Raj Bawa

Nanomedicines: addressing the scientific and regulatory gap.

Nanomedicine is the application of nanotechnology to the discipline of medicine: the use of nanoscale materials for the diagnosis, monitoring, control, prevention, and treatment of disease. Nanomedicine holds tremendous promise to revolutionize medicine across disciplines and specialties, but this promise has yet to be fully realized. Beyond the typical complications associated with drug development, the fundamentally different and novel physical and chemical properties of some nanomaterials compared to materials on a larger scale (i.e., their bulk counterparts) can create a unique set of opportunities as well as safety concerns, which have only begun to be explored. As the research community continues to investigate nanomedicines, their efficacy, and the associated safety issues, it is critical to work to close the scientific and regulatory gaps to assure that nanomedicine drives the next generation of biomedical innovation.

Patents and nanomedicine

Big pharmas business model, which relies on a few blockbusters to generate profits, is clearly broken. Patent expiration on numerous blockbusters in recent years is already altering the drug landscape. Drug companies are also facing other challenges that necessitate development and implementation of novel R&D strategies, including those that focus on nanotechnology and miniaturization. Clearly, there is enormous excitement and expectation regarding nanomedicines potential impact. However, securing valid and defensible patent protection will be critical. Although early forecasts for nanomedicine commercialization are encouraging, there are numerous bottlenecks as well. One of the major hurdles is an emerging thicket of patent claims, resulting primarily from patent proliferation as well as continued issuance of surprisingly broad patents by the US Patent and Trademark Office (PTO). Adding to this confusion is the fact that the US National Nanotechnology Initiatives widely cited definition of nanotechnology is inaccurate and irrelevant from a nanomedicine perspective. It is also the cause of the inadequate patent classification system that was recently unveiled by the PTO. All of this is creating a chaotic, tangled patent landscape in various sectors of nanomedicine where the competing players are unsure of the validity and enforceability of numerous issued patents. If this trend continues, it could stifle competition and limit access to some inventions. Therefore, reforms are urgently needed at the PTO to address problems ranging from poor patent quality and questionable examination practices to inadequate search capabilities, rising attrition, poor employee morale and a skyrocketing patent application backlog. Only a robust patent system will stimulate the development of commercially viable nanomedicine products that can drastically improve a patients quality of life and reduce healthcare costs.

Applications of aptamers in nanodelivery systems in cancer, eye and inflammatory diseases.

Aptamers are an interesting class of molecules that have potential in many facets of human health. They are characterized by high affinity and specificity to their targets, are small in size, have similar properties to antibodies, but are made synthetically. All of these properties, among others, give aptamers the potential to diagnose, image and treat like no other molecules. By combining the unique properties of aptamers with the ever expanding field of nanotechnology and all it has to offer, we are entering a very promising new area of targeted nanodelivery treatments. These treatments have found success in the complex disease processes of cancer, eye and inflammatory diseases.

Emerging Issues in Nanomedicine and Ethics

There is enormous excitement and expectation regarding nanotechnology’s potential impact on every aspect of society. Although early forecasts for commercialization efforts are encouraging, there are bottlenecks as well. Some formidable challenges include legal, environmental, safety, ethical and regulatory questions as well as emerging thickets of overlapping patent claims. In fact, patent systems are under great scrutiny and strain, with patent offices around the world continuing to struggle with evaluating the swarm of nanotechrelated patent applications. Adding to this confusion is the fact that the US National Nanotechnology Initiative’s (NNI) widely-cited definition of nanotechnology is inaccurate and irrelevant, especially in reference to nanomedicine (see §2). Nevertheless, governments around the world are impressed by nanotechnology’s potential and are staking their claims by doling out billions of dollars, euros and yen for research. International rivalries are growing. Political alliances are forming and battle lines are being drawn.

Nucleic Acid-Based Aptamers: Applications, Development and Clinical Trials

Short single-stranded oligonucleotides called aptamers, often termed as chemical antibodies, have been developed as powerful alternatives to traditional antibodies with respect to their obvious advantages like high specificity and affinity, longer shelf-life, easier manufacturing protocol, freedom to introduce chemical modifications for further improvement, etc. Reiterative selection process of aptamers over 10-15 cycles starting from a large initial pool of random nucleotide sequences renders them with high binding affinity, thereby making them extremely specific for their targets. Aptamer-based detection systems are well investigated and likely to displace primitive detection systems. Aptamer chimeras (combination of aptamers with another aptamer or biomacromolecule or chemical moiety) have the potential activity of both the parent molecules, and thus hold the capability to perform diverse functions at the same time. Owing to their extremely high specificity and lack of immunogenicity or pathogenicity, a number of other aptamers have recently entered clinical trials and have garnered favorable attention from pharmaceutical companies. Promising results from the clinical trials provide new hope to change the conventional style of therapy. Aptamers have attained high therapeutic relevance in a short time as compared to synthetic drugs and/or other modes of therapy. This review follows the various trends in aptamer technology including production, selection, modifications and success in clinical fields. It focusses largely on the various applications of aptamers which mainly depend upon their selection procedures. The review also sheds light on various modifications and chimerizations that have been implemented in order to improve the stability and functioning of the aptamers, including introduction of locked nucleic acids (LNAs). The application of various aptamers in detection systems has been discussed elaborately in order to stress on their role as efficient diagnostic agents. The key aspect of this review is focused on success of aptamers on the basis of their performance in clinical trials for various diseases.

The carbon nanotube patent landscape in nanomedicine: an Expert opinion

Carbon nanotubes (CNTs) have extraordinary properties that make them promising candidates for a wide variety of potential biomedical applications, including new therapeutics, drug delivery systems and diagnostics. Because of their enormous commercial potential across industries, a classic patent landgrab is underway as competitors are busy locking up broad patents on CNTs. This is creating a chaotic, tangled patent thicket, where the validity and enforceability of numerous patents is unclear. In this article, the authors summarize the CNT patent landscape for nanomedicine, identifying key building block patents while raising legal questions regarding their validity.

A mitochondrial protein fraction catalyzing transport of the K+ analog Tl+

A protein fraction has been obtained from detergent‐solubilized mitochondrial membranes by its affinity for quinine, an inhibitor of K+ transport. A peptide derived from the predominant 53 kDa protein in this fraction is found to be identical in sequence to a portion of aldehyde dehydrogenase. Antigenically unrelated bands at 97, 77, 57, and 31 kDa are also seen on polyacrylamide gels. Observations utilizing a fluorescent probe entrapped in the lumen of membrane vesicles indicate that the reconstituted protein fraction imparts permeability to the K+ analog Tl+. These and other findings suggest that the affinity purified fraction includes a cation transport catalyst.

Chapter 12:The Challenge of Regulating Nanomedicine: Key Issues

Nano-enabled products and their applications have continued to evolve in recent years. Indeed, nanotechnologies have been integrated into many academic and industrial sectors, and have spurred new directions in terms of research, patents, commercial opportunities and technology transfer. However, many nanopatents are of dubious scope and breadth yet continue to be granted by patent offices internationally. Underpinning many issues in the regulation and patenting of such technologies is the difficulty that has been encountered in agreeing a definition, and this continues to pose a significant problem to regulators, policy-makers, drug companies, ethicists and legal professionals. This chapter aims to provide an overview of the regulatory and scientific landscape for nanotechnologies applied to medicine. The first US Food and Drug Administration (FDA)-approved nanodrug, Doxil®, is discussed as a paradigm for some of the sentient points. The chapter also provides information on the utility of physiologically based pharmacokinetic modeling for nano-enabled regulatory submissions, and a view of important gaps in knowledge relating to the mechanistic basis for modeling in the context of efficacy and safety of novel materials. There are potentially serious and inhibitory consequences if nanodrugs are overregulated, and a balanced approach is required, at least on a case-by-case basis, that addresses the needs of commercialization against mitigation of inadvertent harm to patients or the environment. Obviously, not every nanotherapeutic or nano-enabled product needs to be regulated. However, more is clearly needed from regulatory agencies like the FDA and European Medicines Agency than a stream of guidance documents that are in draft format, position papers that lack any legal implication, presentations that fail to identify key regulatory issues and policy papers that are often short on specifics. There is a very real need for regulatory guidelines that follow a science-based approach that are responsive to the associated shifts in knowledge and risks.

Interdisciplinary nanomedicine publications through interdisciplinary peer-review

Nanomedicine aims to apply and further develop nanotechnology to solve problems in medicine, related to diagnosis, treatment and/or disease prevention at the cellular and molecular level (Feng, 2006; Feng and Chien, 2003). Nanomedicine by nature is interdisciplinary, with benefits being realised at the interface of science and engineering, physical science and engineering, chemical science and engineering, cellular and molecular biology, pharmacology and pharmaceutics, medical sciences and technology and combinations thereof. The difference in perspective between disciplines may be partly responsible for the lack of nomenclature or universally-accepted definition for various “nano” terms, which causes issues with respect to publication consistency, regulatory agencies, patent offices, industry and the business community (Rannard & Owen, 2009; Tinkle et al., 2014; Bawa, 2013; Bawa, 2016). Regulatory agencies such as the US Food and Drug Administration (FDA; http://www.fda.gov/) and European Medicine Agency (EMA; http://www.ema. europa.eu/ema/) have generally failed to employ an interdisciplinary approach to regulate nanoscale technologies in the samemanner as they apply to drugs because they do not fully appreciate the interdisciplinary nature or novel characteristics ofmany submissions that disclose nanomedicines (e.g., as a result of high-surface-area to-volume ratio, inherent reactivity due to a greater proportion of exposed surface atoms, unpredictable properties, or toxicity profiles as compared to bulk). Currently, these agencies instead rely upon established laws and regulations validated through experiencewith conventional small molecule medicines. Synthesis and characterization of molecular biomaterials forms the material basis for nanomedicines. Molecular biomaterials may include synthesized biocompatible polymers such as currently accepted biodegradable polymers including polylactic acid (PLA), polycaprolactone (PCL) and polylactic-co-glycolic acid (PLGA), or molecularly engineered macromolecules such as lipids, DNAs, RNAs, proteins and peptides. Such bio materials are either used to stabilise nanosized particles of drug or to form nano-carrier technologies for sustained, controlled or targeted release of diagnostic and therapeutic agents to enhance their biological effects and to reduce their side effects (Feng et al., 2007; Owen, 2014; Bawa, 2016). Similarly, patent offices also often fail to recognize that an interdisciplinary approach needs to be applied by patent examiners while reviewing nanotechnologybased patent applications, since the technologies reflected in these patent applications often involve a combination of disciplines. In fact, non-uniform or Andrew Owen Steve Rannard

Outer Membrane Lysis Increases Accessibility of Cationic Drugs to the Inner Mitochondrial Membrane

The cationic anticancer drugs adriamycin and MGBG, and the polyamine spermidine, inhibit mitochondrial respiration. This inhibitory effect depends on the integrity of the outer mitochondrial membrane. Lysis of the outer membrane enhances inhibitory interactions of the organic cations with the respiratory chain. Addition of digitonin to Iyse the outer membrane also results in an increment of uptake of isotopically labeled spermidine and MGBG, consistent with rapid penetration of the outer membrane barrier. Subsequent to outer membrane lysis, a slower respiration dependent uptake of spermidine and MGBG is seen, which appears to reflect transport across the inner membrane into the mitochondrial matrix. 14C-Iabeled daunomycin, a structural analog of adriamycin, rapidly binds to the mitochondria by a mechanism which includes non-ionic interactions.