MPC was confirmed through FT-IR spectrum. Stability studies were performed at 25°C±65% relative humidity for 60 days showed no considerable changes. Further the encapsulation efficiency of 63%, loading capacity of 18.2% and drug release of 88.3% for 36h and its kinetics were also reported. The observed results justify the suitability of MPC for possible applications in the magnetic drug targeting for efficient therapy of rheumatoid arthritis.