Non-cancer Applications Research Articles

Sidechain structure-activity relationships of cyclobutane-based small molecule αvβ3 antagonists.

The integrin family of cell surface extracellular matrix binding proteins are key to several physiological processes involved in tissue development, as well as cancer proliferation and dissemination. They are therefore attractive targets for drug discovery with cancer and non-cancer applications. We have developed a new integrin antagonist chemotype incorporating a functionalised cyclobutane ring as the central scaffold in an arginine-glycine-aspartic acid mimetic structure. Here, we report the synthesis of cyclobutanecarboxylic acids and cyclobutylamines with tetrahydronaphthyridine and aminopyridine arginine mimetic sidechains and masked carboxylic acid aspartic acid mimetic sidechains of varying length. Effective αvβ3 antagonists and new aspartic acid mimetics were identified in cell-based adhesion and invasion assays. A lead compound selected based on in vitro activity (IC50 < 1 μM), stability (t 1/2 > 80 minutes) and synthetic tractability was well-tolerated in vivo. These results show the promise of this synthetic approach for developing αvβ3 antagonists and provide a firm foundation to progress into advanced preclinical evaluation prior to progression towards the clinic. Additionally, they highlight the use of functionalised cyclobutanes as metabolically stable core structures and a straightforward and robust method for their synthesis. This important contribution to the medicinal chemists' toolbox paves the way for increased use of cyclobutanes in drug discovery.

Leveraging gene therapy to achieve long-term continuous or controllable expression of biotherapeutics.

T cells redirected to cancer cells either via a chimeric antigen receptor (CAR-T) or a bispecific molecule have been breakthrough technologies; however, CAR-T cells require individualized manufacturing and bispecifics generally require continuous infusions. We created an off-the-shelf, single-dose solution for achieving prolonged systemic serum levels of protein immunotherapeutics via adeno-associated virus (AAV) gene transfer. We demonstrate proof of principle in a CD19+ lymphoma xenograft model using a single intravenous dose of AAV expressing a secreted version of blinatumomab, which could serve as a universal alternative for CD19 CAR-T cell therapy. In addition, we created an inducible version using an exon skipping strategy and achieved repeated, on-demand expression up to at least 36 weeks after AAV injection. Our system could be considered for short-term and/or repeated expression of other transgenes of interest for noncancer applications.

Review of the progress toward achieving heat confinement-the holy grail of photothermal therapy.

Photothermal therapy (PTT) involves the application of normally benign light wavelengths in combination with efficient photothermal (PT) agents that convert the absorbed light to heat to ablate selected cancers. The major challenge in PTT is the ability to confine heating and thus direct cellular death to precisely where PT agents are located. The dominant strategy in the field has been to create large libraries of PT agents with increased absorption capabilities and to enhance their delivery and accumulation to achieve sufficiently high concentrations in the tissue targets of interest. While the challenge of material confinement is important for achieving “heat and lethality confinement,” this review article suggests another key prospective strategy to make this goal a reality. In this approach, equal emphasis is placed on selecting parameters of light exposure, including wavelength, duration, power density, and total power supplied, based on the intrinsic properties and geometry of tissue targets that influence heat dissipation, to truly achieve heat confinement. This review highlights significant milestones researchers have achieved, as well as examples that suggest future research directions, in this promising technique, as it becomes more relevant in clinical cancer therapy and other noncancer applications.

Repurposing existing agents as adjunct therapies for glioblastoma.

Numerous non-oncologic medications have been found in the last decade to have anti-cancer properties. While the focus in oncology research should clearly remain on deriving new therapeutic strategies, repurposing these existing medications may offer the potential to rapidly enhance the effectiveness of treatment for resistant cancers. Glioblastoma, the most common and lethal brain cancer, is highly resistant to standard therapies and would benefit from even minor improvements in treatment. Numerous agents already in the clinic for non-cancer applications have been found to also possess potential against cancer or specifically against glioblastoma. These include agents with activities affecting oxidative stress, the immune reponse, epigenetic modifiers, cancer cell metabolism, and angiogenesis and invasiveness. This review serves as a guide for potential ways to repurpose individual drugs alongside standard glioblastoma therapies.

Sustained-release from nanocarriers: a review.

Nanocarriers have been explored for delivering drugs and other bioactive molecules for well over 35years. Since the introduction of Doxil®, a nanoliposomal delivery system for the cancer drug doxorubicin, several products have been approved worldwide. The majority of these products focus on cancer chemotherapy, and utilize the size advantage of nanocarriers to obtain a favourable distribution of the drug carrier in the human body. In general, such carriers do not sustain drug release over more than a few days at best. In this review, we explore the reasons for this, and present an overview of successful research that is capable of generating sustained-release products in non-cancer applications. A variety of nanocarriers have been studied, and their advantages and shortcomings are highlighted in this review. The achievement of sustained release of bioactive molecules opens new doors in nanotherapeutics.

Editorial [Hot Topic: Methods and Non-Cancer Applications of HDAC Inhibition (Guest Editor: Olaf Wiest)

Editorial [Hot Topic: Methods and Non-Cancer Applications of HDAC Inhibition (Guest Editor: Olaf Wiest)

Green tea and its polyphenolic catechins: Medicinal uses in cancer and noncancer applications

Can drinking several cups of green tea a day keep the doctor away? This certainly seems so, given the popularity of this practice in East Asian culture and the increased interest in green tea in the Western world. Several epidemiological studies have shown beneficial effects of green tea in cancer, cardiovascular, and neurological diseases. The health benefits associated with green tea consumption have also been corroborated in animal studies of cancer chemoprevention, hypercholesterolemia, artherosclerosis, Parkinson's disease, Alzheimer's disease, and other aging-related disorders. However, the use of green tea as a cancer chemopreventive or for other health benefits has been confounded by the low oral bioavailability of its active polyphenolic catechins, particularly epigallocatechin-3-gallate (EGCG), the most active catechin. This review summarizes the purported beneficial effects of green tea and EGCG in various animal models of human diseases. Dose-related differences in the effects of EGCG in cancer versus neurodegenerative and cardiovascular diseases, as well as discrepancies between doses used in in vitro studies and achievable plasma understanding of the in vivo effects of green tea catechins in humans, before the use of green tea is widely adopted as health-promoting measure.

Industry update

Industry update

High intensity focused ultrasound—potential for cancer treatment

The prospect of being able to use "minimally invasive" surgical techniques is of great interest today, particularly for reasons of health economics, patient acceptability and reduced morbidity. High intensity focused ultrasound (HIFU) has long been known to offer the potential of very precise "trackless lesioning" but has only recently, with the advent of high quality methods of medical imaging, become a practicable possibility. High intensity beams can readily be achieved using either bowel or lens focusing procedures and, by choice of a suitable acoustic frequency, regions of tissue destruction--"lesions"--can be induced at depths of up to at least 10 cm with exposure times of the order of 1 s. Theoretical and experimental evidence indicates that the primary mechanism of damage is thermal, i.e. "cooking" of the tissues. Both conventional cavitation and boiling of tissue water may complicate the situation. Furthermore, substantial non-linear behaviour is involved. On histological appearance the lesions have a spatially sharp demarcation between regions of normal and dead cells. When attempts are made to ablate a block of tissue, by creating an array of adjacent elementary lesions, a phenomenon is observed of inhibition of formation of a lesion whose placing is too close to that of a neighbour. Provided that this problem is dealt with, complete ablation of an extended block of tissue can be achieved. For animal tumours in particular, this observation is reinforced by evidence both of in vitro cell survival and of tumour growth delay experiments. Clinically, the sites accessible for HIFU treatment will be limited by the need for a suitably wide acoustic window that either is available naturally or can be provided by a relatively minor surgical procedure. Tumour sites which thus offer a realistic prospect for local control (and some of which are already the subject of phase 1 trials) include liver, bladder, kidney, prostate, breast and brain. There is also considerable interest in non-cancer applications in these and other sites.