In recent years, nanotechnology has been increasingly applied to the area of drug development. Nanoparticle-based therapeutics can confer the ability to overcome biological barriers, effectively deliver hydrophobic drugs and biologics, and preferentially target sites of disease. However, despite these potential advantages, only a relatively small number of nanoparticle-based medicines have been approved for clinical use, with numerous challenges and hurdles at different stages of development. The complexity of nanoparticles as multi-component three dimensional constructs requires careful design and engineering, detailed orthogonal analysis methods, and reproducible scale-up and manufacturing process to achieve a consistent product with the intended physicochemical characteristics, biological behaviors, and pharmacological profiles. The safety and efficacy of nanomedicines can be influenced by minor variations in multiple parameters and need to be carefully examined in preclinical and clinical studies, particularly in context of the biodistribution, targeting to intended sites, and potential immune toxicities. Overall, nanomedicines may present additional development and regulatory considerations compared with conventional medicines, and while there is generally a lack of regulatory standards in the examination of nanoparticle-based medicines as a unique category of therapeutic agents, efforts are being made in this direction. This review summarizes challenges likely to be encountered during the development and approval of nanoparticle-based therapeutics, and discusses potential strategies for drug developers and regulatory agencies to accelerate the growth of this important field.

https://link.springer.com/content/pdf/10.1208%2Fs12248-012-9339-4.pdf

Challenges in Development of Nanoparticle-Based Therapeutics

The paradigm of using nanoparticulate pharmaceutical carriers has been well established over the past decade, both in pharmaceutical research and in the clinical setting. Drug carriers are expected to stay in the blood for long time, accumulate in pathological sites with affected and leaky vasculature (tumors, inflammations, and infarcted areas) via the enhanced permeability and retention (EPR) effect, and facilitate targeted delivery of specific ligand-modified drugs and drug carriers into poorly accessible areas. Among various approaches to specifically target drug-loaded carrier systems to required pathological sites in the body, two seem to be most advanced – passive (EPR effect-mediated) targeting, based on the longevity of the pharmaceutical carrier in the blood and its accumulation in pathological sites with compromised vasculature, and active targeting, based on the attachment of specific ligands to the surface of pharmaceutical carriers to recognize and bind pathological cells. Here, we will consider and discuss these two targeting approaches using tumor targeting as an example.

Passive and active drug targeting: drug delivery to tumors as an example.

In the field of MR imaging and especially in the emerging field of cellular and molecular MR imaging, flexible strategies to synthesize contrast agents that can be manipulated in terms of size and composition and that can be easily conjugated with targeting ligands are required. Furthermore, the relaxivity of the contrast agents, especially for molecular imaging applications, should be very high to deal with the low sensitivity of MRI. Lipid-based nanoparticles, such as liposomes or micelles, have been used extensively in recent decades as drug carrier vehicles. A relatively new and promising application of lipidic nanoparticles is their use as multimodal MR contrast agents. Lipids are amphiphilic molecules with both a hydrophobic and a hydrophilic part, which spontaneously assemble into aggregates in an aqueous environment. In these aggregates, the amphiphiles are arranged such that the hydrophobic parts cluster together and the hydrophilic parts face the water. In the low concentration regime, a wide variety of structures can be formed, ranging from spherical micelles to disks or liposomes. Furthermore, a monolayer of lipids can serve as a shell to enclose a hydrophobic core. Hydrophobic iron oxide particles, quantum dots or perfluorocarbon emulsions can be solubilized using this approach. MR-detectable and fluorescent amphiphilic molecules can easily be incorporated in lipidic nanoparticles. Furthermore, targeting ligands can be conjugated to lipidic particles by incorporating lipids with a functional moiety to allow a specific interaction with molecular markers and to achieve accumulation of the particles at disease sites. In this review, an overview of different lipidic nanoparticles for use in MRI is given, with the main emphasis on Gd-based contrast agents. The mechanisms of particle formation, conjugation strategies and applications in the field of contrast-enhanced, cellular and molecular MRI are discussed.

/pdf/lipid-based-nanoparticles-for-contrast-enhanced-mri-and-m3mvxthxxe.pdf

Lipid-based nanoparticles for contrast-enhanced MRI and molecular imaging.

Integrins, a diverse class of heterodimeric cell surface receptors, are key regulators of cell structure and behaviour, affecting cell morphology, proliferation, survival and differentiation. Consequently, mutations in specific integrins, or their deregulated expression, are associated with a variety of diseases. In the last decades, many integrin-specific ligands have been developed and used for modulation of integrin function in medical as well as biophysical studies. The IC50-values reported for these ligands strongly vary and are measured using different cell-based and cell-free systems. A systematic comparison of these values is of high importance for selecting the optimal ligands for given applications. In this study, we evaluate a wide range of ligands for their binding affinity towards the RGD-binding integrins αvβ3, αvβ5, αvβ6, αvβ8, α5β1, αIIbβ3, using homogenous ELISA-like solid phase binding assay.

/pdf/a-comprehensive-evaluation-of-the-activity-and-selectivity-46glkvq9m7.pdf

A Comprehensive Evaluation of the Activity and Selectivity Profile of Ligands for RGD-binding Integrins.

Ligand-targeted liposome design: challenges and fundamental considerations.

Targeting of immunoliposomes to endothelial cells using a single-chain Fv fragment directed against human endoglin (CD105).

RGD peptides targeting alphav-integrins are promising ligands for the generation of vascular targeting agents. We isolated from phage display RGD motif libraries novel high-affinity cyclic RGD peptides by selection on either endothelial or melanoma cells. Although the starting sequences contained only two cysteine residues flanking the RGD motif, several of the isolated peptides possessed four cysteine residues. A high-affinity peptide (RGD10) constrained by only one disulfide bond was used to generate novel lipopeptides composed of a lipid anchor, a short flexible spacer and the peptide ligand conjugated to the spacer end. Incorporation of RGD10 lipopeptides into liposomes resulted in specific and efficient binding of the liposomes to integrin-expressing cells. In vivo experiments applying doxorubicin-loaded RGD10 liposomes in a C26 colon carcinoma mouse model demonstrated improved efficacy compared with free doxorubicin and untargeted liposomes.

Novel RGD lipopeptides for the targeting of liposomes to integrin-expressing endothelial and melanoma cells

Ligand-targeted anticancer therapeutics represent an opportunity for the selective and efficient delivery of drugs to tumours The chemical coupling of ligands to drugs or drug carrier systems is, however, often hampered by the presence of multiple reactive groups within the ligand, for example, epsilon-NH(2) groups in lysine side chains In this paper, we describe the isolation by phage display of human epidermal growth factor (EGF) variants without lysine and a reduced number of arginine residues The selection on A431 carcinoma cells also revealed that R41 is indispensable for EGF binding activity as all EGF variants contained an arginine residue at this position One EGF variant (EGFm1) with K28Q, R45S, K48S and R53S mutations was expressed in bacteria and showed an identical binding activity as wild-type EGF EGFm1 could be labelled with fluorescein isothiocyanate demonstrating the accessibility of the N-terminal amino group for coupling reagents Furthermore, coupling of EGFm1 to PEGylated liposomes resulted in target cell-specific binding and internalization of the liposomes These human EGF variants should be advantageous for the generation of anticancer therapeutics targeting the EGF receptor, which is overexpressed by a wide variety of different tumours

/pdf/isolation-from-phage-display-libraries-of-lysine-deficient-39pdgrvub9.pdf

Isolation from phage display libraries of lysine‐deficient human epidermal growth factor variants for directional conjugation as targeting ligands

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Targeting of immunoliposomes to endothelial cells using a single-chain Fv fragment directed against human endoglin (CD105).

Novel RGD lipopeptides for the targeting of liposomes to integrin-expressing endothelial and melanoma cells

Isolation from phage display libraries of lysine‐deficient human epidermal growth factor variants for directional conjugation as targeting ligands