Boaz Mizrahi

Near-infrared-actuated devices for remotely controlled drug delivery

Significance Devices that release a drug in response to a remote trigger would enable on-demand control of the timing and dose of drug released. They would allow the patient or physician to adjust therapy precisely to a target effect, thus improving treatment and reducing toxicity. We have developed implantable reservoirs that release a drug when irradiated with near-infrared laser light. The release rate was correlated to laser intensity, with negligible leakage between doses. Devices containing aspart, a fast-acting analog of insulin, were implanted in diabetic rats and were able to achieve glycemic control upon irradiation. Such devices can be loaded with a wide range of drugs to treat a variety of clinical indications. A reservoir that could be remotely triggered to release a drug would enable the patient or physician to achieve on-demand, reproducible, repeated, and tunable dosing. Such a device would allow precise adjustment of dosage to desired effect, with a consequent minimization of toxicity, and could obviate repeated drug administrations or device implantations, enhancing patient compliance. It should exhibit low off-state leakage to minimize basal effects, and tunable on-state release profiles that could be adjusted from pulsatile to sustained in real time. Despite the clear clinical need for a device that meets these criteria, none has been reported to date to our knowledge. To address this deficiency, we developed an implantable reservoir capped by a nanocomposite membrane whose permeability was modulated by irradiation with a near-infrared laser. Irradiated devices could exhibit sustained on-state drug release for at least 3 h, and could reproducibly deliver short pulses over at least 10 cycles, with an on/off ratio of 30. Devices containing aspart, a fast-acting insulin analog, could achieve glycemic control after s.c. implantation in diabetic rats, with reproducible dosing controlled by the intensity and timing of irradiation over a 2-wk period. These devices can be loaded with a wide range of drug types, and therefore represent a platform technology that might be used to address a wide variety of clinical indications.

Long-Lasting Antifouling Coating from Multi-Armed Polymer

We describe a new antifouling surface coating, based on aggregation of a short amphiphilic four-armed PEG-dopamine polymer into particles and on surface binding by catechol chemistry. An unbroken and smooth polymeric coating layer with an average thickness of approximately 4 μm was formed on top of titanium oxide surfaces by a single step reaction. Coatings conferred excellent resistance to protein adhesion. Cell attachment was completely prevented for at least eight weeks, although the membranes themselves did not appear to be intrinsically cytotoxic. When linear PEG or four-armed PEG of higher molecular weight were used, the resulting coatings were inferior in thickness and in preventing protein adhesion. This coating method has potential applicability for biomedical devices susceptible to fouling after implantation.

Elasticity and safety of alkoxyethyl cyanoacrylate tissue adhesives

Cyanoacrylate glues are easily applied to wounds with good cosmetic results. However, they tend to be brittle and can induce local tissue toxicity. A series of cyanoacrylate monomers with a flexible ether linkage and varying side-chain lengths was synthesized and characterized for potential use as tissue adhesives. The effect of side-chain length on synthesis yield, physical and mechanical properties, formaldehyde generation, cytotoxicity in vitro and biocompatibility in vivo were examined. The incorporation of etheric oxygen allowed the production of flexible monomers with good adhesive strength. Monomers with longer side-chains were found to have less toxicity both in vitro and in vivo. Polymerized hexoxyethyl cyanoacrylate was more elastic than its commercially available and widely used alkyl analog 2-octyl cyanoacrylate, without compromising biocompatibility.

Mucoadhesive polymers for delivery of drugs to the oral cavity.

Local therapy of the oral cavity is used to treat conditions such as gingivitis, oral candidosis, oral lesions, dental caries, xerostoma and oral carcinomas. Delivery systems used include mouthwashes, aerosol sprays, chewing gums, bioadhesive tablets, films, gels and pastes. There are three major problems associated with drug therapy within the oral cavity: rapid elimination of drugs due to the flushing action of saliva or the ingestion of food, the non-uniform distribution of drugs within saliva on release from a solid or semisolid delivery system and patient compliance in terms of taste. Prolonged contact time of a drug with body tissue can significantly improve the clinical performance of many agents used for treating oral disorders. These improvements range from better treatment of local pathologies to improved drug bioavailability and controlled release to enhanced patient compliance. There are abundant examples in the literature over the past 15 years of these improvements using bioadhesive polymers. This manuscript summarizes the innovations pertaining to formulation and treatments as described in recent patents.

Locally Applied Leptin Induces Regional Aortic Wall Degeneration Preceding Aneurysm Formation in Apolipoprotein E–Deficient Mice

Objective—Leptin promotes atherosclerosis and vessel wall remodeling. As abdominal aortic aneurysm (AAA) formation involves tissue remodeling, we hypothesized that local leptin synthesis initiates and promotes this process. Methods and Results—Human surgical AAA walls were analyzed for antigen and mRNA levels of leptin and leptin receptor, as well as mRNA for matrix metalloproteinases (MMP)-9 and MMP-12. Leptin and leptin receptor antigen were evident in all AAAs, and leptin, MMP-9, and MMP-12 mRNA was increased relative to age-matched nondilated controls. To simulate in vivo local leptin synthesis, ApoE–/– mice were subjected to a paravisceral periaortic application of low-dose leptin. Leptin-treated aortas exhibited decreased transforming growth factor-&bgr; and increased MMP-9 mRNA levels 5 days after surgery, and leptin receptor mRNA was upregulated by day 28. Serial ultrasonography demonstrated accelerated regional aortic diameter growth after 28 days, correlating with local medial degeneration, increased MMP-9, MMP-12, and periadventitial macrophage clustering. Furthermore, the combination of local periaortic leptin and systemic angiotensin II administration augmented medial MMP-9 synthesis and aortic aneurysm size. Conclusion—Leptin is locally synthesized in human AAA wall. Paravisceral aortic leptin in ApoE–/– mice induces local medial degeneration and augments angiotensin II-induced AAA, thus suggesting novel mechanistic links between leptin and AAA formation.

Injectable formulations of poly(lactic acid) and its copolymers in clinical use.

Poly(lactic acid) and its copolymers have revolutionized the field of drug delivery due to their excellent biocompatibility and tunable physico-chemical properties. These copolymers have served the healthcare sector by contributing many products to combat various diseases and for biomedical applications. This article provides a comprehensive overview of clinically used products of poly(lactic acid) and its copolymers. Multi-dimension information covering product approval, formulation aspects and clinical status is described to provide a panoramic overview of each product. Moreover, leading patented technologies and various clinical trials on these products for different applications are included. This review focuses on marketed injectable formulations of PLA and its copolymers.

Microgels for Efficient Protein Purification

Immobilized metal affinity chromatography (IMAC) is the most frequently used method for the separation and purification of histidine-tagged (His-tagged) proteins.[1] In this technique, the high affinity of metal ions, such as nickel or copper, to a tag sequence of the protein of interest creates strong, yet reversible binding.[2] A major limitation of current systems is their inefficiency in purifying many recombinant proteins, particularly when present in their native state or in low concentrations in the cell lysate.[3,4] Performance deficiencies are caused in part by the clogging or destruction of matrix micropores by undissolved salts and other compounds during particle synthesis,[5] limiting the surface area accessible for binding[6,7] (Figure S1 in the Supporting Information). Low surface metal density can further impair efficiency.[8,9] To overcome these limitations, some alternative chelator complexes have been suggested, including magnetic anoparticles,[10] cobalt-based affinity resins (Talon),[11] and gels.[12] However, the efficiency of these systems have not been clearly proven to be superior to others, they are relatively expensive, and they may require longer operation times.[13]

Tissue Adhesives as Active Implants

Tissue adhesives are substances that hold tissues together, and could be broadly applicable in medicine and surgery. In appropriate circumstances, such materials could be attractive alternatives to sutures and staples since they can be applied more quickly, causes less pain and may require less equipment. In addition, there is no risk to the practitioner from sharp instruments (Singer et al., Acad. Emerg. Med. 5(2):94, 1998), and they may obviate the need for suture removal (Coulthard et al., Cochrane Database Syst. Rev. 5:CD004287, 2010). An ideal surgical tissue adhesive should allow rapid adhesion and maintain strong and close apposition of wound edges for an amount of time sufficient to allow wound healing. It should not interfere with body’s natural healing mechanisms and should degrade without producing an excessive localized or generalized inflammatory response (Mobley et al., Facial Plast. Surg. Clin. North Am. 10(2):147, 2002). The clinical and scientific potential of adhesives can be enhanced by a variety of functionalities that may not be directly related to their function as glues or sealants. Here we will review adhesives in general, with an emphasis on enhancements that render those otherwise passive materials “active”. We note that some glues also have intrinsic secondary functionalities that can be direct or indirect consequences of their primary function, but that is not the focus of this chapter. (For example, they may augment local hemostasis directly, or by improving tissue apposition, without affecting clotting mechanisms (Reece et al., Am. J. Surg. 182(2 Suppl):40S, 2001)).

A flexible polymersome system with tunable morphology and release profiles for efficient intracellular delivery.

Polymersomes are widely used as drug delivery system however they have shortcomings in drug-eluting properties that are attributable to the high molecular weight of the copolymers forming their membrane. Here we demonstrate for the first time how novel class of polymersomes from very short, liquid to soft star-shaped copolymers can be empowered to form an efficient drug delivery system. The copolymers undergo self-assembly in water into a stable, nano-sized rod or a spherical shape polymersomes. Increasing the Mw of the hydrophobic moieties the CMC value is decreased accompanied with the tendency to form a more spherical structure. The poorly water-soluble anticancer drug camptothecin was loaded into the fabricated polymersomes, resulting in a high drug loading content, and released over a period of over three days. Furthermore, this biocompatible system could deliver a variety of drugs intracellularly in a rapid yet controlled manner. Therefore, this nano systems tailorable properties, biocompatibility and ability to incorporate hydrophobic drugs and release them intracellularly are desirable traits for anti-cancer delivery system and other biomedical applications.

Amphiphilic star PEG-Camptothecin conjugates for intracellular targeting.

ABSTRACT Camptothecin (CPT) is a naturally occurring cytotoxic alkaloid having a broad spectrum of antitumor activity. Unfortunately, it has low bioavailability and encapsulation efficiency, limiting its clinical use. We report on our efforts to develop a novel drug delivery prototype composed of a short, star hydrophilic polyethylene glycol (PEG) backbone and hydrophobic CPT (PEG4‐CPT). The amphiphilic bio‐conjugate self‐assembles in water into stable spherical nano‐particles with a mean diameter of 200 nm and CPT substitution percentage of 27%w/w. CPT is released in a sustained release profile without burst effect. In addition, PEG4‐CPT nano‐particles are able to load a co‐drug, water soluble or non‐water soluble doxorubicin and release them simultaneously with the free CPT. The biological evaluation of PEG4‐CPT against HeLa cells showed improved cellular uptake and enhanced cytotoxicity compared to free CPT. Thus, in this approach CPT acts in two ways: As the hydrophobic segment that enables self‐assembly in water and as a potent anticancer agent. This concept of combining hydrophobic drugs and short star polymers shows great potential for efficient delivery of hydrophobic chemotrophic drugs as well as for drugs with inherent stability and pharmacokinetic barriers.