The application of liposomes to assist drug delivery has already had a major impact on many biomedical areas. They have been shown to be beneficial for stabilizing therapeutic compounds, overcoming obstacles to cellular and tissue uptake, and improving biodistribution of compounds to target sites in vivo. This enables effective delivery of encapsulated compounds to target sites while minimizing systemic toxicity. Liposomes present as an attractive delivery system due to their flexible physicochemical and biophysical properties, which allow easy manipulation to address different delivery considerations. Despite considerable research in the last 50 years and the plethora of positive results in preclinical studies, the clinical translation of liposome assisted drug delivery platforms has progressed incrementally. In this review, we will discuss the advances in liposome assisted drug delivery, biological challenges that still remain, and current clinical and experimental use of liposomes for biomedical applications. The translational obstacles of liposomal technology will also be presented.

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Advances and Challenges of Liposome Assisted Drug Delivery.

There are many potential barriers to the effective delivery of a drug in its active form to solid tumors. Most small-molecule chemotherapeutic agents have a large volume of distribution on i.v. administration ([Speth et al., 1988][1]; [Chabner and Longo, 1996][2]). The result of this is often a

Optimizing Liposomes for Delivery of Chemotherapeutic Agents to Solid Tumors

Aptamers are single-stranded nucleic acid molecules that possess properties comparable to those of protein monoclonal antibodies, and thus are clear alternatives to long established antibody-based diagnostic or biotechnological products for research, diagnostics, and therapy. 1-4 This class of functional nucleic acids can fold into complex three-dimensional shapes, 5-7 forming binding pockets and clefts for the specific recognition and tight binding of any given molecular target, 8-10 from metal ions and small chemicals to large proteins and higher order protein complexes, whole cells, viruses, or parasites. Aptamers can be isolated in Vitro from vast combinatorial libraries that comprise trillions of different sequences, by a process called “ in Vitro selection”, or “SELEX”, an acronym for “systematic evolution of ligands by exponential enrichment”. An in Vitro selection experiment comprises a number of sequential steps, the first of which is the generation of a nucleic acid library of random sequences. This starting pool of mainly nonfunctional RNA or DNA sequences is generated using a standard DNA-oligonucleotide synthesizer. 11 The design of such libraries involves the synthesis of a short defined sequence, followed by a random region of variable length and another defined sequence at the 5 ′-end. This pool of synthetic single-stranded DNA (ssDNA) is amplified in the polymerase chain reaction (PCR), generating several copies of each DNA in its double-stranded form. By in Vitro transcription, a corresponding library of RNA molecules can be generated which can then be used for the in Vitro selection. If the transcription reaction contains nucleoside triphosphate derivatives that are chemically modified but still are substrates for RNA polymerases, libraries of modified RNAs can be generated in which sequences are equipped with a broad variety of additional chemical functionalities, normally not present in natural nucleic acids. 12-14 Aptamers selected from chemically modified libraries can, in some cases, be completely resistant toward degradation by nucleases. The additional functional groups can lead to ligands with novel * To whom correspondence should be addressed: telephone, +49-228735661; fax,+49-228-735388; e-mail, m.famulok@uni-bonn.de. † LIMES Institute. ‡ University of Konstanz. Volume 107, Number 9

Functional Aptamers and Aptazymes in Biotechnology, Diagnostics, and Therapy

Role of nanotechnology in targeted drug delivery and imaging: a concise review.

The use of nanotechnology in medicine has the potential to have a major impact on human health for the prevention, diagnosis, and treatment of diseases. One particular aspect of the nanomedicine field which has received a great deal of attention is the design and development of nanoparticulate nanomedicines (NNMs) for drug delivery (i.e., drug-containing nanoparticles). NNMs are intended to deliver drugs via various mechanisms: solubilization, passive targeting, active targeting, and triggered release. The NNM approach aims to increase therapeutic efficacy, decrease the therapeutically effective dose, and/or reduce the risk of systemic side effects. In order to move a NNM from the bench to the bedside, several experimental challenges need to be addressed. This review will discuss the current trends and challenges in the clinical translation of NNMs as well as the potential pathways for translational development and commercialization. Key issues related to the clinical development of NNMs will be covered, including biological challenges, large-scale manufacturing, biocompatibility and safety, intellectual property (IP), government regulations, and overall cost-effectiveness in comparison to current therapies. These factors can impose significant hurdles limiting the appearance of NNMs on the market, irrelevant of whether they are therapeutically beneficial or not.

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Current Trends and Challenges in the Clinical Translation of Nanoparticulate Nanomedicines: Pathways for Translational Development and Commercialization

Michael Willis

Papers

Ligand-targeted liposomes.