Alexander T. Florence

NANOPARTICLE UPTAKE BY THE RAT GASTROINTESTINAL MUCOSA : QUANTITATION AND PARTICLE SIZE DEPENDENCY

Abstract— Polystyrene microspheres in the size range 50 nm to 3 μm were fed by gavage to female Sprague Dawley rats daily for 10 days at a dose of 1.25 mg kg−1. Previous histological evidence of the uptake of these particles and their absorption across the gastrointestinal tract and passage via the mesentery lymph supply and lymph nodes to the liver and spleen was confirmed by analysis of tissues for the presence of polystyrene by gel permeation chromatography. Measurement of radioactivity of tissues following administration of 100 nm and 1 μm I125‐labelled polystyrene latex particles for 8 days was corroborative although less secure because of the potential lability of the labelled particles. The extent of absorption of 50 nm particles under the conditions of these experiments was 34% and of the 100 nm particles 26% (as measured by determination of polystyrene content), of which total, about 7% (50 nm) and 4% (100 nm), was in the liver, spleen, blood and bone marrow. Particles larger than 100 nm did not reach the bone marrow, and those larger than 300 nm were absent from blood. No particles were detected in heart or lung tissue.

Physicochemical Principles of Pharmacy

Physicochemical Principles of Pharmacy provides basic information on physicochemical properties of drugs in order to allow the reader to understand, recognize, and predict the behavior of the drugs before and during their transit through the body. Each chapter is introduced with a brief description of the extent of the material covered, emphasizing the importance of its content in relation to pharmaceutical sciences – a clear and nicely written invitation to go over the material. Whenever equations are described within the context of each chapter, examples with practical calculations are given in order to familiarize the reader with the use of the parameters and their units. Graphs and tables are used to help explain the dynamic of the processes and to compare those processes across different chemical groups of compounds. Also, the main concepts and equations are highlighted throughout the chapters with the aid of small summary boxes. At the end of the chapters the authors finalize with a recap of the most important concepts in a bullet-summary format followed by a list of review articles published on the different covered matters under references. This book brings together the importance of the physicochemical principles in terms of formulation and quality control, and the final goal of pharmacy assistance, which is to ensure the delivery of the drug to its site of action and promote a safe and desired response. This book provides the student with all the main tools necessary to understand the broad scope of the pharmacy and pharmaceutical sciences. I highly recommend this book as a good addition to a pharmacy library and should be considered as a textbook for advanced students in pharmacy practice and as a reference book for undergraduate courses in the pharmaceutical sciences field.

The Oral Absorption of Micro- and Nanoparticulates: Neither Exceptional Nor Unusual

This mini-review covers some of the historical and recent arguments over the experimental evidence on the uptake by and translocation from the intestinal mucosa of microparticulates after oral administration. It is concluded that there is now no dispute over the fact that this is a normal occurrence. Particulate uptake does take place, not only via the M-cells in the Peyers patches and the isolated follicles of the gut-associated lymphoid tissue, but also via the normal intestinal enterocytes. Factors affecting uptake include particle size, surface charge and hydrophobicity and the presence or absence of surface ligands. The covalent attachment of lectin or invasin molecules to the surface of carrier particles leads to greater systemic uptake. Whether or not the route can be utilized for the routine administration of therapeutic agents which are not normally absorbed from the gut is not yet proven. Many studies show that 2−3% of the ingested dose of submicron particles can be absorbed. The increasing diversity of carrier systems, which includes dendrimers and liposomes, needs to be exploited fully. More also must be learned about the inter- and intra-subject variability of lymphoid tissue so that appropriate selectivity can be achieved through the design of specific carriers.

Liposomes in Drug Delivery

SummaryLiposomes (phospholipid-based vesicles) have been investigated since 1970 as a system for the delivery or targeting of drugs to specific sites in the body. Because of their structural versatility in terms of size, composisition, surface charge, bilayer fluidity and ability to incorporate almost any drug regardless of solubility, or to carry on their surface cell-specific ligands, liposomes have the potential to be tailored in a variety of ways to ensure the production of formulations that are optimal for clinical use. This includes controlled retention of entrapped drugs in the presence of biological fluids, controlled vesicle residence in the blood circulation or other compartments in the body, and enhanced vesicle uptake by target cells.Accumulated in vivo evidence, particularly in areas such as cancer chemotherapy, antimicrobial therapy, vaccines, diagnostic imaging and the treatment of ophthalmic disorders has indicated clearly that some liposome-entrapped drugs and vaccines exhibit superior pharmacological properties to those observed with conventional formulations. Such work has encouraged the application of liposomes in the treatment of diseases in humans. A large number of trials in patients with cancer or infections suggest that certain liposomal drug formulations are likely to prove clinically useful.

The Uptake and Translocation of Latex Nanospheres and Microspheres after Oral Administration to Rats

Abstract— Non‐ionic and carboxylated fluorescent polystyrene microspheres (100, 500 nm, 1 and 3 μm in diameter), were fed by gavage (2·5% w/v; 1·25 mg kg−1) daily for 10 days to female Sprague Dawley rats. Peyers patches, villi, liver, lymph nodes and spleen of animals fed the non‐ionic microspheres from 100 nm to 1 μm showed unequivocal evidence of uptake and translocation of the particles. Heart, kidney and lung showed no evidence of the presence of microspheres. Carboxylated microspheres were taken up to a lesser degree than the non‐ionised particles. Experiments with 125I radiolabeled 100 nm and 1 μm particles showed a higher uptake of the smaller particles, which were concentrated in GI tissue and liver. Particles were not distributed randomly in the tissues, but were concentrated at the serosal side of the Peyers patches and could be seen traversing the mesentery lymph vessels towards the lymph nodes. The results demonstrate a need to re‐examine the possibilities of particulate oral delivery, as well as the potential toxicity of ingested particulates.

Preparation and properties of vesicles (niosomes) of sorbitan monoesters (Span 20, 40, 60 and 80) and a sorbitan triester (Span 85)

Abstract Formation of multilamellar vesicles (niosomes) of a series of sorbitan monoesters (Span 20, 40, 60 and 80) and a sorbitan trioleate (Span 85) has been studied using a mechanical shaking technique without sonication. 5(6)-Carboxyfluorescein (CF) was used as a model solute to investigate entrapment efficiency and release. For Span 80, cholesterol and dicetyl phosphate (DCP) in the molar ratio 47.5:47.5:5.0, entrapment efficiency increased linearly with increasing concentration of lipid. Entrapment efficiency per mmol lipid, however, was constant at about 34%, independent of the lipid concentration. Entrapment efficiency increased with increasing cholesterol content when vesicles were prepared by changing the molar ratio of non-ionic surfactant to cholesterol. Most efficient entrapment of CF occurred with Span 60 (HLB 4.7). Mean size of the un-sonicated niosomes showed a regular increase with increasing HLB from Span 85 (HLB 1.8) to Span (HLB 8.6). The release rate of CF from vesicles depended on the surfactant used in the preparation of the vesicles.

Transcytosis of nanoparticle and dendrimer delivery systems:evolving vistas

The translocation of particulate matter across the gastrointestinal tract is now a well documented phenomenon offering new potential for the delivery of drugs with poor dissolution profiles and labile chemistries via encapsulation in biodegradable nanoparticles. The last few years have seen an acceleration in the number of publications describing the varying facets of this approach and the multidisciplinary nature of this field. This review delineates data from this rather fragmented area and from cognate fields to provide a physicochemical viewpoint of the importance of surface chemistries of oral drug delivery vehicles and their interactions in and with gut contents prior to uptake. The role of lymphoid and non-lymphoid tissues is examined, and the role of bioadhesion is discussed. The exciting potential of molecular encapsulation of drugs via dendrimers and star branched molecules is discussed in the context of nanotechnological applications for the oral route. Evolving vistas include a better understanding of the plasticity of the intestinal epithelium and M-cell induction as well as the influence of disease states on particulate uptake. In this review we address a number of issues deemed vital to an understanding of the subject including (i) some background knowledge on particulate uptake (the subject of several reviews), (ii) factors affecting uptake such as diameter and surface charge and character, (iii) the dynamic nature of particle interactions in the gut, (iv) the dynamic nature of the processes of capture, adhesion, uptake, transcytosis and translocation, and (v) the influence of surface ligands.

Nanosystem drug targeting: Facing up to complex realities

This review considers some of the obstacles to successful drug targeting and delivery of therapeutic agents to desired target sites in the body, in the context of the sometimes overblown claims made for nanoparticle and nanosystem based delivery. It covers aspects of issues surrounding the instability of particles in vivo through flocculation and aggregation, their complex flow and adhesion patterns in the capillary network, particle jamming and bridging, the heterogeneity of access of drugs to some sites such as tumours even in their free molecular state, the diffusion of free drug and nanoparticles in tumour tissue and in single cells. There are the fundamental laws of physics and materials, especially in relation to diffusion, adsorption, adhesion and hydrodynamics, which apply and these cannot be denied in our attempts to target carriers to anatomically distant targets, tumours being the archetypal target experiencing most of the barriers which prevent quantitative carrier and hence drug uptake. The paper closes with a discussion of some of the unmet challenges which must be addressed before quantitative delivery and targeting is achieved in many disease states. It is clear that if progress is to be made an International System for testing nanoparticulate delivery systems should be established. In this way data from different laboratories will be comparable. The International protocol should cover both in vitro and in vivo testing.

Nanoparticle uptake by the oral route: Fulfilling its potential?

The absorption of nanoparticles from the gastrointestinal tract is discussed first from a recent historical perspective, emphasising the crucial parameters that influence uptake, such as particle diameter, the nature of the particle and any surface modification with ligands designed to interact with receptors to facilitate targeting to and uptake into cells. Post-absorptive events, including translocation processes, are suggested here to be as important as initial uptake into the epithelial cells or M-cells of the gut associated lymphoid tissue.:

Enhanced oral uptake of tomato lectin-conjugated nanoparticles in the rat

AbstractPurpose. To investigate the usefulness of a surface-conjugated, bioadhesive molecule, tomato lectin, to augment intestinal uptake of orally administered inert nanoparticles. Methods. Fluorescent 500 nm polystyrene nanoparticles with tomato lectin covalently surface coupled using a carbodiimide reaction were administered to female Wistar rats by oral gavage daily for 5 days. Results. Analysis of tissue extracted polymer by gel permeation chromatography revealed a 23% systemic uptake of tomato lectin conjugated nanoparticles compared to < 0.5% of TL nanoparticles blocked with N-acetylchitotetraose thus representing an increase of almost 50 fold across the intestine. Intestinal uptake of tomato lectin-conjugated nanoparticles via the villous tissue was 15 times higher than uptake by the gut-associated lymphoid tissue. Conclusions. The application of tomato lectin as a bioadhesive agent in vivo has been demonstrated to enhance subsequent intestinal transcytosis of colloidal particulates to which it is bound.