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Surface modification of liposomes for selective targeting in cardiovascular drug delivery
Abstract and Figures
Cardiovascular disease processes such as atherosclerosis, restenosis, and inflammation are typically localized to discrete regions of the vasculature, affording great opportunity for targeted pharmacological treatment. Liposomes are potentially advantageous targeted drug carriers for such intravascular applications. To facilitate their use as drug delivery vehicles, we have considered three components of liposome design: (i) identification of candidate cell surface receptors for targeting; (ii) identification of ligands that maintain binding specificity and affinity; and (iii) prevention of rapid nonspecific clearance of liposomes into the reticuloendothelial organs. In this report, we describe our work in developing liposomal surface modifications that address both targeting and clearance. An arginine-glycine-aspartic acid (RGD) containing peptide was used as a model ligand to target liposomes to the integrin GPIIb-IIIa on activated platelets. Additionally, oligodextran surfactants incorporated into liposomes provided insight into the effect of vesicle perturbations on liposome clearance, and the importance of molecular geometry in designing oligosaccharide surface modifications. Together these studies demonstrate the feasibility of using peptides to guide liposomes to desired receptors, and illustrate the influence of vesicle stability on liposome interactions in vivo. Furthermore, they underscore the importance of simultaneously considering both targeting specificity and vesicle longevity in the design of effective targeted drug delivery systems.
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... For post-myocardial infarction settings, peptide-modified liposomal systems which have enhanced the bioavailability of drugs like the poly(ADP ribose) polymerase-1 inhibitor AZ7379 are used (Dasa et al., 2015). Additionally, ligand-gated delivery systems, such as those using arginine-glycine-aspartic acid (RGD), have been employed to target integrin receptors on activated platelets (Lestini et al., 2002). ...
Cardiovascular diseases (CVDs) have become the world's leading malady claiming lives of 17.9 million people every year. CVDs are a group of disorders related to the heart and the blood vessels. Conventional treatments have always been a concern due to several limitations such as off-target effects, effectivity and bioavailability. The use of nanotechnology has expanded the feasibility of its treatment with accuracy and specificity. Among them, targeted nanotherapeutics have improved the quality of drug delivery enabling to target selectively while keeping the side effects to a minimum. This chapter explores the field of targeted nanotherapeutics for cardiovascular disorders.
... This unique structure enables the encapsulation of a wide variety of both hydrophilic and hydrophobic diagnostic [52,53] or therapeutic [54,55] agents, offering protection from clearance by the body. Since liposomes can be easily taken up by the reticuloendothelial system, structural and surface modifications have been reported to improve the efficiency and widen the applicability of liposomes [56]; liposomes have been used for environmental sensing [57][58][59][60][61][62], specific active targeting [63][64][65], and long circulation [66][67][68]. Applications of liposomes are currently limited by low loading capacity and fixed release kinetics [69,70]. Lipid nanoparticles (LNPs) are primarily comprised of cationic ionizable lipids [71]. ...
Nanomedicine has been extensively explored for therapeutic and diagnostic applications in recent years, owing to its numerous advantages such as controlled release, targeted delivery, and efficient protection of encapsulated agents. Integration of microneedle technologies with nanomedicine has the potential to address current limitations in nanomedicine for drug delivery including relatively low therapeutic efficacy and poor patient compliance and enable theragnostic uses. In this Review, we first summarize representative types of nanomedicine and describe their broad applications. We then outline the current challenges faced by nanomedicine, with a focus on issues related to physical barriers, biological barriers, and patient compliance. Next, we provide an overview of microneedle systems, including their definition, manufacturing strategies, drug release mechanisms, and current advantages and challenges. We also discuss the use of microneedle-mediated nanomedicine systems for therapeutic and diagnostic applications. Finally, we provide a perspective on the current status and future prospects for microneedle-mediated nanomedicine for biomedical applications.
... Liposomal platforms have also demonstrated their efficacy in treating CVDs by targeting platelets (Ruiz-Esparza et al., 2013). Due to their enhanced and improved ability to distribute drugs to damaged cardiovascular tissues and surroundings, liposomes with changed surfaces are always used to treat cardiovascular diseases (Lestini et al., 2002). It was reported that the ability of liposomes to target platelets in a rat model of restenosis with catheter-induced carotid artery damage. ...
The increasing burden of cardiovascular disease (CVD) remains responsible for morbidity and mortality worldwide; their effective diagnostic or treatment methods are of great interest to researchers. The use of NPs and nanocarriers in cardiology has drawn much interest. The present comprehensive review provides deep insights into the use of current and innovative approaches in CVD diagnostics to offer practical ways to utilize nanotechnological interventions and the critical elements in the CVD diagnosis, associated risk factors, and management strategies of patients with chronic CVDs. We proposed a decision tree-based solution by discussing the emerging applications of NPs for the higher number of rules to increase efficiency in treating CVDs. This review-based study explores the screening methods, tests, and toxicity to provide a unique way of creating a multi-parametric feature that includes cutting-edge techniques for identifying cardiovascular problems and their treatments. We discussed the benefits and drawbacks of various NPs in the context of cost, space, time and complexity that have been previously suggested in the literature for the diagnosis of CVDs risk factors. Also, we highlighted the advances in using NPs for targeted and improved drug delivery and discussed the evolution toward the nano-cardiovascular potential for medical science. Finally, we also examined the mixed-based diagnostic approaches crucial for treating cardiovascular disorders, broad applications and the potential future applications of nanotechnology in medical sciences.
... The most currently available drugs used in the management of cardiovascular diseases lack the ability to target the damaged tissue, thereby reaching low concentration and significant damage to other tissues [2]. An important component of cardiovascular diseases is atherosclerosis, which may result in localized reduced blood flow and impaired drug or contrast agent delivery at the area of interest [3]. ...
Cardiovascular diseases are the main cause of death worldwide, a trend that will continue to grow over the next decade. The heart consists of a complex cellular network based mainly on cardiomyocytes, but also on endothelial cells, smooth muscle cells, fibroblasts, and pericytes, which closely communicate through paracrine factors and direct contact. These interactions serve as valuable targets in understanding the phenomenon of heart remodeling and regeneration. The advances in nanomedicine in the controlled delivery of active pharmacological agents are remarkable and may provide substantial contribution to the treatment of heart diseases. This review aims to summarize the main mechanisms involved in cardiac remodeling and regeneration and how they have been applied in nanomedicine.
Gene therapy is a technique that rectifies defective or abnormal genes by introducing exogenous genes into target cells to cure the disease. Although gene therapy has gained some accomplishment for the diagnosis and therapy of inherited or acquired cardiovascular diseases, how to efficiently and specifically deliver targeted genes to the lesion sites without being cleared by the blood system remains challenging. Based on nanotechnology development, the non-viral vectors provide a promising strategy for overcoming the difficulties in gene therapy. At present, according to the physicochemical properties, nanotechnology-based non-viral vectors include polymers, liposomes, lipid nanoparticles, and inorganic nanoparticles. Non-viral vectors have an advantage in safety, efficiency, and easy production, possessing potential clinical application value when compared with viral vectors. Therefore, we summarized recent research progress of gene therapy for cardiovascular diseases based on commonly used non-viral vectors, hopefully providing guidance and orientation for future relevant research.
Background: Cardiovascular disorders (CVDs) are the most prominent killer in the twenty‐first century. Antioxidant therapy has represented an effective strategy for the treatment of CVDs. However, the conventional phytoantioxidant agents showed limited in vivo effects owing to their nonspecific distribution and low retention in target sites. Objective: This chapter focuses on the recent approaches in the nano‐based drug delivery carriers of phytoantioxidants to develop new formulations to manage CVDs. Also, it describes the present challenges and future perspectives to promote clinical translation of phytoantioxidant nanotherapies involved with the conventional treatment modalities compared to the nano‐based medicine for CVDs. Methods: In this perspective, an extensive literature survey was carried out in various search engines and books to understand the mechanism, control, and management of CVDs for the potential application of nano‐based novel drug delivery carrier approaches for the administration of phytoantioxidants to treat CVDs. Results: Nanotechnology and nanocarriers for drug delivery open a new window in the area of CVDs with an opportunity to achieve effective treatment through passive and active targeting of the cardiac tissues, improved target specificity, and minimizing the adverse effects on nontarget tissues. It also exhibits multiple advantages, like excellent pharmacokinetics, stable antioxidative activity, and intrinsic ROS‐scavenging properties. It has been reported that more than 50% of CVDs can be treated effectively through the use of nanotherapeutics. Conclusion: Thus, nano‐drug delivery carrier systems have been employed as a vehicle for efficient and controlled delivery of the phytoantioxidant into cardiac tissue. Although clinical translation is under the development stage, owing to the lack of pharmaceutical scale‐up, release efficiency, substantial regulatory requirements exhibiting safety and good manufacturing practice (GMP). The future nano‐cardio therapeutic oriented study might improve our quality of life.
Effective disease the executives relies upon precise diagnostics alongside explicit treatment conventions. Current analytic procedures should be improved towards give prior discovery abilities, also customary chemotherapy ways towards deal with disease treatment are restricted by absence of explicitness also foundational harmfulness. This audit features propels in nanotechnology that have permitted the improvement of multifunctional stages for malignant growth discovery, treatment, also checking. Nanomaterial’s can be utilized as MRI, optical imaging, furthermore, photo acoustic imaging contrast specialists. When utilized as medication transporters, Nano formulations can increment growth openness towards remedial specialists also result in superior treatment impacts by dragging out flow times, shielding entangled drugs from corruption, also improving cancer take-up through the upgraded porousness also maintenance impact also as receptor-interceded endocytosis. Numerous restorative specialists like chemotherapy, antiangiogenic, or quality treatment specialists can be all the while conveyed by Nano carriers towards growth locales towards improve the adequacy of treatment. Moreover, imaging also treatment specialists can be co-conveyed towards give consistent combination of diagnostics, treatment, also follow-up, also different helpful modalities, for example, chemotherapy also hyperthermia can be co-controlled towards exploit synergistic impacts.
The spatial relationship between the binding sites for two cyclic peptides, cyclo(S,S)KYGCRGDWPC (cRGD) and cyclo(S,S)KYGCHarGDWPC (cHarGD), high affinity analogs for the RGD and HLGGAKQAGDV peptide ligands, in integrin alpha(IIb)beta(3) (GPIIb-IIIa) has been characterized. For this purpose, cRGD and cHarGD were labeled with fluorescein isothiocyanate and tetramethylrhodamine B-isothiocyanate, respectively, Both cyclic peptides were potent inhibitors of fibrinogen binding to alpha(IIb)beta(3), particularly in the presence of Mn2+; IC50 values for cRGD and cHarGD were 1 and < 0.1 nM in the presence of Mn2+. Direct binding experiments and fluorescence resonance energy transfer analysis using the purified receptor showed that both peptides interacted simultaneously with distinct sites in alpha(IIb)beta(3). The distance between these sites was estimated to be 6.1 +/- 0.5 nm, Although cRGD bound preferentially to one site and cHarGD to the other, the sites were not fully specific, and each cyclic peptide or its Linear counterpart could displace the other to some extent. The binding affinity of the cHarGD site was dramatically affected by Mn2+. cRGD, but not cHarGD, bound to recombinant beta(3)-(95-373) in a cation-dependent manner, indicating that the cRGD site is located entirely within this fragment. With intact platelets, binding of c-RGD and cHarGD to alpha(IIb)beta(3) resulted in distinct conformational alterations in the receptor as indicated by the differential exposure of Ligand-induced binding site epitopes and also induced the opposite on membrane fluidity as shown by electron paramagnetic resonance analyses using 5-doxylstearic acid as a spin probe, These data support the concept the two peptide Ligands bind to distinct sites in alpha(IIb)beta(3) and initiate different functional consequences within the receptor itself and within platelets.
A simple theory is developed that accounts for many of the observed physical properties of micelles, both globular and rod-like, and of bilayer vesicles composed of ionic or zwitterionic amphiphiles. The main point of departure from previous theories lies in the recognition and elucidation of the role of geometric constraints in self-assembly. The linking together of thermodynamics, interaction free energies and geometry results in a general framework which permits extension to more complicated self-assembly problems.
Objective:
To evaluate the capacity of local irrigation with tissue factor pathway inhibitor (TFPI) to inhibit vessels from neointimal lesion formation following intimectomy or balloon angioplasty.
Design:
The common carotid arteries in New Zealand white rabbits were subjected to either intimectomy or balloon angioplasty.
Intervention:
Before restoring blood flow, the lumina of the vessels were irrigated with 1 mL of Dulbecco phosphate-buffered saline either with TFPI (100 μg/mL [TFPI group, n=10]) or without TFPI (control group, n=10).
Main Outcome Measures:
The area of neointimal formation and the ratio of the intimal to medial areas (I/M) were determined from elastin-stained sections.
Results:
The area of neointima and the I/M ratio were not significantly different at 2 weeks postoperatively. However, at 4 weeks, TFPI-treated vessels demonstrated a significant reduction in the neointimal lesion and the I/M ratio compared with those of controls, following both angioplasty and intimectomy. Transmission electron microscopy showed a lack of platelet aggregation and thrombus formation at the intimal surface in the TFPI-treated vessels.
Conclusions:
Local irrigation with TFPI at the time of arterial interventional therapy inhibits intimal hyperplasia following either balloon angioplasty or intimectomy. We hypothesize that TFPI binds to the injured vessel surface and inhibits the cascade of thrombotic events that promote intimal hyperplasia.Arch Surg. 1996;131:1086-1090
The effect of lipid dose (4.3–512.8 μmol total lipid/kg body weight), administered intravenously as liposomes encapsulating radioactive inulin, upon the ability of mouse organs to bind and/or take-up the radioactive label has been studied in vivo. Three different liposome diameters were investigated: 0.46 μm (L) 0.16 μm (M) and 0.058 μm (S). All liposomes were negatively charged with a lipid composition of phosphatidylcholine/phosphatidic acid/cholesterol/α-tocopherol in the molar ratio 4 : 1 : 5 : 0.1 or 4 : 1 : 1 : 0.05. Overall radioactive label disposition after 2 h was consistent with localization predominantly in the reticuloendothelial system. A saturation of liver with increasing lipid dose was demonstrated for all three sizes, together with a corresponding increase in blood levels. Spleen radioactivity increased with increasing dose of l- and M-liposomes, but decreased for increasing doses of S-liposomes. Levels in residual carcass exhibited no trend. It was noted that by adjusting liposomal lipid dose and vesicle diameter the percentage of administered dose present in blood could be varied 733-fold, that in spleen 9-fold, liver 4-fold. Stability in vivo was ranked l > M > S-liposomes. Correction for differences of in vivo stability reduced the differences in organ accumulation between the three liposome sizes. The organ accumulation pattern suggested a dose- and diameter-dependent mechanism for liposome disposition. It was expected that when doses of fixed liposome composition were expressed as number of liposomes or their total surface area, organ saturation patterns would be similar. However, re-plotting the percent dose values for liver and spleen versus the number of liposomes administered revealed a saturation pattern for L-, M- and S-liposomes which was different in each case. Plotting the data versus the total surface area of the dose revealed a similar disposition pattern for l-, m- and S-liposomes in liver and l- and M-liposomes in spleen. The data indicate that in addition to composition, the lipid dose, total liposomal surface area and effective mean diameter are important pharmacokinetic variables. Further, the optimization of the therapeutic index of an encapsulated agent or target-tissue delivery via liposomes will require consideration of both the surface area and diameter of the liposome doses together with liposome composition.
Applying local drug delivery techniques in treating restenosis with antiproliferative agents may prove useful in enhancing drug efficacy while minimizing inherent systemic toxicity. Using direct intramural delivery of drug-loaded nanoparticles (U-86NP) composed of the biodegradable co-polymer polylactic-polyglycolic acid (PLGA), we evaluated the in vivo antiproliferative effect of a novel 2-aminochromone, U-86983, in a porcine model of coronary artery neointimal hyperplasia. In vitro, PLGA nanoparticles proved a suitable carrier for U-86983, promoting the gradual release of biologically active drug over a 2-week period. A series of acute canine and porcine experiments subsequently clarified such delivery conditions as catheter device, nanoparticle surface modification, and suspension concentration that maximized U-86NP retention in balloon-injured arterial segments. A chronic efficacy study implementing these delivery conditions was then performed in domestic feeder pigs. Site-specific delivery of U-86NP significantly reduced neointimal hyperplasia in severely balloon-injured porcine coronary arteries but also increased the incidence of medial dissection at the treated site. Delivery conditions designed to maximize drug effects without exacerbating existing vascular injury remain to be elucidated.
A series of nonionic saccharide surfactants with an amide group linking hydrophilic saccharide segment to hydrophobic alkyl segment were synthesized and their surface active properties were determined. We examine the effects of hydrophobic and hydrophilic chain lengths on the surface active properties and correlate our results to structural differences in the saccharide surfactants.N-Alkylmaltonamides were synthesized with hexyl, octyl, decyl, dodecyl, and octadecyl alkyl segments andN-dodecyl aldonamides were synthesized with glucose, maltose, and dextran (DP = 9) saccharide segments. Increasing the alkyl chain length inN-alkylmaltonamides decreases the critical micelle concentration, and increases the efficiency of reducing water surface tension and emulsification ability, but the effectiveness in reducing water surface tension is about the same. Increasing the saccharide size inN-dodecyl aldonamides from glucose to maltose to dextran increases the critical micelle concentration, decreases the efficiency and effectiveness of reducing water surface tension, but has little effect on emulsification properties. We show that the size of the saccharide segment is important in determining the interfacial surface area occupied by the surfactant molecules. An octyl, decyl, or dodecyl maltonamide occupies about 40 Å2at the air/water interface, but this increases to 60 Å2when maltose is replaced by the larger dextran.
ReceiVed: August 2, 1996 X In dilute aqueous mixtures of the detergent C 12 EO 8 and the phospholipid POPC the phase and partition behavior as well as the transfer enthalpies of the respective molecules between the various states (monomers, bilayers, micelles) have been measured by isothermal titration calorimetry [Heerklotz et al., J. Phys. Chem. 1996, 100, 6764]. To derive more information about the molecular interpretation of the thermodynamic data, we performed additional experiments for a series of detergents, C 12 EO n with n) 3-8 and dependent on temperature (for C 12 EO 8). The data can be discussed in terms of a three-stage model (bilayers, coexistence, micelles) considering nonideal mixing within the aggregates. The mixing properties are determined by packing effects controlling the hydration of the headgroups, the water exposure of the hydrocarbon core, and the order of the hydrocarbon chains. Additionally, two types of systematic deviations from the simple three-stage behavior are found for low n and low detergent contents in the bilayer. These effects could be related to special properties of detergents surrounded by lipids only and to solubilization intermediates occurring close to the lytic detergent content.
The authors's recent work on matters pertinent to the in vivo processing of systemically administered liposomes is reviewed. Particular emphasis is given to factors influencing blood clearance rates, hepatic and splenic uptake and intrahepatic as well as intrasplenic distribution. In addition to size, liposomal composition plays a crucial role in determining these parameters as was shown by comparing the fate of liposomes composed of egg phosphatidylcholine (eggPC), cholesterol (Chol) and either phosphatidylglycerol (PG) or different molar fractions of phosphatidylserine (PS) as negatively charged components. Neutral eggPC/Chol liposomes with and without lipid-anchored poly(ethylene glycol) were also compared. The experimental approach included the measurement of radiolabel distribution from [3H]cholesterylether-labeled liposomes in blood, liver and spleen and in isolated hepatic cell fractions as well as morphological observations on colloidal gold containing liposomes at the light- and electronmicroscopical level. Evidence is presented that apolipoprotein-E plays an important role in the clearance and hepatic uptake and processing of some liposomes but not of others.
The incorporation of polymer–lipid conjugates, initially using PEG and subsequently other selected flexible, hydrophilic polymers, into lipid bilayers gives rise to sterically stabilized liposomes that exhibit reduced blood clearance and concomitant changes in tissue distribution largely because of reduced, but not eliminated, phagocytic uptake. Changes in tissue distribution includes `passive' targeting localization into sites of tumors, infection, inflammation characterized by presence of a `leaky' vasculature which represent useful applications for drug delivery. The polymer forms a surface coating which has been characterized by physical measurements and it appears to function through steric inhibition of the protein binding and cellular interactions leading to phagocytic uptake. The current understanding of the physical and biological properties are reviewed. Ongoing work in the field involves interests to increase complexity such as addition of (1) selective targeting ligands by chemical conjugation to the exterior surface of the polymer coating, (2) capabilities for intracellular release of encapsulated agents into the cytoplasm, and (3) both simultaneously.
Association of drugs with carriers such as liposomes has marked effects on both the pharmacokinetic profiles of the carrier and of the carrier-associated drug. In general, association of drugs with liposomes delays drug absorption, alters and restricts drug biodistribution, decreases the volume of distribution, delays clearance and retards drug metabolism. Surface modification of liposomes by the inclusion of hydrophilic components (e.g., carbohydrates, glycolipids or polymers) to form long-circulating liposomes causes changes in the pharmacokinetic pattern seen for unmodified (classical) liposomes. While classical liposomes have non-linear, saturable kinetics, long-circulating liposomes possess dose-independent, non-saturable, log-linear kinetics. The log-linear kinetics for long-circulating liposomes results from a significant decrease in the first phase of clearance into a high affinity, low capacity system, probably the cells of the mononuclear phagocyte system. An understanding of the pharmacokinetics of liposome-associated drugs is critical to the development of rationale strategies for therapeutic applications of long-circulating liposomes.