‘Pharmacy on a chip‘: remote-controlled drug delivery first-in-human study
Results from a first-in-human clinical trial on a wirelessly controlled microchip device for delivery of an osteoporosis drug have been received with much excitement by the drug-delivery community. The study, a collaborative work between researchers at MIT (Boston, MA, USA) and MicroCHIPS, Inc. (Waltham, MA, USA), could represent a key step for translating drug delivery and microchip technology to clinical practice. Commenting on their results, joint lead author Robert Langer says “You could literally have a pharmacy on a chip.”
Human parathyroid hormone fragment (1-34) (hPTH[1-34]), the only approved anabolic osteoporosis treatment, represents a patient compliance dilemma to effective treatment as it requires daily injections. Additionally, in order to achieve the desired net increase in bone mineral density, pulsatile hPTH(1-34) delivery is necessary, a technical challenge for drug-delivery implants. The researchers addressed this challenge using a wireless communication link to their microchip implant, which programmed the dosing schedule. Robert Farra at MicroCHIPS, Inc speaks exclusively to Therapeutic Delivery on the compliance implications of their chip-based platform. “Everyone has directly, or through a family member or friend, experienced the burden of injections. The microchip provides 100% compliance and allows patients to be freed from the daily routine and pain of an injection.” He continues, “The response we have received from the press, individuals and companies has been phenomenal.”
The trial results, published recently in Science Translational Medicine represent a key progression of this technology.
The trial, which began in Denmark, in January 2011, involved implanting microchip-based devices, which contained doses of lyophilized hPTH(1-34), into eight osteoporotic postmenopausal women for a 4-month period. A bidirectional wireless communication link between the device and external programming was established in order to program the release of doses from the device, once daily for up to 20 days, as well as receive implant operation-status updates. Each participant received hPTH(1-34) injections in escalating doses, based on device programming and the pharmacokinetics, safety, tolerability and bioequivalence of hPTH(1-34) delivery from the microchip set up assessed.
The results demonstrated that dosing from the device gave rise to a similar pharmacokinetic profile as multiple injections, but with lower coefficients of variation, summarizing this, Farra states “The microchip is capable of delivering a precise dose at a precise time, automatically.” Further, evaluation of bone-markers indicated daily release from the device increases bone formation. No toxic or adverse events as a result of the device or drug were reported. “The microchip is capable of containing more than one drug type as well as varying doses. This, combined with the flexibility of adjusting the dosing schedule truly makes the microchip an effective means to personalize delivery for each patient,” concludes Farra.
In terms of future work, the MIT researchers and MicroCHIP are developing a microchip to provide daily dosing for up to 1 year as well as being in discussions to extend their device technology to multiple sclerosis, congestive heart failure and pain management medications.
Written by Laura Harvey, Commissioning Editor. Source: Successful human tests for first wirelessly controlled drug-delivery chip: www.sciencedaily.com/releases/2012/02/120216144236.htm?utm_source=feedburner&utm_medium=email&utm_campaign=Feed%3A+sciencedaily%2Fhealth_medicine+%28ScienceDaily%3A+Health+%26+Medicine+News%29
3D tissues and drug-delivery issues
Researchers develop 3D tissue model for nanoparticle drug-targeting studies
Researchers at Brown University have developed a novel 3D glioma tissue model for the in vitro investigation of iron oxide nanoparticles (IONPs) as potential vascular targeting agents for tumor therapy. IONPs have been widely investigated as diagnostic and delivery agents to date, however, of paramount importance in furthering this research and testing the many characteristics required for a successful nanoparticle delivery platform, is the availability of a robust biological model prior to animal and human studies.
Explaining the importance of such models to Therapeutic Delivery, Don Ho at Brown University, contributing author on this work says “Advanced in vitro models can help researchers examine specific characteristics that are not fully seen in either traditional cell culture or in vivo models, such as diffusion and targeting.” He continues, “These characteristics are difficult to isolate in an in vivo model with more complex events such as immunological responses and filter effects of the liver and kidneys … with more robust models, we can understand specific interactions and isolate these effects to better design our nanoparticle systems.”
In their study, published in Theranostics, the scientists investigated IONPs targeted to tumor vasculature using the tumstatin peptide, as a potential targeted cancer therapy in their 3D glioma model. The model served to closely resemble the in vivo tumor environment.
“By maintaining an endothelial cell barrier on a 3D glioma, we examined the effects of diffusion and targeting,” explains Ho. Highlighting the advantages of the in vitro model, he continues, “the competing interactions of targeting and diffusion help us to understand the micro-envrionment response that we could not see in traditional cell culture and would be difficult in an in vivo model.”
The tumstatin–IONPs demonstrated selective targeting and penetration to the endothelial cells coating the tumor in the 3D model, with approximately 2-times greater uptake in to these cells and 2.7-times tumor neo-vascularization inhibition when compared to control tests.
“As a drug-screening tool, the amount of time and costs saved would be much greater (than progressing to in vivo models). There is the potential for reducing in vivo studies if you can first screen for desired properties in vitro.” says Ho, on the time and cost-saving potential of the 3D model.
In terms of future work, the group are looking to develop models to incorporate more ‘in vivo-like‘ conditions as well as working on other tumor models and models for organ-specific microenvironments.
Written by Laura Harvey, Commissioning Editor. Source: Ho DN, Kohler N, Sigdel A et al. Penetration of endothelial cell coated multicellular tumor spheroids by iron oxide nanoparticles. Theranostics 2(1), 66–75 (2012).
Fooling cancer cells with virus-coated nanoparticles
Scientists from the City College of New York have used a coating based on the Sendai virus to achieve in vitro delivery of quantum dots to cancer cells.
The team, led by Maribel Vazquez (Associate Professor of Biomedical Engineering, City College of New York, NY, USA), used the Sendai virus, a mouse parainfluenza virus previously used as a delivery vector in vivo and in vitro, to generate virus-based liposomes, which in turn enabled the delivery of quantum dots into live human brain cancer cells. The quantum dots were functionalized with a monoclonal biotinylated antibody. This antibody was designed specifically to recognize the EGF receptor, often over-expressed and up-regulated by tumors. The team noticed that when liposomes were used for intracellular delivery, the quantum dots were internalized non-specifically and remained trapped within the liposomes themselves. However, when the team used virus-based liposomes for intracellular delivery, the quantum dots were released in the cytosol and were free to bind to their target. According to the study, the results show a 50% increase in the number of intracelluarly delivered quantum dots that are free to bind to their targets compared with liposomes alone. By measuring the fluorescence of the quantum dots, the amount of bound target could also be measured.
According to Vazquez and her team, previous studies have examined nanoparticles for the detection of biomarkers in various types of cancers, but only a few have investigated the potential applications of quantum dots in malignant brain tumors. The team hopes that this work could improve detection in several cancer diagnostic assays.
Written by Hannah Stanwix, Assistant Commissioning Editor. Source: Dudu V, Rotari V, Vazquez MJ. Source: Sendai virus-based liposomes enable targeted cytosolic delivery of nanoparticles in brain tumor-derived cells. Nanobiotechnology doi:10.1186/1477-3155-10-9 (2012) (Epub ahead of print).
Carbon nanoparticles mixed with paclitaxel and cetuximab show promise in treating cancer
A team of researchers from Rice University (Houston, TX, USA) and the University of Texas MD Anderson Cancer Center (Houston, TX, USA) have developed a new nanoparticle-based strategy that could enhance the treatment of head and neck cancers.
The collaboration of scientists, led by James Tour (Professor of Chemistry, Rice University) and Jeffrey Myers (Professor of Head and Neck Surgery, University of Texas, MD Anderson Cancer Center) loaded hydrophilic carbon clusters (HCC) covalently modified with polyethylene glycol (PEG) with paclitaxel (PTX), an effective drug used in the therapy of several different cancers. The team initially showed that the PEG–HCC nanovector was able to sequester PTX and deliver the drug to cancer cells, both in vitro and in vivo. The PTX–PEG–HCC nanovectors were also found to be stable in solution for up to 5 months. The efficacy of the PTX–PEG–HCCs was equivalent to that of a commercially available PTX formulation, Taxol®. However, by mixing these loaded nanoparticles with Cetuximab (Cet), an IgG monoclonal antibody that binds exclusively to EGF receptor, the team developed a targeted delivery system. As Tour explains, the aim was to increase the efficacy of their system, “We needed to boost the efficacy beyond what the commercial Taxol could give us. Without the targeting, we were only ‘as effective as‘ the Taxol. But once we had targeting, and especially when combined with radiation, then we could cruise past Taxol‘s effectiveness.”
For the in vivo experiments, the team used mice with tumors derived from two different cell lines, OSC-19 and HN5. In the OSC-19 model a significant antitumor effect was noted on day 20 after treatment with a Cet/PTX–PEG–HCC mixture and radiotherapy. Treatment with this combination of drug-loaded nanovector and radiotherapy also resulted in the greatest increase in survival times. In the second cell line, HN5, the researchers found that the mice treated with the Cet/PTX–PEG–HCC mixture and radiotherapy had a lower mean tumor volume than mice treated with PTX–PEG–HCCs, Cet/PTX–PEG–HCCs or radiotherapy alone. As for the OSC-19 cell type, treatment with the Cet/PTX–PEG–HCC mixture and radiotherapy again resulted in the greatest increase in survival time.
When commenting on the significance of the methods described in this study, Tour was enthusiastic, “We show that without any drug or antibody modification, both can be associated with the nanovector simply by shaking them up together. No bond-forming chemistry changes to drug or antibody are needed. We get effective drug delivery and then a good enhancement of activity furthered through radiation treatment. So it is a great combined package.”
Looking to the future, Tour described the next steps for this work, “We are moving this to the treatment of a very deadly type of cancer: brain glioblastoma. Using three different drugs and three different antibodies, we are seeking to overwhelm the traditional drug-rejection mechanisms.” The team hopes to optimize the formulation and treatment protocol, so that this work can be translated in to the clinic.
Written by Hannah Stanwix, Assistant Commissioning Editor. Source: Sano D, Berlin JM, Pham TT et al. Noncovalent assembly of targeted carbon nanovectors enables synergistic drug and radiation cancer therapy in vivo. ACS Nano. (2012) (Epub ahead of print).
Proof-of-principle DNA nanorobot
In a proof-of-concept study, researchers at Harvard Medical School have designed a nanorobot, capable of delivering molecular payloads to cells, changing shape for optimum payload delivery and sensing cell-surface receptors for triggered activation.
The nanodelivery platform, developed by George Church and his team is an autonomous DNA nanorobot and can be loaded with molecular payloads in an organized manner. The device can respond to a wide array of cellular cues by virtue of the fact it is controlled by an aptamer-encoded logic gate.
The researchers used several logical AND gates (a type of logic gate with two inputs that only results in a ‘high‘ output when both inputs are ‘high‘) to selectively regulate the nanorobot function. Following this, in a proof-of-principle experiment the scientists loaded the DNA nanorobots with antibody-fragment combinations to stimulate two different cell-signaling processes.
The researchers conclude their study outlining that their prototype may potentially inspire new designs for drug-delivery nanomachines with different selectivities and payloads for cell-targeting.
Written by Laura Harvey, Commissioning Editor. Source: Douglas S, Bachelet I, Church G. A logic-gated nanorobot for targeted transport of molecular payloads. Science 335(6070), 831–834 (2012).