Advances in Particulate Polymeric Drug Delivery - ACS Publications

Chapter 1

Advances in Particulate Polymeric Drug Delivery Sönke Svenson

Downloaded by 198.91.36.79 on February 16, 2015 | http://pubs.acs.org Publication Date: February 16, 2006 | doi: 10.1021/bk-2006-0923.ch001

Dendritic NanoTechnologies Inc., 2625 Denison Drive, Mount Pleasant, MI 48858 (email: [email protected])

An ο verview is given presenting various strategies to deliver small molecule and macromolecule drugs. Micelles, lipo somes, emulsions, dendrimers and micro and nanocontainers are the carrier types employed in these strategies. Targeting of specific organs and triggered release of the drugs from their carriers are being highlighted.

Introduction The development of molecular nanostructures with well-defined particle size and shape is of eminent interest in biomedical applications such as the delivery of active pharmaceuticals, imaging agents, or gene transfection. For example, structures utilized as carriers in drug delivery generally should be in the nanometer range and uniform in size to enhance their ability to cross cell membranes and reduce the risk of undesired clearance from the body through the liver or spleen. Two traditional routes to produce particles that will meet these requirements to some extent have been widely investigated. The first route takes advantage of the ability of amphiphilic molecules (i.e., molecules consisting of a hydrophilic and hydrophobic moiety) to self-assemble in water above a systemspecific critical micelle concentration (CMC) to form micelles. Size and shape

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© 2006 American Chemical Society

In Polymeric Drug Delivery I; Svenson, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.


3 of these micelles depend on the geometry of the constituent monomers, intermolecular interactions, and conditions of the bulk solution (i.e., concentration, ionic strength, pH, and temperature). Spherical micelles are monodisperse in size; however, they are highly dynamic in nature with monomer exchange rates in millisecond to microsecond time ranges. Μ icelies have the ability to encapsulate and carry lipophilic actives within their hydrocarbon cores. Depending on the specific system, some micelles either spontaneously rearrange to form liposomes after a change of solution conditions, or when exposed to external energy input such as agitation, sonication, or extrusion through a filter membrane. Liposomes consist of bilayer lipid membranes (BLM) enclosing an aqueous core, which can be utilized to carry hydrophilic actives. Furthermore, liposomes with multilamellar membranes provide cargo space for lipophilic actives as well. However, most liposomes are considered energetically metastable and eventually will rearrange to form planar bilayers. (1,2) The second route relies on engineering the well-defined particles through processing protocols. Examples for this approach include (i) shearing or homogenization ο f ο il-in-water (o/w) e mulsions ο r w/o/w d ouble e mulsions to produce stable and monodisperse droplets, (ii) extrusion of polymer strands or viscous gels through nozzles of defined size to manufacture stable and monodisperse micro and nanospheres, and (iii) layer-by-layer (LbL) deposition of polyelectrolytes and other polymeric molecules around colloidal cores, resulting in the formation of monodisperse nanocapsules after removal of the templating core. Size, degree of monodispersity, and stability of these structures depend on the systems that are being used in these applications. (3) Currently, a new third route to create very well-defined, monodisperse, stable molecular level nanostructures is being studied based on the "dendritic state" architecture. (4,5) The challenge is to develop critical structure-controlled methodologies to produce appropriate nanoscale modules that will allow costeffective synthesis and controlled assembly of more complex nanostructures in a very routine manner. Dendritic architecture is undoubtedly one of the most pervasive topologies observed throughout biological systems at virtually all dimensional length scales. This architecture offers unique interfacial and functional performance advantages because of the high level of control over its size, shape, branching density and composition, utilizing well established organic synthesis protocols. The fourth route utilizes natural carriers, for example viruses and microorganisms such as yeast cells. Adenovirus is a natural carrier studied for gene transfection applications because of its high efficiency in crossing cell membranes. However, the risk of potential adverse health effects limits the regulatory and public acceptance of viral carriers. As a viable alternative, in recent years microorganisms such as live lactobacillus species and common baker's yeast have been considered as novel vectors for the delivery of bioactive


4 proteins and peptides via the gastrointestinal tract. (6,7) The potential risk of using live organisms for drug delivery have resulted in a shift to using non-viable bacteria, yeast and yeast cell walls, where much of the site-specific targeting remains possible without problematic issues in controlling the activity of the microorganism. (8) Several of these systems and their utilization in drug delivery and gene transfection are being highlighted in this overview and some will be discussed in detail in the following chapters of this book.


Results and Discussion Micelles and Liposomes Regardless of the specific type, carriers utilized in drug delivery and gene transfection must fulfill two requirements to avoid non-specific capture at nontumor sites. First, drug carriers must be smaller than approximately 200 nm to evade uptake by the reticuloendothelial system, and their molecular weights should be larger than the critical value of approximately 40,000 Da to prevent renal filtration. Second, drug carriers should not strongly interact or randomly being taken up by organs, especially the reticuloendothelial system. Therefore, hydrophobic and cationic carrier surfaces should be avoided, while hydrophilic surfaces with neutral or weak negative overall charge will reduce or even prevent random uptake. The average size (i.e., 10 to 100 nm in diameter) of micelles makes them suitable carriers for these medical applications. The use of polymeric con stituents, formed from block or graft copolymers, will reduce the aforementioned high exchange rate between micelles and monomers and, thus, increase micelle stability. Most studies of polymeric micelles have employed AB or ABA-type block copolymers because the close relationship between micelle-forming behavior and structure of the polymers can be evaluated more easily with these copolymers than with graft or multi-segmented block copolymers. A more detailed discussion of these considerations is presented by Yohoyama in chapter 3 of this volume. The hydrophobic core - hydrophilic shell structure of micelles can be achieved through various routes, generally utilizing the amphiphilic character of the constituent polymeric monomers. Pluronics® (ABA block copolymers), Polyethylene glycol)-6-poly(ester)s, poly(ethylene glycol)-6-poly(L-amino acid) and ρ oly(ethylene glycol)-phospholipid micelles have been studied extensively for drug delivery. (9,10) An interesting approach is the employment of Polyethylene glycol)-phospholipid micelles for the delivery of the antifungal, amphotericin Β (AmB), described by Kwon et al. in chapter 2. Advantages of this system are the presumed compatibility between drug and phospholipid, the


5 proven safety profile of poly(ethylene glycol)-phospholipid, which are generally regarded as safe materials (GRAS), and perhaps the ability to disaggregate AmB to reduce its toxicity. Another approach to combine safe materials with hydrophobic character relies on polysaccharide-based micelles, where hydrophobicity is induced through alkyl chains that connect to the polysaccharides via poly(oxyethylene) linkers (POE -C ). Size, stability, and colloidal properties of these hydrophobically-modified (HM) polysaccharide micelles depend on their chemical composition, the number of saccharide units, and the architecture of the polymer. (11) While a number of fundamental studies of HM-polysaccharides have b een r eported, t heir u se a s c arriers o f p oorly water-soluble drugs in oral delivery has only been studied very recently. (12) The stability of micellar carriers can be enhanced beyond hydrophobic interactions through chemical cross-linking between monomers, either within the core or the shell domain. (13,14) The other major group of drug carriers based on self-assembly of amphiphilic monomers is comprised of liposomes. Liposomes can be con structed from biodegradable and nontoxic constituents and are able to noncovalently encapsulate molecules (i.e., chemotherapeutic agents, hemoglobin, imaging agents, drugs, and genetic material) within their 100-200 nm diameter interior. Liposomes are typically categorized in one of four categories: (i) conventional liposomes, which are composed of neutral and/or negativelycharged lipids and often cholesterol; (ii) long-circulating liposomes, which incorporate P E G covalently bound to a lipid; (iii) immunoliposomes, used for targeting where antibodies or antibody fragments are bound to the surface, and (iv) cationic liposomes, that are used to condense and deliver DNA. Liposomes are characterized by their surface charge, size, composition, and number and fluidity of their lamellae. (15,16) Immune recognition results in liposome clearance from the body and accumulation in liver, kidney, and spleen. For delivery to tumors, increased circulation time and evasion of the immune system is vital. The attachment of biocompatible groups onto the surface of liposome such as PEG chains ("Stealth liposomes") is a common approach to increase the circulation time. These PEG chains produce a steric barrier to protein binding. However, detachment of the PEG chains with time results in deprotection of the liposomes and constitutes a serious limitation to this approach. A very elegant solution to this dilemma is presented by Auguste et ah in chapter 8, using multiply attached polymers as a means for constructing polymer-protected liposomes. The concept is established by a series of PEG-based comb copolymers with concatenated PEG chains having hydrophobic anchoring groups between the linked PEG chains. In a related approach, PEG-lipid conjugates, connected via acid-labile linkers, have been inserted into the surface of planar lamellae and used to force


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6 curvature into these lamellae, resulting in the formation of pH-sensitive liposomes. The intrinsic low pH within the endosomal compartment results in hydrolysis of the PEG chains and re-transformation of the liposome into its parent lamellae, releasing the drug content within the cell. Eight acid-labile poly(ethylene glycol) conjugated vinyl ether lipids have been synthesized to test the efficiency of this approach. (17,18) Another dilemma in particulate drug delivery is manifested in the fact that cationic carriers are very efficient in DNA compaction and transfection but, at the same time, form aggregates upon contact with serum that in its worst block capillaries in vivo or, in milder forms, restrict transfection to the immediate vicinity of the injection site. Anionic or neutral liposomes, on the other hand, are unable to incorporate large pieces of DNA due to electrostatic repulsion. One proposed solution to this dilemma is the use of liposomes composed of lipids that have an anionic charge under physiological conditions but become cationic at a pH1 nm in size) to oligonucleotides (1-10 nm) and plasmids (30-200 nm when condensed). (26) In an effort to create nontoxic and highly effective synthetic transfection reagents, a tartarate comonomer has been polymerized with a series of amine comonomers to yield a new family of copolymers. Four new poly(L-tartaramidoamine)s have been designed and studied. Results of gel shift assays indicated that the polymers can bind plasmid DNA (pDNA) at polymer nitrogen to pDNA phosphate (N/P) ratios higher than one. Dynamic light scattering experiments revealed that each polymer compacted pDNA into nanoparticles (polyplexes) in the approximate size range to be endocytosed by cultured cells. These polyplexes exhibited high delivery efficiency without cytotoxic effects, indicating that these polymers have great promise as new gene delivery vehicles. The details of this study by Liu et al are being presented in chapter 15. Crossing biological barriers, a main obstacle in drug delivery and gene transfection, has triggered a mechanistic hypothesis for how water-soluble guanidinium-rich transporters, attached to small cargos (MW

Advances in Particulate Polymeric Drug Delivery - ACS Publications

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