Current Drug Delivery

ISSN: 1567-2018

OPEN ACCESS PLUS

Contents

Editorial: Nanotechnology Enables Superior Medical Therapies, 2011, 8, 225-226


Regulating Nanomedicine – Can the FDA Handle It?, 2011, 8, 227-234
Raj Bawa
[Abstract] [Full Text Article]


Non-Viral Nucleic Acid Delivery: Key Challenges and Future Directions, 2011, 8, 235-244
Mahmoud Elsabahy, Adil Nazarali and Marianna Foldvari
[Abstract] [Full Text Article]


Nanomedicine: A New Frontier in Cancer Therapeutics, 2011, 8, 245-253
Pui Yan Lee and Kenneth K.Y. Wong
[Abstract] [Full Text Article]


Cancer, Signal Transduction and Nanotechnology, 2011, 8, 254-260
Poulomi Sengupta, Sudipta Basu and Shiladitya Sengupta
[Abstract] [Full Text Article]


Part I: Targeted Particles for Cancer Immunotherapy, 2011, 8, 261-273
Samar Hamdy, Azita Haddadi, Zahra Ghotbi, Ryan W. Hung and Afsaneh Lavasanifar
[Abstract] [Full Text Article]


Part II: Targeted Particles for Imaging of Anticancer Immune Responses, 2011, 8, 274-281
Ryan W. Hung, Samar Hamdy, Azita Haddadi, Zahra Ghotbi and Afsaneh Lavasanifar
[Abstract] [Full Text Article]


Peptide-Based Subunit Nanovaccines, 2011, 8, 282-289
Mariusz Skwarczynski and Istvan Toth
[Abstract] [Full Text Article]


CH₅₀: A Revisited Hemolytic Complement Consumption Assay for Evaluation of Nanoparticles and Blood Plasma Protein Interaction, 2011, 8, 290-298
Ameena Meerasa, Jasper G. Huang and Frank X. Gu
[Abstract] [Full Text Article]


Amino Acid-Substituted Gemini Surfactant-Based Nanoparticles as Safe and Versatile Gene Delivery Agents, 2011, 8, 299-306
Jagbir Singh, Peng Yang, Deborah Michel, Ronald E. Verrall, Marianna Foldvari and Ildiko Badea
[Abstract] [Full Text Article]


Biphasic Vesicles for Topical Delivery of Interferon Alpha in Human Volunteers and Treatment of Patients with Human Papillomavirus Infections, 2011, 8, 307-319
Marianna Foldvari, Ildiko Badea, Praveen Kumar, Shawn Wettig, Ravinder Batta,Martin J. King, Zhihong He, Emmanuel Yeboah, Kimberly Gaspar, Peter Hull and Neil H. Shear
[Abstract] [Full Text Article]


M Cells Prefer Archaeosomes: An In Vitro/In Vivo Snapshot Upon Oral Gavage in Rats, 2011, 8, 320-329
Maria Jose Morilla, Diego Mengual Gomez, Pablo Cabral, Mirel Cabrera, Henia Balter, Maria Victoria Defain Tesoriero, Leticia Higa, Diana Roncaglia and Eder L Romero
[Abstract] [Full Text Article]


Multifunctional Nanomedicine Platform for Cancer Specific Delivery of siRNA by Superparamagnetic Iron Oxide Nanoparticles-Dendrimer Complexes, 2011, 8, 59-69
Oleh Taratula, Olga Garbuzenko, Ronak Savla, Y. Andrew Wang, Huixin He and Tamara Minko
[Abstract] [Full Text Article]


Pharmacogenetics of Intestinal Absorption, 2008, 5, 153-169
Tsutomu Nakamura, Motohiro Yamamori and Toshiyuki Sakaeda
[Abstract] [Full Text Article]




Abstracts


[Back to top]
Regulating Nanomedicine – Can the FDA Handle It?
Raj Bawa

[Full Text Article]

There is enormous excitement and expectation surrounding the multidisciplinary field of nanomedicine – the application of nanotechnology to healthcare – which is already influencing the pharmaceutical industry. This is especially true in the design, formulation and delivery of therapeutics. Currently, nanomedicine is poised at a critical stage. However, regulatory guidance in this area is generally lacking and critically needed to provide clarity and legal certainty to manufacturers, policymakers, healthcare providers as well as the public. There are hundreds, if not thousands, of nanoproducts on the market for human use but little is known of their health risks, safety data and toxicity profiles. Less is known of nanoproducts that are released into the environment and that come in contact with humans. These nanoproducts, whether they are a drug, device, biologic or combination of any of these, are creating challenges for the Food and Drug Administration (FDA), as regulators struggle to accumulate data and formulate testing criteria to ensure development of safe and efficacious nanoproducts (products incorporating nanoscale technologies). Evidence continues to mount that many nanoproducts inherently possess novel size-based properties and toxicity profiles. Yet, this scientific fact has been generally ignored by the FDA and the agency continues to adopt a precautionary approach to the issue in hopes of countering future potential negative public opinion. As a result, the FDA has simply maintained the status quo with regard to its regulatory policies pertaining to nanomedicine. Therefore, there are no specific laws or mechanisms in place for oversight of nanomedicine and the FDA continues to treat nanoproducts as substantially equivalent (“bioequivalent”) to their bulk counterparts. So, for now, nanoproducts submitted for FDA review will continue to be subjected to an uncertain regulatory pathway. Such regulatory uncertainty could negatively impact venture funding, stifle nanomedicine research and development (R&D) and erode public acceptance of nanoproducts. The end-result of this could be a delay or loss of commercialized nanoproducts. Whether the FDA eventually creates new regulations, tweaks existing ones or establishes a new regulatory center to handle nanoproducts, for the time being it should at least look at nanoproducts on a case-by-case basis. The FDA should not attempt regulation of nanomedicine by applying existing statutes alone, especially where scientific evidence suggests otherwise. Incorporating nanomedicine regulation into the current regulatory scheme is a poor idea. Regulation of nanomedicine must balance innovation and R&D with the principle of ensuring maximum public health protection and safety.


[Back to top]
Non-Viral Nucleic Acid Delivery: Key Challenges and Future Directions
Mahmoud Elsabahy, Adil Nazarali and Marianna Foldvari

[Full Text Article]

Gene therapy holds the promise of correcting a genetic defect. It can be achieved with the introduction of a normal wild-type transgene into specific cells of the patient where the endogenous gene is underexpressing or by the introduction of a therapeutic agent, such as, antisense oligonucleotides (AON) or small interfering RNA (siRNA) to inhibit transcription and/or translation of an overexpressing endogenous gene or a cancer causing oncogene. Gene therapy has been utilized for vaccination and for the treatment of several diseases, such as, cancer, viral infections and dermatological diseases. However, there are many hurdles to overcome in developing effective gene-based therapeutics, including cellular barriers, enzymatic degradation and rapid clearance after administration. Successful transfer of nucleic acids (e.g. plasmid DNA, AON, siRNA, small hairpin RNA and micro RNA) into cells usually relies on the use of efficient carriers, commonly viral or non-viral vectors. Presently, viral vectors are more efficient than non-viral systems. However, immunogenicity, inflammatory reactions and problems associated with scale-up limit their clinical use. The ideal carriers for gene delivery should be safe and yet ensure that the DNA/RNA survives the extra- and intracellular environment and efficiently transfer to the appropriate cellular compartments. This review discusses some of the strategies that have been employed to overcome the barriers towards successful gene delivery.


[Back to top]
Nanomedicine: A New Frontier in Cancer Therapeutics
Pui Yan Lee and Kenneth K.Y. Wong

[Full Text Article]

Nanotechnology is a cutting edge and rapidly evolving technology in medicine. The potential of nanomedicine in cancer therapy is infinitely promising due to the fact that novel developments are constantly being explored. This is particularly the case in the use of nanoparticles in both tumor diagnosis, as well as treatment. This article will attempt to describe some recent advances using nanoparticle drug delivery system in cancer therapy. The evolution history, the challenges and the role of nanoparticles in cancer drug delivery will briefly be discussed together with additional opportunities in cancer therapy. An overall understanding of these issues will help with further advancement of designing better drug delivery system that can be applied clinically.


[Back to top]
Cancer, Signal Transduction and Nanotechnology
Poulomi Sengupta, Sudipta Basu and Shiladitya Sengupta

[Full Text Article]

Understanding the mechanisms underlying different cellular signaling pathways implicated in the pathogenesis of cancer are leading to the identification of novel drug targets as well as novel drug candidates. Multiple targeted therapeutics that modulate aberrant molecular pathways have already reached the clinic. However, targeted therapeutics can exert mechanism-driven side effects as a result of the implication of the molecular target in normal physiological functions besides tumorigenesis. We hypothesize that targeted therapeutics can be optimized by merging them with nanotechnology, which offers the potential for preferential targeting to the tumor, resulting in increased intratumoral concentrations of the active agent with reduced distribution to other parts of the body. This review will address some of the emerging concepts that integrate these two disciplines to engineer novel nanovectors that target different signaling pathways.


[Back to top]
Part I: Targeted Particles for Cancer Immunotherapy
Samar Hamdy, Azita Haddadi, Zahra Ghotbi, Ryan W. Hung and Afsaneh Lavasanifar

[Full Text Article]

Dendritic cells (DCs) are the key antigen presenting cells that link innate and adaptive immunity. In the periphery, DCs capture antigens, process them and migrate into the regional lymph nodes where they could initiate antigen specific T cell immune responses. Immunotherapeutic strategies that aim to deliver tumor antigens specifically to DCs could not only boost anti-tumor immune responses but also could alleviate non-specific immune activation and/or unwanted side effects. Nano-sized particulate delivery systems are efficient modalities that can deliver tumor antigens to DCs in a targeted and specific manner. This review will provide general information on the rationale behind targeting antigens to DCs and the crucial role of DCs in initiating antigen specific T cell responses. Different strategies that have been employed in delivering antigens to DCs will be also discussed. A special emphasis will be put on specific targeting of cancer vaccine formulations to DC-specific receptors (e.g. CD11c, CD40, Fcγ, CCR6, pathogenic recognition receptors such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs)).


[Back to top]
Part II: Targeted Particles for Imaging of Anticancer Immune Responses
Ryan W. Hung, Samar Hamdy, Azita Haddadi, Zahra Ghotbi and Afsaneh Lavasanifar

[Full Text Article]

The interaction of dendritic cells (DCs) and T cells has been the cornerstone of approaches to cancer immunotherapy. Antitumoral immune responses can be elicited by delivering cancer antigens to DCs. As antigen presenting cells, these DCs activate cancer antigen specific T cells. Whereas the first part of the review discusses methods for delivery of cancer vaccines to DCs, in this part the focus is on the potential role of nanoscopic devices for molecular imaging of these immune responses. Nanoscopic devices could potentially deliver tracking molecules to DCs, enabling monitoring of DCs and/or T cell activation and tumoricidal activity during immunotherapy, using non-invasive imaging modalities such as nuclear imaging (single photon emission computed tomography (SPECT), positron emission tomography (PET)), magnetic resonance imaging (MRI) and optical imaging.


[Back to top]
Peptide-Based Subunit Nanovaccines
Mariusz Skwarczynski and Istvan Toth

[Full Text Article]

Classical vaccines incorporating live or attenuated microorganisms possess several disadvantages and cannot be applied against cancer and some pathogens. Modern vaccines utilizing immunogenic subunits derived from a particular pathogen are able to overcome these obstacles but need a specific delivery system for their efficacy. Nanotechnology has opened a new window into these delivery methodologies. A nano-sized formulation of subunit vaccines has been proven to be very effective in inducing cellular and humoral immune responses. Here, we review a number of peptide vaccine delivery strategies based on nanoparticles composed of polymers, peptides, lipids, and inorganic materials.


[Back to top]
CH₅₀: A Revisited Hemolytic Complement Consumption Assay for Evaluation of Nanoparticles and Blood Plasma Protein Interaction
Ameena Meerasa, Jasper G. Huang and Frank X. Gu

[Full Text Article]

The use of nanoparticles as platforms or vehicles for applications in nanomedicine, such as drug delivery and medical imaging, has been widely reported in the literature. A key area of potential improvement in the development and implementation of nanoparticles is the design of surface treatments to maximize residence time in the bloodstream. Major obstacles to the prolonged circulation of nanoparticles include complement activation and opsonization, both of which contribute to the removal of foreign matter from the vasculature. A greater understanding of the mechanisms through which nanoparticles interact with the complement system of innate immunity may be necessary in future endeavours to optimize nanoparticle design. The range of experimental techniques available for measuring complement interaction is presented. In particular, an in vitro hemolytic complement consumption assay called the CH₅₀ method is compared with alternative complement measurement techniques and cellular uptake studies in order to demonstrate its effectiveness as a quantitative evaluation of overall complement interaction. Moreover, establishing the usefulness of CH₅₀ results as predictors of in vivo behaviour is identified as a critical area for future research.


[Back to top]
Amino Acid-Substituted Gemini Surfactant-Based Nanoparticles as Safe and Versatile Gene Delivery Agents
Jagbir Singh, Peng Yang, Deborah Michel, Ronald E. Verrall, Marianna Foldvari and Ildiko Badea

[Full Text Article]

Gene based therapy represents an important advance in the treatment of diseases that heretofore have had either no treatment or cure. To capitalize on the true potential of gene therapy, there is a need to develop better delivery systems that can protect these therapeutic biomolecules and deliver them safely to the target sites. Recently, we have designed and developed a series of novel amino acid-substituted gemini surfactants with the general chemical formula C₁₂H₂₅(CH₃)₂N⁺-(CH₂)₃-N(AA)-(CH₂)₃-N⁺(CH₃)₂-C₁₂H₂₅ (AA= glycine, lysine, glycyl-lysine and, lysyl-lysine). These compounds were synthesized and tested in rabbit epithelial cells using a model plasmid and a helper lipid. Plasmid/gemini/lipid (P/G/L) nanoparticles formulated using these novel compounds achieved higher gene expression than the nanoparticles containing the parent unsubstituted compound. In this study, we evaluated the cytotoxicity of P/G/L nanoparticles and explored the relationship between transfection efficiency/toxicity and their physicochemical characteristics (such as size, binding properties, etc.). An overall low toxicity is observed for all complexes with no significant difference among substituted and unsubstituted compounds. An interesting result revealed by the dye exclusion assay suggests a more balanced protection of the DNA by the glycine and glycyl-lysine substituted compounds. Thus, the higher transfection efficiency is attributed to the greater biocompatibility and flexibility of the amino acid/peptide-substituted gemini surfactants and demonstrates the feasibility of using amino acid-substituted gemini surfactants as gene carriers for the treatment of diseases affecting epithelial tissue.


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Biphasic Vesicles for Topical Delivery of Interferon Alpha in Human Volunteers and Treatment of Patients with Human Papillomavirus Infections
Marianna Foldvari, Ildiko Badea, Praveen Kumar, Shawn Wettig, Ravinder Batta,Martin J. King, Zhihong He, Emmanuel Yeboah, Kimberly Gaspar, Peter Hull and Neil H. Shear

[Full Text Article]

Purpose: Topical biphasic vesicle delivery system encapsulating interferon alpha (IFN α) was developed as an alternative to injections used to treat human papillomavirus (HPV) infections.

Methods: Biphasic lipid vesicles encapsulating increasing doses of IFN α (biphasic IFN α) were characterized for encapsulation efficiency, size, zeta potential and vesicle structure by centrifugation, dynamic light scattering, confocal microscopy and small-angle x-ray scattering. Biphasic IFN α delivery into human skin in vivo and topical efficacy in patients with genital warts were evaluated.

Results:Averageencapsulation efficiency of IFN a was 81-91%. The average particle size was 1000-1100 nm and zeta potential +70 to +78 mV. After application of 5, 15 and 40MU/g biphasic IFN α formulation in a topical patch on the upper inner arm in healthy volunteers, skin IFN α levels increased to 120±30, 380±60 and 400±80 IU/mg protein in skin homogenates (n=5, 5, and 7), respectively. Topical application of biphasic IFN α (1 MU/dose) twice daily for two weeks in a pilot study with 12 patients with external condylomata acuminata resulted in a decrease in lesion size, in 2’,5’-oligoadenylate synthetase activity and in tissue viral load.

Conclusions: Biphasic vesicles delivered clinically significant levels of IFN α across intact human skin and elicited marked therapeutic effect in patients.


[Back to top]
M Cells Prefer Archaeosomes: An In Vitro/In Vivo Snapshot Upon Oral Gavage in Rats
Maria Jose Morilla, Diego Mengual Gomez, Pablo Cabral, Mirel Cabrera, Henia Balter, Maria Victoria Defain Tesoriero, Leticia Higa, Diana Roncaglia and Eder L Romero

[Full Text Article]

The archaeolipids (lipids extracted from archaebacterias) are non saponificable molecules that form self sealed mono or bilayers (archaeosomes-ARC). Different to liposomes with bilayers made of conventional glycerophospholipids, the bilayer of ARC posses a higher structural resistance to physico chemical and enzymatic degradation and surface hydrophobicity. In this work we have compared the binding capacity of ARC exclusively made of archaeols containing a minor fraction of sulphoglycophospholipids, with that of liposomes in gel phase on M-like cells in vitro. The biodistribution of the radiopharmaceutical ^99mTc-DTPA loaded in ARC vs that of liposomes upon oral administration to Wistar rats was also determined. The fluorescence of M-like cells upon 1 and 2h incubation with ARC loaded with the hydrophobic dye Rhodamine-PE (Rh-PE) and the hydrophilic dye pyranine (HPTS) dissolved in the aqueous space, was 4 folds higher than upon incubation with equally labeled liposomes. Besides, 15% of Rh-PE and 13 % of HPTS from ARC and not from liposomes, were found in the bottom wells, a place that is equivalent to the basolateral pocket from M cells. This fact suggested the occurrence of transcytosis of ARC. Finally, 4 h upon oral administration, ARC were responsible for the 22.3 % (3.5 folds higher than liposomes) shuttling of ^99mTc-DTPA to the blood circulation. This important amount of radioactive marker in blood could be a consequence of an extensive uptake of ARC by M cells in vivo, probably favored by their surface hydrophobicity. Taken together, these results suggested that ARC, proven their adjuvant capacity when administered by parenteral route and high biocompatibility, could be a suitable new type of nanoparticulate material that could be used as adjuvants by the oral route.


[Back to top]
Multifunctional Nanomedicine Platform for Cancer Specific Delivery of siRNA by Superparamagnetic Iron Oxide Nanoparticles-Dendrimer Complexes
Oleh Taratula, Olga Garbuzenko, Ronak Savla, Y. Andrew Wang, Huixin He and Tamara Minko

[Full Text Article]

The ability of Superparamagnetic Iron Oxide (SPIO) nanoparticles and Poly(Propyleneimine) generation 5 dendrimers (PPI G5) to cooperatively provoke siRNA complexation was investigated in order to develop a targeted, multifunctional siRNA delivery system for cancer therapy. Poly(ethylene glycol) (PEG) coating and cancer specific targeting moiety (LHRH peptide) have been incorporated into SPIO-PPI G5-siRNA complexes to enhance serum stability and selective internalization by cancer cells. Such a modification of siRNA nanoparticles enhanced its internalization into cancer cells and increased the efficiency of targeted gene suppression in vitro. Moreover, the developed siRNA delivery system was capable of sufficiently enhancing in vivo antitumor activity of an anticancer drug (Cisplatin). The proposed approach demonstrates potential for the creation of targeted multifunctional nanomedicine platforms with the ability to deliver therapeutic siRNA specifically to cancer cells in order to prevent severe adverse side effects on healthy tissues and in situ monitoring of the therapeutic outcome using clinically relevant imaging techniques.


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Pharmacogenetics of Intestinal Absorption
Tsutomu Nakamura, Motohiro Yamamori and Toshiyuki Sakaeda

[Full Text Article]

The small intestine is the primary site of absorption for many drugs administered orally and so is the target tissue for pharmacotherapeutic strategies to control the oral absorption of drugs. Drug transporters, including the ATP-binding cassette (ABC) superfamily and the solute carrier (SLC) superfamily, have been considered to play a physiological role in regulating the absorption of xenobiotics, and variations in their expression level and function in the small intestine cause intra- and inter-individual variation in the oral absorption of drugs. Recent advances in molecular biology have suggested that genetic polymorphisms are associated with the expression level and function, and thereby inter-individual variation. In this review, the pharmacogenetics of these transporters is summarized, and their future significance in the clinical setting is discussed.