Tumor-specific intracellular delivery: peptide-guided transport of a catalytic toxin.

There continues to be a need for cancer-specific ligands that can deliver a wide variety of therapeutic cargos. Ligands demonstrating both tumor-specificity and the ability to mediate efficient cellular uptake of a therapeutic are critical to expand targeted therapies. We previously reported the selection of a peptide from a peptide library using a non-small cell lung cancer (NSCLC) cell line as the target. Here we optimize our lead peptide by a series of chemical modifications including truncations, N-terminal capping, and changes in valency. The resultant 10 amino acid peptide has an affinity of <40 nM on four different NSCLC cell lines as a monomer and is stable in human serum for >48 h. The peptide rapidly internalizes upon cell binding and traffics to the lysosome. The peptide homes to a tumor in an animal model and is retained up to 72 h. Importantly, we demonstrate that the peptide can deliver the cytotoxic protein saporin specifically to cancer cells in vitro and in vivo, resulting in an effective anticancer agent.

Drug Delivery Applications of Nanoparticles in the Spine.

Nanoparticles offer several applications in the field of medicine such as targeted drug delivery, controlled drug release, and imaging applications. The central nervous system (CNS), in particular, has remained a challenge for drug delivery. This is mainly due to barriers such as the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), which hinder drug molecules from reaching the brain and spinal cord tissue. Although researchers have mainly focused on applying nanotechnology in the brain, there is an increase in applications of nanomaterials in the spine as well. This chapter focuses on the potential of nanomedicine for medical applications in the spine, including unique drug delivery systems and gene therapy applications, and for enhancement of medical imaging. We look at the problems and recent advances in the development of nanoparticles for spine-related applications and provide a comprehensive review on recent research work.

Magnetic Drug Targeting: A Novel Treatment for Intramedullary Spinal Cord Tumors.

Most applications of nanotechnology in cancer have focused on systemic delivery of cytotoxic drugs. Systemic delivery relies on accumulation of nanoparticles in a target tissue through enhanced permeability of leaky vasculature and retention effect of poor lymphatic drainage to increase the therapeutic index. Systemic delivery is limited, however, by toxicity and difficulty crossing natural obstructions, like the blood spine barrier. Magnetic drug targeting (MDT) is a new technique to reach tumors of the central nervous system. Here, we describe a novel therapeutic approach for high-grade intramedullary spinal cord tumors using magnetic nanoparticles (MNP). Using biocompatible compounds to form a superparamagnetic carrier and magnetism as a physical stimulus, MNP-conjugated with doxorubicin were successfully localized to a xenografted tumor in a rat model. This study demonstrates proof-of-concept that MDT may provide a novel technique for effective, concentrated delivery of chemotherapeutic agents to intramedullary spinal cord tumors without the toxicity of systemic administration.

Intrathecal magnetic drug targeting for localized delivery of therapeutics in the CNS.

AIM: The challenge in treating neurological diseases is not lack of drug potency, but ineffective targeting techniques. We propose a technique called intrathecal magnetic drug targeting (IT-MDT), in which intrathecally injected magnetic nanoparticles (MNPs) are targeted to specific sites using external magnets. MATERIALS & METHODS: MRI and histology confirmed localization of MNPs via IT-MDT at target sites along the spine of Sprague-Dawley rats. RESULTS: MRI results confirmed greater MNP localization when the duration of magnet application was extended. Histological analysis quantified MNP tissue uptake and provided insight into their route of transport into deeper tissue regions. CONCLUSION: IT-MDT has potential for future use in neurological disease treatments. It can produce localized therapeutic effect, with decreased systemic toxicity.

Implant-Assisted Intrathecal Magnetic Drug Targeting to Aid in Therapeutic Nanoparticle Localization for Potential Treatment of Central Nervous System Disorders.

There is an ongoing struggle to develop efficient drug delivery and targeting methods within the central nervous system. One technique known as intrathecal drug delivery, involves direct drug infusion into the spinal canal and has become standard practice for treating many central nervous system diseases due to reduced systemic toxicity from the drug bypassing the blood-brain barrier. Although intrathecal drug delivery boasts the advantage of reduced systemic toxicity compared to oral and intravenous drug delivery techniques, current intrathecal delivery protocols lack a means of sufficient drug targeting at specific locations of interest within the central nervous system. We previously proposed the method of intrathecal magnetic drug targeting in order to overcome the limited targeting capabilities of standard intrathecal drug delivery protocols, while simultaneously reducing the systemic toxicity as well as the amount of drug required to produce a therapeutic effect. Building off of our previous work, this paper presents the concept of implant-assisted intrathecal magnetic drug targeting. Ferritic stainless steel implants were incorporated within the subarachnoid space of our in vitro human spine model, and the targeting magnet was placed at a physiological distance away from the model and implant to mimic the distance between the epidermis and spinal canal. Computer simulations were performed to optimize implant design for generating high gradient magnetic fields and to study how these fields may aid in therapeutic nanoparticle localization. Experiments aiming to determine the effects of different magnetically-susceptible implants placed within an external magnetic field on the targeting efficiency of gold-coated magnetite nanoparticles were then performed on our in vitro human spine model. Our results indicate that implant-assisted intrathecal magnetic drug targeting is an excellent supplementary technique to further enhance the targeting capabilities of our previously established method of intrathecal magnetic drug targeting.

Intrathecal magnetic drug targeting using gold-coated magnetite nanoparticles in a human spine model.

AIM: We aimed to magnetically guide and locally confine nanoparticles in desired locations within the spinal canal to achieve effective drug administration for improved treatment of chronic pain, cancers, anesthesia and spasticity. MATERIALS & METHODS: We developed a physiologically and anatomically consistent in vitro human spine model to test the feasibility of intrathecal magnetic drug targeting. Gold-coated magnetite nanoparticles were infused into the model and targeted to specific regions using external magnetic fields. Experiments and simulations aiming to determine the effect of key parameters, such as magnet strength, duration of magnetic field exposure, magnet location and ferrous implants, on the collection efficiency of superparamagnetic nanoparticles in targeted regions were performed. RESULTS: An 891% increase in nanoparticle collection efficiency within the target region was achieved using intrathecal magnetic drug targeting when compared with the control. Nanoparticle collection efficiency at the target region increased with time and reached a steady value within 15 min. Ferrous epidural implants generated sufficiently high-gradient magnetic fields, even when magnets were placed at a distance equal to the space between a patient's epidermis and spinal canal. CONCLUSION: Our experiments indicate that intrathecal magnetic drug targeting is a promising technique for concentrating and localizing drugs at targeted sites within the spinal canal for treating diseases affecting the CNS.