Researchers at MIT are using ultrasound waves to enable the rapid delivery of drugs to the gastrointestinal tract. This approach could make it easier to administer therapeutics to patients suffering from GI disorders.
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Nanoformulated drugs, genes, and imaging agents have the opportunity to improve cancer treatment and diagnosis. This Review describes the many approaches to nanomedicine, how they are being tested for cancer therapy and imaging, and what obstacles remain in translation.
Nanotechnology-based chemotherapeutics and imaging agents represent a new era of “cancer nanomedicine” working to deliver versatile payloads with favorable pharmacokinetics and capitalize on molecular and cellular targeting for enhanced specificity, efficacy, and safety. Despite the versatility of many nanomedicine-based platforms, translating new drug or imaging agents to the clinic is costly and often hampered by regulatory hurdles. Therefore, translating cancer nanomedicine may largely be application-defined, where materials are adapted only toward specific indications where their properties confer unique advantages. This strategy may also realize therapies that can optimize clinical impact through combinatorial nanomedicine. In this review, we discuss how particular materials lend themselves to specific applications, the progress to date in clinical translation of nanomedicine, and promising approaches that may catalyze clinical acceptance of nano.
Zwitterionic polypeptides with high chemical specificity and “stealth”-like behavior have superior pharmacokinetics compared with uncharged polypeptides in mice.
Drug delivery is often limited by the short half-lives and circulation times of peptide- and protein-based drugs. A common approach to overcoming this challenge conjugates drugs to poly(ethylene glycol) (PEG), a process also known as PEGylation. PEG serves as a “stealth” drug carrier that protects the drug and prolongs bioactivity during circulation. Unfortunately, PEG has several limitations, including that (i) a large portion of the human population has developed anti-PEG antibodies, (ii) PEG is not biodegradable and can accumulate in the body, and (iii) PEG’s polydispersity limits the ability to tune its in vivo behavior. In comparison with synthetic polymers, polypeptides have emerged as a new class of materials with high sequence specificity and monodispersity. Recently, researchers have discovered that zwitterionic polymers—neutral polymers that contain both positive and negative charges—have similar “stealth” properties as PEG. Here, the authors propose using zwitterionic polypeptides as a new drug carrier that offers increased control over the chemical structure and “stealth”-like behavior.
Banskota et al. synthesized a small library of zwitterionic polypeptides with different combinations of oppositely charged amino acid residues and different numbers of repeat units. A similar amino acid sequence with uncharged amino acid residues was also synthesized and served as the uncharged polypeptide control. To evaluate the influence of zwitterionic polypeptides on pharmacokinetics, polypeptide half-life and circulation time were measured after intravenous and subcutaneous injection in mice. In both cases, the zwitterionic polypeptides resulted in improved pharmacokinetics, with the best performing zwitterionic polypeptide displaying a half-life and total exposure time twofold greater than the uncharged polypeptide control. To evaluate clinical potential, glucagon like peptide-1 (GLP1)—a peptide used clinically to treat type 2 diabetes (T2D)—was conjugated to the best performing zwitterionic polypeptide and delivered in a mouse model of T2D. Subcutaneous injection of GLP1-conjugated zwitterionic polypeptide reduced blood glucose levels for three days, 70 times longer than the drug alone and 1.5 times longer than the uncharged polypeptide control.
A new class of drug carriers with high specificity and “stealth”-like behavior would be broadly applicable to a range of diseases and treatments that require sustained drug delivery. Nonetheless, ongoing research is needed to evaluate the zwitterionic polypeptides against the current gold standard of PEGylation and in larger animal models.
In a study of mice, MIT chemists demonstrated that their multidrug nanoparticle shrank tumors much more than when drugs were given at the same ratio but untethered to a particle. Their nanoparticle platform could potentially be deployed to deliver drug combinations against a variety of cancers.
Their findings are published in Nature Nanotechnology in an article titled, “Molecular bottlebrush prodrugs as mono- and triplex combination therapies for multiple myeloma.”
“Cancer therapies often have narrow therapeutic indexes and involve potentially suboptimal combinations due to the dissimilar physical properties of drug molecules,” wrote the researchers. “Nanomedicine platforms could address these challenges, but it remains unclear whether synergistic free-drug ratios translate to nanocarriers and whether nanocarriers with multiple drugs outperform mixtures of single-drug nanocarriers at the same dose. Here we report a bottlebrush prodrug (BPD) platform designed to answer these questions in the context of multiple myeloma therapy.”
“There’s a lot of interest in finding synergistic combination therapies for cancer, meaning that they leverage some underlying mechanism of the cancer cell that allows them to kill more effectively, but oftentimes we don’t know what that right ratio will be,” explained Jeremiah Johnson, PhD, an MIT professor of chemistry and one of the senior authors of the study.
For several years, Johnson’s lab has been working on polymer nanoparticles designed to carry multiple drugs. In the new study, he and his team focused on a bottlebrush-shaped particle.
“If we want to make a bottlebrush that has two drugs or three drugs or any number of drugs in it, we simply need to synthesize those different drug-conjugated monomers, mix them together, and polymerize them. The resulting bottlebrushes have exactly the same size and shape as the bottlebrush that only has one drug, but now they have a distribution of two, three, or however many drugs you want within them,” Johnson said.
The researchers first tested particles carrying just one drug: bortezomib, which is used to treat multiple myeloma, a cancer that affects a type of B cells known as plasma cells. Bortezomib is a proteasome inhibitor, a type of drug that prevents cancer cells from breaking down the excess proteins they produce.
On its own, bortezomib tends to accumulate in red blood cells, which have high proteasome concentrations. However, when the researchers gave their bottlebrush prodrug version of the drug to mice, they found that the particles accumulated primarily in plasma cells because the bottlebrush structure protects the drug from being released right away, allowing it to circulate long enough to reach its target.
“If you inject three drugs into the body, the likelihood that the correct ratio of those drugs will arrive at the cancer cell at the same time can be very low. The drugs have different properties that cause them to go to different places, and that hinders the translation of these identified synergistic drug ratios quite immensely,” Johnson said.
In tests in two mouse models of multiple myeloma, the researchers observed that three-drug bottlebrushes with a synergistic ratio significantly inhibited tumor growth compared to the free drugs given at the same ratio and to mixtures of three different single-drug bottlebrushes.
“We were happy to see that the bortezomib bottlebrush prodrug on its own was an excellent drug, displaying improved efficacy and safety compared to bortezomib, and that has led us to pursue trying to bring this molecule to the clinic as a next-generation proteasome inhibitor,” Johnson said. “It has completely different properties than bortezomib and gives you the ability to have a wider therapeutic index to treat cancers that bortezomib has not been used in before.”
Johnson’s lab is also working on using these particles to deliver therapeutic antibodies along with drugs, as well as combining them with larger particles that could deliver messenger RNA along with drug molecules. “The versatility of this platform gives us endless opportunities to create new combinations,” he added.
Scientists at the Baylor College of Medicine and collaborators say they have been exploring a better way of delivering medications that does not require injections but could be as easy as swallowing a pill. Their study “A bioengineered probiotic for the oral delivery of a peptide Kv1.3 channel blocker to treat rheumatoid arthritis” appears in PNAS.
“People don’t like to have injections for the rest of their lives,” said co-corresponding author Christine Beeton, PhD, professor of integrative physiology at Baylor. “In the current work, we explored the possibility of using the probiotic bacteria Lactobacillus reuteri as a novel oral drug delivery platform to treat rheumatoid arthritis in an animal model.”
Previous work from the Beeton lab had shown that a peptide derived from sea anemone toxin effectively and safely reduces disease severity in rat models of rheumatoid arthritis and patients with plaque psoriasis. “However, peptide treatment requires repeated injections, reducing patient compliance, and direct oral delivery of the peptide has low efficacy,” noted Beeton.
She began working with Robert A. Britton, PhD, professor of molecular virology and microbiology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. The Britton lab has genetically modified probiotic bacteria to produce and release compounds. In the current study, the team bioengineered the probiotic L. reuteri to secrete peptide ShK-235 derived from sea anemone toxin.
They chose L. reuteri because these bacteria are indigenous to human and other animal guts. It is one of the lactic acid bacteria groups that has long been used as a cell factory in the food industry and is recognized as safe by the FDA L. reuteri has an excellent safety profile in infants, children, adults and even in an immunosuppressed population, according to Beeton.
“Engineered microbes for the delivery of biologics are a promising avenue for the treatment of various conditions such as chronic inflammatory disorders and metabolic disease. In this study, we developed a genetically engineered probiotic delivery system that delivers a peptide to the intestinal tract with high efficacy,” write the investigators.
“We constructed an inducible system in the probiotic Lactobacillus reuteri to secrete the Kv1.3 potassium blocker ShK-235 (LrS235). We show that LrS235 culture supernatants block Kv1.3 currents and preferentially inhibit human T effector memory (TEM) lymphocyte proliferation in vitro. A single oral gavage of healthy rats with LrS235 resulted in sufficient functional ShK-235 in the circulation to reduce inflammation in a delayed-type hypersensitivity model of atopic dermatitis mediated by TEM cells.
“Furthermore, the daily oral gavage of LrS235 dramatically reduced clinical signs of disease and joint inflammation in rats with a model of rheumatoid arthritis without eliciting immunogenicity against ShK-235.
“This work demonstrates the efficacy of using the probiotic L. reuteri as a novel oral delivery platform for the peptide ShK-235 and provides an efficacious strategy to deliver other biologics with great translational potential.”
“The results are encouraging,” Beeton said. “Daily delivery of these peptide-secreting bacteria, called LrS235, dramatically reduced clinical signs of disease, including joint inflammation, cartilage destruction and bone damage in an animal model of rheumatoid arthritis.”
The researchers followed bacteria LrS235 and the peptide ShK-235 it secretes inside the animal model. They found that after feeding rats live LrS235 that release ShK-235, they could detect ShK-235 into the blood circulation.
“Another reason we chose L. reuteri is that these bacteria do not remain in the gut permanently. They are removed as the gut regularly renews its inner surface layer to which the bacteria attach,” explained Beeton. “This opens the possibility for regulating treatment administration.”
More research is needed to bring this novel drug delivery system into the clinic, but the researchers anticipate that it could make treatment easier for patients in the future.
“These bacteria could be stored in capsules that can be kept on the kitchen counter,” pointed out Beeton. “A patient could take the capsules when on vacation without the need of refrigeration or carrying needles and continue treatment without the inconvenience of daily injections.”
The findings provide an alternative delivery strategy for peptide-based drugs and suggest that such techniques and principles can be applied to a broader range of drugs and the treatment of chronic inflammatory diseases.
Tiny carbon dots have, for the first time, been applied to intracellular imaging and tracking of drug delivery involving various optical and vibrational spectroscopic-based techniques such as fluorescence, Raman, and hyperspectral imaging. Researchers from the University of Illinois at Urbana-Champaign have demonstrated, for the first time, that photo luminescent carbon nanoparticles can exhibit reversible switching of their optical properties in cancer cells.
“One of the major advantages of these agents are their strong intrinsic optical sensitivity without the need for any additional dye/fluorophore and with no photo-bleaching issues associated with it,” explained Dipanjan Pan, an assistant professor of bioengineering and the leader of the study. “Using some elegant nanoscale surface chemistry, we created a molecular ‘masking’ pathway to turn off the fluorescence and then selectively remove the mask leading to regaining the brightness.
“Using carbon dots for illuminating human cells is not new. In fact, my laboratories, and several other groups around world, have shown that these tiny dots represent a unique class of luminescent materials with excellent biocompatibility, degradability, and relatively facile access to large-scale synthesis in comparison to other popular luminescent materials such as quantum dots,” added Pan.
And, the entire process of is highly controlled and can be observed in living cells as they reported in the group’s study, “Macromolecularly ‘Caged’ Carbon Nanoparticles for Intracellular Trafficking via Switchable Photoluminescence,” appearing in the Journal of the American Chemical Society.
“We can apply this technique for intracellular trafficking by means of switchable photo-luminescence in mammalian cells in vitro, wherein the endocytic membrane-abundant anionic amphiphilic molecules participates in the ‘de-caging’ process,” stated Pan. “The carbon dots, each measuring less than 50 nanometers in diameter, are derived from agave nectar and are highly luminescent. The in situ nanoscale chemical exchange further probed into the mechanistic understanding of the origin of carbon luminescence and indicated that it is primarily a surface phenomenon.
“This can be reversibly turned on and off by a simple counter-ionic nanoscale chemistry,” Pan said. “These results can become the basis for new and interesting designs for carbon-based materials for intracellular imaging probing cellular function and to study other biological processes.”
UNSW chemical engineers have synthesised a new iron oxide nanoparticle that delivers cancer drugs to cells while simultaneously monitoring the drug release in real time.
The result, published online in the journal ACS Nano, represents an important development for the emerging field of theranostics – a term that refers to nanoparticles that can treat and diagnose disease.
“Iron oxide nanoparticles that can track drug delivery will provide the possibility to adapt treatments for individual patients,” says Associate Professor Cyrille Boyer from the UNSW School of Chemical Engineering.
By understanding how the cancer drug is released and its effect on the cells and surrounding tissue, doctors can adjust doses to achieve the best result.
Importantly, Boyer and his team demonstrated for the first time the use of a technique called fluorescence lifetime imaging to monitor the drug release inside a line of lung cancer cells.
“Usually, the drug release is determined using model experiments on the lab bench, but not in the cells,” says Boyer. “This is significant as it allows us to determine the kinetic movement of drug release in a true biological environment.”
Magnetic iron oxide nanoparticles have been studied widely because of their applications as contrast agents in magnetic resonance imaging, or MRI. Several recent studies have explored the possibility of equipping these contrast agents with drugs.
However, there are limited studies describing how to load chemotherapy drugs onto the surface of magnetic iron oxide nanoparticles, and no studies that have effectively proven that these drugs can be delivered inside the cell. This has only been inferred.
With this latest study, the UNSW researchers engineered a new way of loading the drugs onto the nanoparticle’s polymer surface, and demonstrated for the first time that the particles are delivering their drug inside the cells.
“This is very important because it shows that bench chemistry is working inside the cells,” says Boyer. “The next step in the research is to move to in-vivo applications.”
Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.
Since the introduction of the first metered dose inhalers to the market in 1956,88 pulmonary drug delivery has made substantial progress, even leading to the first introduction of an inhalation form of insulin (Exubera) to the market. However, since the withdrawal of Exubera from the market in 2007, the field of advanced pulmonary drug delivery, other than delivery of anti-asthma and bronchodilating drugs, has stagnated. Until now the main focus of research and development efforts has been on generation of better aerosols by engineering more sophisticated particles or devices. However, optimised aerosol deposition is a necessary, but not sufficient component of pulmonary drug delivery. To overcome the biopharmaceutical challenges associated with absorption across the alveolar epithelium, control of particle clearance and targeting of specific regions or cells within the lungs requires a thorough understanding of the processes occurring at the cellular and non-cellular elements of the air—blood—barrier after aerosol drug deposition.
To achieve these goals, advanced in-vitro models, preferentially based on human cells and tissues, will be important. Furthermore, nanotechnology might contribute to the development of aerosol drug carriers, and might be necessary for the success of pulmonary drug delivery in the future.
Source: Lancet
Research in pulmonary drug delivery has focused mainly on new particle or device technologies to improve the aerosol generation and pulmonary deposition of inhaled drugs. Although substantial progress has been made in this respect, no significant advances have been made that would lead pulmonary drug delivery beyond the treatment of some respiratory diseases. One main reason for this stagnation is the still very scarce knowledge about the fate of inhaled drug or carrier particles after deposition in the lungs. Improvement of the aerosol component alone is no longer sufficient for therapeutic success of inhalation drugs; a paradigm shift is needed, with an increased focus on the pulmonary barriers to drug delivery. In this Review, we discuss some pathophysiological disorders that could benefit from better control of the processes after aerosol deposition, and pharmaceutical approaches to achieve improved absorption across the alveolar epithelium, prolonged pulmonary clearance, and targeted delivery to specific cells or tissues.
Source: Lancet
In convection-enhanced delivery (CED), drugs are infused locally into tissue through a cannula inserted into the brain parenchyma to enhance drug penetration over diffusion strategies. The purpose of this study was to demonstrate the feasibility of ultrasound-assisted CED (UCED) in the rodent brain in vivo using a novel, low-profile transducer cannula assembly (TCA) and portable, pocket-sized ultrasound system.
Methods
Forty Sprague-Dawley rats (350–450 g) were divided into 2 equal groups (Groups 1 and 2). Each group was divided again into 4 subgroups (n = 5 in each). The caudate of each rodent brain was infused with 0.25 wt% Evans blue dye (EBD) in phosphate-buffered saline at 2 different infusion rates of 0.25 μl/minute (Group 1), and 0.5 μl/minute (Group 2). The infusion rates were increased slowly over 10 minutes from 0.05 to 0.25 μl/minute (Group 1) and from 0.1 to 0.5 μl/minute (Group 2). The final flow rate was maintained for 20 minutes. Rodents in the 4 control subgroups were infused using the TCA without ultrasound and without and with microbubbles added to the infusate (CED and CED + MB, respectively). Rodents in the 4 UCED subgroups were infused without and with microbubbles added to the infusate (UCED and UCED + MB) using the TCA with continuous-wave 1.34-MHz low-intensity ultrasound at a total acoustic power of 0.11 ± 0.005 W and peak spatial intensity at the cannula tip of 49.7 mW/cm2. An additional 4 Sprague-Dawley rats (350–450 g) received UCED at 4 different and higher ultrasound intensities at the cannula tip ranging from 62.0 to 155.0 mW/cm2 for 30 minutes. The 3D infusion distribution was reconstructed using MATLAB analysis. Tissue damage and morphological changes to the brain were assessed using H & E.
Results
The application of ultrasound during infusion (UCED and UCED + MB) improved the volumetric distribution of EBD in the brain by a factor of 2.24 to 3.25 when there were no microbubbles in the infusate and by a factor of 1.16 to 1.70 when microbubbles were added to the infusate (p < 0.001). On gross and histological examination, no damage to the brain tissue was found for any acoustic exposure applied to the brain.
Conclusions
The TCA and ultrasound device show promise to improve the distribution of infused compounds during CED. The results suggest further studies are required to optimize infusion and acoustic parameters for small compounds and for larger molecular weight compounds that are representative of promising antitumor agents. In addition, safe levels of ultrasound exposure in chronic experiments must be determined for practical clinical evaluation of UCED. Extension of these experiments to larger animal models is warranted to demonstrate efficacy of this technique.
Source: Journal of neurosurgery.
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