Paradigm For Drug Delivery Research Articles

Overcoming Limitations in Nanoparticle Drug Delivery: Triggered, Intravascular Release to Improve Drug Penetration into Tumors

Traditionally, the goal of nanoparticle-based chemotherapy has been to decrease normal tissue toxicity by improving drug specificity to tumors. The enhanced permeability and retention effect can permit passive accumulation into tumor interstitium. However, suboptimal delivery is achieved with most nanoparticles because of heterogeneities of vascular permeability, which limits nanoparticle penetration. Furthermore, slow drug release limits bioavailability. We developed a fast drug-releasing liposome triggered by local heat that has already shown substantial antitumor efficacy and is in human trials. Here, we show that thermally sensitive liposomes (Dox-TSL) release doxorubicin inside the tumor vasculature. Real-time confocal imaging of doxorubicin delivery to murine tumors in window chambers and histologic analysis of flank tumors illustrates that intravascular drug release increases free drug in the interstitial space. This increases both the time that tumor cells are exposed to maximum drug levels and the drug penetration distance, compared with free drug or traditional pegylated liposomes. These improvements in drug bioavailability establish a new paradigm in drug delivery: rapidly triggered drug release in the tumor bloodstream.

Controlled Release of Biologically Active Silver from Nanosilver Surfaces

Major pathways in the antibacterial activity and eukaryotic toxicity of nanosilver involve the silver cation and its soluble complexes, which are well established thiol toxicants. Through these pathways, nanosilver behaves in analogy to a drug delivery system, in which the particle contains a concentrated inventory of an active species, the ion, which is transported to and released near biological target sites. Although the importance of silver ion in the biological response to nanosilver is widely recognized, the drug delivery paradigm has not been well developed for this system, and there is significant potential to improve nanosilver technologies through controlled release formulations. This article applies elements of the drug delivery paradigm to nanosilver dissolution and presents a systematic study of chemical concepts for controlled release. After presenting thermodynamic calculations of silver species partitioning in biological media, the rates of oxidative silver dissolution are measured for nanoparticles and macroscopic foils and used to derive unified area-based release kinetics. A variety of competing chemical approaches are demonstrated for controlling the ion release rate over 4 orders of magnitude. Release can be systematically slowed by thiol and citrate ligand binding, formation of sulfidic coatings, or the scavenging of peroxy-intermediates. Release can be accelerated by preoxidation or particle size reduction, while polymer coatings with complexation sites alter the release profile by storing and releasing inventories of surface-bound silver. Finally, the ability to tune biological activity is demonstrated through a bacterial inhibition zone assay carried out on selected formulations of controlled release nanosilver.

Rhesus macaque model of chronic opiate dependence and neuro-AIDS: longitudinal assessment of auditory brainstem responses and visual evoked potentials.

Our work characterizes the effects of opiate (morphine) dependence on auditory brainstem and visual evoked responses in a rhesus macaque model of neuro-AIDS utilizing a chronic continuous drug delivery paradigm. The goal of this study was to clarify whether morphine is protective, or if it exacerbates simian immunodeficiency virus (SIV)-related systemic and neurological disease. Our model employs a macrophage tropic CD4/CCR5 coreceptor virus, SIV(mac)239 (R71/E17), which crosses the blood-brain barrier shortly after inoculation and closely mimics the natural disease course of human immunodeficiency virus infection. The cohort was divided into three groups: morphine only, SIV only, and SIV + morphine. Evoked potential (EP) abnormalities in subclinically infected macaques were evident as early as 8 weeks postinoculation. Prolongations in EP latencies were observed in SIV-infected macaques across all modalities. Animals with the highest cerebrospinal fluid viral loads and clinical disease showed more abnormalities than those with subclinical disease, confirming our previous work (Raymond et al., J Neurovirol 4:512-520, 1998; J Neurovirol 5:217-231, 1999; AIDS Res Hum Retroviruses 16:1163-1173, 2000). Although some differences were observed in auditory and visual evoked potentials in morphine-treated compared to morphine-untreated SIV-infected animals, the effects were relatively small and not consistent across evoked potential type. However, morphine-treated animals with subclinical disease had a clear tendency toward higher virus loads in peripheral and central nervous system tissues (Marcario et al., J Neuroimmune Pharmacol 3:12-25, 2008) suggesting that if had been possible to follow all animals to end-stage disease, a clearer pattern of evoked potential abnormality might have emerged.

From Systemic Shotgun to Site-Specific Nanoparticle-Targeted Delivery

Since the introduction of percutaneous techniques for the relief of symptomatic obstructive atherosclerotic coronary artery disease in the late 1970s, the major Achilles heel was restenosis. After nearly 3 decades of study, the cellular and molecular biology of this complex response to injury is now far better understood and includes the role of thrombosis, cellular proliferation, inflammation, matrix production, and elastic recoil.1,2 Some 15 years ago there was enthusiastic interest in the concept of “site specific” or “direct delivery” of antiproliferative or anticoagulant therapies.3–6 Edelman et al reported on the inhibition of SMC proliferation after vascular injury by surgical placement of heparin-impregnated polymer matrix in the periadventitial tissue of rat carotid arteries.3 At that time a catheter-based porous balloon catheter became available for “site specific” delivery7 but failed to be effective in limiting restenosis in an atherosclerotic rabbit femoral artery injury model.4 Although labeled heparin could be demonstrated to be present in the injured vessel wall, retention time of the drug and potential additional injury created by a jet effect of the porous balloon catheter were cited as potential explanations for the lack of efficacy. Subsequently, the concept of local delivery remained dormant and a multitude of clinical trials using systemically administered pharmacological agents to reduce or prevent restenosis demonstrated no benefit.8 See accompanying article on page 1960 In the late 1980s and early 1990s, coronary stents, providing the necessary scaffolding to prevent elastic recoil become the new standard for the percutaneous treatment of obstructive …

Preparation and in vitro Evaluation of Linear and Star-branched PLGA Nanoparticles for Insulin Delivery

Biodegradable nanoparticles, as drug delivery paradigms, have been extensively used for delivery of a wide range of small molecules as well as macromolecules, such as peptides, proteins, and genes. The morphological modification may improve the physicochemical characteristics of the biodegradable polymers. In the current investigation, the synthesis and characterization of linear, poly(D,L-lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG-PLGA), star-branched β-cyclodextrin-PLGA (β-CD-PLGA), and glucose-PLGA (Glu-PLGA) copolymers containing insulin as a model peptide drug have been reported. Linear and star-branched copolymers of PLGA were synthesized by bulk melt polymerization of the lactones (lactide and glycolide) in the presence of PEG, glucose, or β-CD using Sn-octoate as catalyst. Nanoparticles were prepared by a modified (w1/o/w 2) double emulsion method. Bovine insulin was successfully encapsulated into the linear and star-branched PLGA nanoparticles with retention of insulin stability and the nanoparticles preparation process was optimized to reduce the burst effect and provide in vitro sustained release. The average particle size of samples was 120—355 nm. The cumulative amount of 65—84% insulin was released from the samples after 24 days. The yield of encapsulation of insulin was superior to 95%. Based on these findings, it is suggested that the novel PLGA nanoparticles can be used as a carrier for prolonged delivery of protein—peptide drugs.

Polymer genomics: shifting the gene and drug delivery paradigms

Pluronic, the A–B–A amphiphilic block copolymers of poly(ethylene oxide) and poly(propylene oxide), can up-regulate the expression of selected genes in cells and alter genetic responses to antineoplastic agents in cancer. Two key new findings are discussed in relation to current drug and gene delivery strategies. First, these block copolymers alone and in combination with a polycation, polyethyleneimine, can up-regulate the expression of reporter genes in stably transfected cells. This underscores the ability of selected synthetic polymers to enhance transgene expression through a mechanism that augments improved DNA delivery into a cell. Second, although, when used alone, Pluronic is “genetically benign,” when combined with an antineoplastic agent, doxorubicin, it drastically alters pharmacogenomic responses to this agent and prevents the development of multidrug resistance in breast cancer cells. Collectively, these studies propose the need for a thorough assessment of pharmacogenomic effects of polymer therapeutics to maximize the clinical outcomes and understand the pharmacological and toxicological effects of polymer-based drugs and delivery systems.

Endothelial endocytic pathways: gates for vascular drug delivery.

Vascular endothelium plays strategic roles in many drug delivery paradigms, both as an important therapeutic target itself and as a barrier for reaching tissues beyond the vascular wall. Diverse means are being developed to improve vascular drug delivery including stealth liposomes and polymer carriers. Affinity carriers including antibodies or peptides that specifically bind to endothelial surface determinants, either constitutive or pathological, enhance targeting of drugs to endothelial cells (EC) in diverse vascular areas. In many cases, binding to endothelial surface determinants facilitates internalization of the drug/carrier complex. There are several main endocytic pathways in EC, including clathrin- and caveoli-mediated endocytosis, phagocytosis and macropinocytosis (these two are less characteristic of generic EC) and the recently described Cell Adhesion Molecule (CAM)-mediated endocytosis. The latter may be of interest for intracellular drug delivery to EC involved in inflammation or thrombosis. The metabolism and effects of internalized drugs largely depend on the routes of intracellular trafficking, which may lead to degrading lysosomal compartments or other organelles, recycling to the plasma membrane or transcytosis to the basal surface of endothelium. The latter route, characteristic of caveoli-mediated endocytosis, may serve for trans-endothelial drug delivery. Paracellular trafficking, which can be enhanced under pathological conditions or by auxiliary agents, represents an alternative for transcytosis. Endothelial surface determinants involved in endocytosis, mechanisms of the latter and trafficking pathways, as well as specific characteristics of EC in different vascular areas, are discussed in detail in the context of modern paradigms of vascular drug delivery.

DYNAMIC FEEDBACK AND THE DESIGN OF CLOSED-LOOP DRUG DELIVERY SYSTEMS

A closed-loop drug delivery system is constructed in which external negative feedback is used to regulate the dynamics of a time-delayed negative feedback mechanism which regulates hormone concentration. This results in a control system composed of two time-delayed negative feedback loops arranged in parallel. Stability regions in parameter space and the location of steady states are determined for the cases when the time delays are equal and when they are unequal. The advantage of this paradigm for drug delivery is that both the steady states and stability of the multiple loop feedback system can be influenced in a precisely controllable manner.

Testing of a hypothesis for osmotic opening of the blood-brain barrier.

Testing of a hypothesis for osmotic opening of the blood-brain barrier.