Local Drug Delivery Strategies Research Articles

Endovascular Drug Delivery.

Drug-eluting stents (DES) and balloons revolutionize atherosclerosis treatment by targeting hyperplastic tissue responses through effective local drug delivery strategies. This review examines approved and emerging endovascular devices, discussing drug release mechanisms and their impacts on arterial drug distribution. It emphasizes the crucial role of drug delivery in modern cardiovascular care and highlights how device technologies influence vascular behavior based on lesion morphology. The future holds promise for lesion-specific treatments, particularly in the superficial femoral artery, with recent CE-marked devices showing encouraging results. Exciting strategies and new patents focus on local drug delivery to prevent restenosis, shaping the future of interventional outcomes. In summary, as we navigate the ever-evolving landscape of cardiovascular intervention, it becomes increasingly evident that the future lies in tailoring treatments to the specific characteristics of each lesion. By leveraging cutting-edge technologies and harnessing the potential of localized drug delivery, we stand poised to usher in a new era of precision medicine in vascular intervention.

Local Drug Delivery Strategies towards Wound Healing.

A particular biological process known as wound healing is connected to the overall phenomena of growth and tissue regeneration. Several cellular and matrix elements work together to restore the integrity of injured tissue. The goal of the present review paper focused on the physiology of wound healing, medications used to treat wound healing, and local drug delivery systems for possible skin wound therapy. The capacity of the skin to heal a wound is the result of a highly intricate process that involves several different processes, such as vascular response, blood coagulation, fibrin network creation, re-epithelialisation, collagen maturation, and connective tissue remodelling. Wound healing may be controlled with topical antiseptics, topical antibiotics, herbal remedies, and cellular initiators. In order to effectively eradicate infections and shorten the healing process, contemporary antimicrobial treatments that include antibiotics or antiseptics must be investigated. A variety of delivery systems were described, including innovative delivery systems, hydrogels, microspheres, gold and silver nanoparticles, vesicles, emulsifying systems, nanofibres, artificial dressings, three-dimensional printed skin replacements, dendrimers and carbon nanotubes. It may be inferred that enhanced local delivery methods might be used to provide wound healing agents for faster healing of skin wounds.

Proliposome: A Novel Solution for the Stability of Liposomes - A Review

Proliposome are phospholipid-based vesicular drug delivery systems that have specialized applications in drug delivery via various routes of administration. They are widely researched as potential carriers for improving bioavailability through oral administration of drugs with low bioavailability and are composed of the drug, phospholipid, and a water-soluble carrier or porous powder. The technology is based on the inherent ability of hydrated membrane lipids to form liposomal vesicles when exposed to water. It is specifically designed for molecular dispersion and delivery of hydrophilic and hydrophobic drugs to achieve good bioavailability, local, systemic effects, and site-specific drug delivery strategies. By utilizing phospholipids and various carriers, these vesicular systems play critical roles in improving bioavailability and solubility. An in-depth understanding of the physical and biological behavior of Proliposome is required for designing an effective delivery system that will increase drug availability at the anticipated site. Proliposome provide an opportunity to improve drug therapeutic action by modifying drug uptake mechanisms. The Proliposome approach was developed as a simple, repeatable, and dependable manufacturing technique for large-scale production of liposome dispersions. The present review discusses the use of Proliposome to improve the oral bioavailability of poorly water-soluble drugs, components for the formulation, effects of excipients, techniques for preparation, evaluation of Proliposome, and other key issues related to various routes of administration. Proliposome formulation is an alternative, novel solution for liposome stability.

Local Drug Delivery Strategies for Glioblastoma Treatment.

Glioblastoma multiforme (GBM) is a brain tumor notorious for its malignancy. The key reason for the limited efficacy of standard treatment is the high recurrence rate of GBM, even after surgical resection. Hence, intensive postsurgical chemical therapies, such as the systemic delivery of various drugs and/or drug combinations, are typically followed after surgery. However, overcoming the blood-brain barrier by systemic administration to efficiently deliver drugs to the brain tumor remains a daunting goal. Therefore, various local drug delivery methods showing potential for improved therapeutic efficacy have been proposed. In particular, the recent application of electronic devices for the controlled delivery of chemotherapy drugs to GBM tissue has attracted attention. We herein review the recent progress of local drug delivery strategies, including electronics-assisted strategies, at the research and commercial level. We also present a brief discussion of the unsolved challenges and future research direction of localized chemotherapy methods for GBM.

Effect of poly lactic-co-glycolic acid encapsulation on drug delivery kinetics from vancomycin-impregnated Ca-Mg silicate scaffolds

The identification of drug delivery mechanisms is critical to design a device that offers a drug release kinetics within the therapeutic window. In this paper, the drug release kinetics of bioresorbable tissue engineering scaffolds coated/uncoated with biodegradable polymer layers is studied. Interconnectedly porous bredigite (MgCa7Si4O16) scaffolds were fabricated by a sacrificial urethane foam replica method, loaded with vancomycin hydrochloride (C66H75Cl2N9O24) and then encapsulated in poly lactic-co-glycolic acid (PLGA, LA/GA = 50:50) coatings of two different thicknesses. Field-emission scanning electron microscopy (FESEM) and Fourier-transform infrared spectroscopy (FTIR) were used to verify the macroporous morphology and chemical constituents of the devices. The release profiles of vancomycin from these systems into phosphate buffered saline (PBS) at 37 °C were also recorded by ultraviolet-visible (UV–vis) spectroscopy. To explore the dominant drug delivery mechanisms, the experimental data of the drug release was then fitted with several drug delivery mathematical models, including the Higuchi, Hixson-Crowell, Korsmeyer-Peppas, Peppas-Sahlin, Weibull, zero-order and first-order. Comparing the correlation coefficient of the regressions as a measure of goodness-of-fit, it was found that vancomycin release from the bare scaffold is subjected to a dissolution-controlled kinetics, whereas the PLGA-coated scaffolds mainly display a combination of diffusion- and dissolution-controlled mechanisms for the drug release. It can be accordingly concluded that the bredigite scaffolds are a versatile device for different local drug delivery strategies offering rapid, single-stage and dissolution-controlled release kinetics that can be easily modulated into a diffusion-controlled, biphasic and prolonged release through biopolymer coating.

Hydrogel-based local drug delivery strategies for spinal cord repair.

Spinal cord injury results in significant loss of motor, sensory, and autonomic functions. Although a wide range of therapeutic agents have been shown to attenuate secondary injury or promote regeneration/repair in animal models of spinal cord injury, clinical translation of these strategies has been limited, in part due to difficulty in safely and effectively achieving therapeutic concentrations in the injured spinal cord tissue. Hydrogel-based drug delivery systems offer unique opportunities to locally deliver drugs to the injured spinal cord with sufficient dose and duration, while avoiding deleterious side effects associated with systemic drug administration. Such local drug delivery systems can be readily fabricated from biocompatible and biodegradable materials. In this review, hydrogel-based strategies for local drug delivery to the injured spinal cord are extensively reviewed, and recommendations are made for implementation.

Emerging technologies for local cancer treatment.

The fundamental limitations of systemic therapeutic administration have prompted the development of local drug delivery platforms as a solution to increase effectiveness and reduce side effects. By confining therapeutics to the site of disease, local delivery technologies can enhance therapeutic index. This review highlights recent advances and opportunities in local drug delivery strategies for cancer treatment in addition to challenges that need to be addressed to facilitate clinical translation. The benefits of local cancer treatment combined with technological advancements and increased understanding of the tumor microenvironment, present a prime breakthrough opportunity for safer and more effective therapies.

Drug Delivery Strategies for the Treatment of Metabolic Diseases.

Metabolic diseases occur when normal metabolic processes are disrupted in the human body, which can be congenital or acquired. The incidence of metabolic diseases worldwide has reached epidemic proportions. So far, various methods including systemic drug therapy and surgery are exploited to prevent and treat metabolic diseases. However, current pharmacotherapeutic options for treatment of these metabolic disorders remain limited and ineffective, especially reducing patient compliance to treatment. Therefore, it is desirable to exploit effective drug delivery approaches to effectively treat metabolic diseases and reduce side effects. This brief review summarizes novel delivery strategies including local, targeted, and oral drug delivery strategies, as well as intelligent stimulus-responsive drug delivery strategy, for the treatment of metabolic disorders including diabetes, obesity, and atherosclerosis.

Development of Drug Targeting and Delivery in Cervical Cancer.

Cervical cancer is the second most common cancer in women. Standard treatment options available for cervical cancer include chemotherapy, surgery and radiation therapy associated with their own side effects and toxicities. Tumor-targeted delivery of anticancer drugs is perhaps one of the most appropriate strategies to achieve optimal outcomes from the treatment and improve the quality of life. Recently nanocarriers based drug delivery systems owing to their unique properties have been extensively investigated for anticancer drug delivery. In addition to that addressing the anatomical significance of cervical cancer, various local drug delivery strategies for the cancer treatment are introduced like: gels, nanoparticles, polymeric films, rods and wafers, lipid based nanocarrier. Localized drug delivery systems allow passive drug targeting results in high drug concentration at the target site. Further they can be tailor made to achieve both sustained and controlled release behavior, substantially improving therapeutic outcomes and minimizing side effects. This review summarizes the meaningful advances in drug delivery strategies to treat cervical cancer.

Intracochlear administration of steroids with a catheter during human cochlear implantation: a safety and feasibility study.

Suppression of foreign body reaction, improvement of electrode-nerve interaction, and preservation of residual hearing are essential research topics in cochlear implantation. Intracochlear pharmaco- or cell-based therapies can open new horizons in this field. Local drug delivery strategies are desirable as higher local concentrations of agents can be realized and side effects can be minimized compared to systemic administrations. When administered locally at accessible, basal parts of the cochlea, drugs reach apical regions later and in much lower concentrations due to poor diffusion patterns in cochlear fluids. Therefore, new devices are needed to warrant rapid distribution of agents into all parts of the cochlea. Five patients received a deep intracochlear injection of triamcinolone with a specifically designed cochlear catheter during cochlear implantation right before inserting a cochlear implant electrode. As a measure for formation of fibrous tissue around the electrode, electrical impedances were measured in the operation room and over 4months thereafter. No adverse events were observed peri- and postoperatively. The handling of the device was easy. Severe damage to the microstructure of the cochlea was excluded as far as possible by cone beam computed tomography and vestibular testing. A delayed rise of the impedances was seen in the catheter group compared to controls over all regions of the cochlea. A statistical significance, however, was only obtained at the midregion of the cochlea. Consequently, the cochlear catheter is a safe and feasible device for local drug delivery of pharmaceutical agents into deeper regions of the cochlea.

Sustained Delivery of Doxorubicin via Acetalated Dextran Scaffold Prevents Glioblastoma Recurrence after Surgical Resection.

The primary cause of mortality for glioblastoma (GBM) is local tumor recurrence following standard-of-care therapies, including surgical resection. With most tumors recurring near the site of surgical resection, local delivery of chemotherapy at the time of surgery is a promising strategy. Herein drug-loaded polymer scaffolds with two distinct degradation profiles were fabricated to investigate the effect of local drug delivery rate on GBM recurrence following surgical resection. The novel biopolymer, acetalated dextran (Ace-DEX), was compared with commercially available polyester, poly(l-lactide) (PLA). Steady-state doxorubicin (DXR) release from Ace-DEX scaffolds was found to be faster when compared with scaffolds composed of PLA, in vitro. This increased drug release rate translated to improved therapeutic outcomes in a novel surgical model of orthotopic glioblastoma resection and recurrence. Mice treated with DXR-loaded Ace-DEX scaffolds (Ace-DEX/10DXR) resulted in 57% long-term survival out to study completion at 120 days compared with 20% survival following treatment with DXR-loaded PLA scaffolds (PLA/10DXR). Additionally, all mice treated with PLA/10DXR scaffolds exhibited disease progression by day 38, as defined by a 5-fold growth in tumor bioluminescent signal. In contrast, 57% of mice treated with Ace-DEX/10DXR scaffolds displayed a reduction in tumor burden, with 43% exhibiting complete remission. These results underscore the importance of polymer choice and drug release rate when evaluating local drug delivery strategies to improve prognosis for GBM patients undergoing tumor resection.

Abstract 808: PDGF-A overexpression and p53 depletion in rat neural precursor cells induces large brain tumors that resemble human glioblastoma

Abstract One of the major obstacles in developing new therapeutics for glioblastoma is testing these agents in reliable models that recapitulate the tumor biology of human disease. The RCAS/tv-a system enables spatial, temporal, and cell-type specific control of oncogenic transformations in the brain. In this study, we sought to develop a rat RCAS-TVA model of glioblastoma to eventually facilitate translational studies using magnetic resonance imaging (MRI), targeted radiation, focused ultrasound, and local drug delivery strategies. We developed a high copy number nestin-promoter driven tv-a (Ntv-a) transgenic Sprague-Dawley rat line. To initiate tumors, RCAS PDGF-A and p53 shRNA constructs were injected intracranially. The tumors were followed over time using MRI and MR proton spectroscopy. Animal survival was monitored and histopathology and gene expression analyses were performed. All animals (n=8) developed tumors that could be visualized with MRI throughout the tumor formation process. Early stage tumors showed relatively homogenous characteristics with minimal mass effect. Later stage tumors demonstrated large heterogeneous lesions with evidence of necrosis, increased vascularity, and significant mass effect. MR proton spectroscopy revealed increases in choline to creatinine ratio (Cho/Cr) and decreases in NAA, consistent with aggressive tumor progression. Immunohistochemistry revealed pseudopallisading necrosis, brain invasion, and vascular proliferation, all key features of human GBM. Immunohistochemistry confirmed a high proliferative index within the tumor core as well as neovascularization as evidenced by positive Ki67 and Smooth Muscle Actin (SMA) respectively. Gene expression analysis revealed approximately 1000 differentially expressed transcripts between the normal and tumor tissue. In addition to typical markers such as Ki67 and PDGFR-A overexpression, SPP1 and POSTN both of which are linked to glioma and tumor-associated macrophages, were found to be differentially expressed in the tumor. Comparisons between the rat gene expression profile and published human TCGA data indicated that the RCAS/tv-a tumors appear to align with the proneural GBM subtype. In summary, transgenic Ntv-a rats generate reproducible brain tumors following combined PDGF-A and p53 genetic alterations. The tumor progression process from low-grade tumor to high grade malignancy can be visualized with MRI. Histopathological features strongly resemble human GBM, and gene expression analysis suggests these tumors correspond to the proneural subtype. Citation Format: Nina P. Connolly, Craig S. Schneider, Amol Shetty, Su Xu, Tatsuya Ozawa, Anthony J. Kim, Jeffrey A. Winkles, Eric Holland, Graeme F. Woodworth. PDGF-A overexpression and p53 depletion in rat neural precursor cells induces large brain tumors that resemble human glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 808. doi:10.1158/1538-7445.AM2017-808

Prevention of lung cancer recurrence using cisplatin-loaded superhydrophobic nanofiber meshes

For early stage lung cancer patients, local cancer recurrence after surgical resection is a significant concern and stems from microscopic disease left behind after surgery. Here we apply a local drug delivery strategy to combat local lung cancer recurrence after resection using non-woven, biodegradable nanofiber meshes loaded with cisplatin. The meshes are fabricated using a scalable electrospinning process from two biocompatible polymers—polycaprolactone and poly(glycerol monostearate-co-caprolactone)—to afford favorable mechanical properties for use in a dynamic tissue such as the lung. Owing to their rough nanostructure and hydrophobic polymer composition, these meshes exhibit superhydrophobicity, and it is this non-wetting nature that sustains the release of cisplatin in a linear fashion over ∼90 days, with anti-cancer efficacy demonstrated using an in vitro Lewis Lung carcinoma (LLC) cell assay. The in vivo evaluation of cisplatin-loaded superhydrophobic meshes in the prevention of local cancer recurrence in a murine model of LLC surgical resection demonstrated a statistically significant increase (p = 0.0006) in median recurrence-free survival to >23 days, compared to standard intraperitoneal cisplatin therapy of equivalent dose. These results emphasize the importance of supplementing cytoreductive surgery with local drug delivery strategies to improve prognosis for lung cancer patients undergoing tumor resection.

Antitumor activity of TNF-α after intratumoral injection using an in situ thermosensitive hydrogel

Local drug delivery strategies based on nanoparticles, gels, polymeric films, rods and wafers are increasingly used in cancer chemotherapy in order to enhance therapeutic effect and reduce systemic toxicity. Herein, a biodegradable and biocompatible in situ thermosensitive hydrogel was designed and employed to deliver tumor necrosis factor-α (TNF-α) locally by intratumoral injection. The triblock copolymer was synthesized by ring-opening polymerization (ROP) of β-butyrolactone (β-BL) and lactide (LA) in bulk using polyethylene glycol (PEG) as an initiator and Sn(Oct)2 as the catalyst, the polymer was characterized by NMR, gel permeation chromatography and differential scanning calorimetry. Blood and tumor pharmacokinetics and in vivo antitumor activity of TNF-α after intratumoral administration in hydrogel or solution with the same dose were evaluated on S180 tumor-bearing mice. Compared with TNF-α solution, TNF-α hydrogel exhibited a longer T1/2 (4-fold) and higher AUCtumor (19-fold), but Cmax was lower (0.5-fold), which means that the hydrogel formulation improved the efficacy with a lower systhemic exposure than the solution formation. In addition, TNF-α hydrogel improved the antitumor activity and survival due to lower systemic exposure than the solution. These results demonstrate that the in situ thermosensitive hydrogel-based local delivery system by intratumoral injection is well suited for the administration of TNF-α.

Synthesis and in vitro studies of biodegradable thiolated chitosan hydrogels for breast cancer therapy

Local drug delivery strategies have gained momentum recently as a promising modality in cancer therapy. In order to deliver Letrozole (LTZ) at the tumor site in therapeutically relevant concentrations, acetyl-polyamidoamine (Ac-PAMAM)–thiolated chitosan (TCS) films were fabricated. LTZ could be loaded at 31% wt/wt in films, which were translucent and flexible. Physicochemical characterization of LTZ via thermal technique revealed information on solid-state properties of LTZ as well as thiolated chitosan in films. While thiolated chitosan was in amorphous form, LTZ seemed to be present in both amorphous and crystalline forms in film. The lack of formulation-induced local inflammatory responses of LTZ-acetyl-polyamidoamine (Ac-PAMAM)–thiolated chitosan (TCS) films a new paradigm for localized chemotherapy based on breast delivery systems.

Coupled Porohyperelastic Mass Transport (PHEXPT) Finite Element Models for Soft Tissues Using ABAQUS

Finite element models (FEMs) including characteristic large deformations in highly nonlinear materials (hyperelasticity and coupled diffusive/convective transport of neutral mobile species) will allow quantitative study of in vivo tissues. Such FEMs will provide basic understanding of normal and pathological tissue responses and lead to optimization of local drug delivery strategies. We present a coupled porohyperelastic mass transport (PHEXPT) finite element approach developed using a commercially available ABAQUS finite element software. The PHEXPT transient simulations are based on sequential solution of the porohyperelastic (PHE) and mass transport (XPT) problems where an Eulerian PHE FEM is coupled to a Lagrangian XPT FEM using a custom-written FORTRAN program. The PHEXPT theoretical background is derived in the context of porous media transport theory and extended to ABAQUS finite element formulations. The essential assumptions needed in order to use ABAQUS are clearly identified in the derivation. Representative benchmark finite element simulations are provided along with analytical solutions (when appropriate). These simulations demonstrate the differences in transient and steady state responses including finite deformations, total stress, fluid pressure, relative fluid, and mobile species flux. A detailed description of important model considerations (e.g., material property functions and jump discontinuities at material interfaces) is also presented in the context of finite deformations. The ABAQUS-based PHEXPT approach enables the use of the available ABAQUS capabilities (interactive FEM mesh generation, finite element libraries, nonlinear material laws, pre- and postprocessing, etc.). PHEXPT FEMs can be used to simulate the transport of a relatively large neutral species (negligible osmotic fluid flux) in highly deformable hydrated soft tissues and tissue-engineered materials.

Evaluating Intra-Articular Drug Delivery for the Treatment of Osteoarthritis in a Rat Model

Osteoarthritis (OA) is a degenerative joint disease that can result in joint pain, loss of joint function, and deleterious effects on activity levels and lifestyle habits. Current therapies for OA are largely aimed at symptomatic relief and may have limited effects on the underlying cascade of joint degradation. Local drug delivery strategies may provide for the development of more successful OA treatment outcomes that have potential to reduce local joint inflammation, reduce joint destruction, offer pain relief, and restore patient activity levels and joint function. As increasing interest turns toward intra-articular drug delivery routes, parallel interest has emerged in evaluating drug biodistribution, safety, and efficacy in preclinical models. Rodent models provide major advantages for the development of drug delivery strategies, chiefly because of lower cost, successful replication of human OA-like characteristics, rapid disease development, and small joint volumes that enable use of lower total drug amounts during protocol development. These models, however, also offer the potential to investigate the therapeutic effects of local drug therapy on animal behavior, including pain sensitivity thresholds and locomotion characteristics. Herein, we describe a translational paradigm for the evaluation of an intra-articular drug delivery strategy in a rat OA model. This model, a rat interleukin-1beta overexpression model, offers the ability to evaluate anti-interleukin-1 therapeutics for drug biodistribution, activity, and safety as well as the therapeutic relief of disease symptoms. Once the action against interleukin-1 is confirmed in vivo, the newly developed anti-inflammatory drug can be evaluated for evidence of disease-modifying effects in more complex preclinical models.

Structural biomechanics modulate intramuscular distribution of locally delivered drugs

As local drug delivery continues to emerge as a clinical force, so does understanding of its potentially narrow therapeutic window. Classic molecular transport studies are of value but do not typically account for the local nature of drug transport or the effects of regional dynamic function in target tissues like muscle that may undergo cyclical and variable mechanical motion and loading. We examined the impact of dynamic architecture on intramuscular drug distribution. We designed a tissue mounting technique and mechanical loading system that uniquely enables pharmacokinetics investigations in association with control of muscle biomechanics while preserving physiologic tissue architecture. The system was validated and used to elucidate the influence of architecture and controlled cyclic strain on intramuscular drug distribution. Rat soleus muscles underwent controlled deformations within a drug delivery chamber that preserved in vivo physiology. Penetration of 1 mM 20 kDa FITC-dextran at planar surfaces of the soleus axial cross-section increased significantly from 0.52±0.09 mm under 80 min of static (0%) strain to 0.81±0.09 mm under cyclic (3 Hz, 0–20% peak-to-peak) strain, demonstrating the driving effect of cyclic loading on transport. Penetration at curved margins was 1.57- and 2.53-fold greater than at planar surfaces under static and cyclic strain, respectively, and was enhanced 1.6-fold more by cyclic strain, revealing architecturally dictated spatial heterogeneity in transport and modulation of motion dynamics. Architectural geometry and dynamics modulate the impact of mechanical loading on local drug penetration and intramuscular distribution. Future work will use the biomechanical test system to investigate mechanisms underlying transport effects of specific loading regimens. It is hoped that this work will initiate a broader understanding of intramuscular pharmacokinetics and guide local drug delivery strategies.

Development and characterization of biodegradable chitosan films for local delivery of Paclitaxel.

Intratumoral and local drug delivery strategies have gained momentum recently as a promising modality in cancer therapy. In order to deliver paclitaxel at the tumor site in therapeutically relevant concentrations, chitosan films were fabricated. Paclitaxel could be loaded at 31% wt/wt in films, which were translucent and flexible. Physicochemical characterization of paclitaxel via thermal, spectroscopic, x-ray diffraction, and electron microscopy techniques revealed information on solid-state properties of paclitaxel as well as chitosan in films. While chitosan was in amorphous form, paclitaxel seemed to be present in both amorphous and crystalline forms in film. The polymeric dispersion of paclitaxel in poloxamer formed fibrous structures generating discontinuities in the film matrix, thereby leading to the introduction of perturbations in the packing arrangement of polymer chains. These films released only 10% to 15% of loaded paclitaxel by a burst effect under in vitro testing conditions, with lysozyme having no effect on the release. However, films softened after implantation in mice and lost integrity over time. The implantable delivery system is not only biodegradable but also well tolerated in vivo and hence, biocompatible as revealed by histological studies. The lack of formulation-induced local inflammatory responses of paclitaxel chitosan films suggests a new paradigm for localized chemotherapy based on implantable systems.

Expression Patterns of Integrins on Quiescent and Invasive Smooth Muscle Cells and Impact on Cell Locomotion

R. Blindt, N. Krott, P. Hanrath, J. vom Dahl, G. van Eys and A.-K. Bosserhoff. Expression Patterns of Integrins on Quiescent and Invasive Smooth Muscle Cells and Impact on Cell Locomotion. Journal of Molecular and Cellular Cardiology (2002) 34, 1633–1644. Migration and invasion of human arterial smooth muscle cells (haSMCs) are essential steps during the development of atherosclerosis, restenosis, and transplant vasculopathy. The molecular mechanisms leading to these processes are only incompletely understood. Due to their contact to the surrounding extracellular matrix, integrins have been shown to be essentially involved in cell locomotion. Therefore, the function of integrins during this process was analyzed in an in vitro model which was based on the defined quiescent and invasive phenotypes of human haSMCs induced by cell culture conditions. Flow-cytometric analysis of integrin expression between both phenotypes showed a strong upregulation of alpha 5 beta 1 (13.1×) and a modest upregulation of alpha vs beta 3 (3.4×) and alpha IIb (3.0×) in invasive haSMCs in comparison to quiescent ones. Other integrins analyzed (alpha 2, alpha 3, alpha 4, beta 1) did not show differential regulation. Functional inhibition of alpha 5 beta 1 reduced cell migration (−29%±8), invasion (−49%±16), collagen contraction (−125%), and attachment to fibronectin. Although, there was a clear discrepancy between alpha 5 beta 1 and alpha vs beta 3 expression levels, inhibition of alpha vs beta 3 (−45%±9) reduced haSMC invasion equally. Interestingly, alpha vs beta 3 unlike alpha 5 beta 1 blockade caused a significant stimulation of collagen contraction (+52% vs 154%) with possible implications on vascular remodeling. In conclusion, alpha 5 beta 1 blockade or combined alpha 5 beta 1/alpha v beta 3 blockade by specific antibodies or selective RGD peptides together with local drug delivery strategies could be a promising strategy for the therapy of restenotic lesions or atheromatous plaques.