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Frontiers of Engineering: Reports on Leading-Edge Engineering from the 2008 Symposium Targeted Polymeric Nanotherapeutics JEFF HRKACH BIND Biosciences Inc. Cambridge, Massachusetts This paper provides an overview of steps being taken by BIND Biosciences Inc. to translate innovative research conducted at the Massachusetts Institute of Technology (MIT) and Harvard Medical School into novel, targeted, polymeric nanotherapeutics. Advances in drug delivery have significantly affected the lives of patients afflicted with a variety of diseases. New drug-delivery strategies can improve the efficacy, safety, and/or compliance of existing approved medicines and can lead to the development and approval of new drugs with inherent properties (e.g., solubility, bioavailability, off-target side effects) that might otherwise keep them from being approved. In many cases, these improvements are the result of changes in formulation leading to, for example, longer lasting action or a change in delivery modality (e.g., transdermal or inhalation). Particle-based drug delivery, particularly polymeric particle systems wherein delivery is achieved by encapsulation, or physical entrapment, of a drug within the particle matrix, has been a very active area of interest that has resulted in several successful products. One example is Risperdal CONSTA®, which is indicated for the treatment of schizophrenia.1 1 See http://www.risperdalconsta.com.
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Frontiers of Engineering: Reports on Leading-Edge Engineering from the 2008 Symposium Risperdal delivers the drug risperidone encapsulated in poly(lactide-co-glycolide) (PLGA) biodegradable polymeric microspheres with a particle diameter of about 100 microns via intramuscular injection once every two weeks. The drug is released over time from the particles by slowly diffusing out of the polymeric matrix as water diffuses in and as the polymer chains degrade via hydrolysis, causing particles to lose their structure and fall apart. PLGA-based particle drug-delivery systems can be tailored to the properties of the drug, appropriate dosage, and the mechanism of action for releasing the encapsulated drug over a period of weeks or months in a controlled way. Risperdal®, the original risperidone product, is taken orally by patients with schizophrenia on a daily basis. In most cases, the simplicity of taking a pill is very strongly preferred as a method of administering a drug, and designing a drug-delivery system to change the administration from oral delivery to a more complicated (e.g., inhalation) or painful (e.g., injection) delivery, would normally be unsuccessful (unless the oral drug had a significant shortcoming). For patients with schizophrenia, however, taking a pill every day can be problematic, and missing a dose one day can lead to a downward spiral of missing more doses. In this case, intramuscular injection administered by a doctor or nurse once every two weeks has not only increased patient compliance, but also improved the efficacy of the drug, resulting in a significant improvement in the treatment of patients with schizophrenia. Microparticle delivery systems, such as Risperdal CONSTA, are too big to be administered intravenously. Their particle size would result in very fast clearance by the body’s defense mechanisms or could potentially pose a significant safety risk if they were to lodge in capillary beds in the heart or lungs. Nanoparticle-based drug-delivery systems, in which particle sizes generally range from about 20 to 200 nanometers, are being investigated for delivering therapeutic agents, imaging diseased tissues or organs, and sensing the effectiveness of drug delivery or the status of disease. As a point of reference, a nanometer is one-billionth of a meter or one-millionth of a millimeter. Because of their very small size, nanoparticles administered systemically (i.e., by intravenous injection or infusion) circulate through the bloodstream carrying their therapeutic payloads directly to the site of disease in the body. NANOPARTICLE-BASED DRUG-DELIVERY SYSTEMS Diseases associated with defects or irregularities in the endothelial cells of blood vessels in the diseased area, creating what is called “leaky vasculature,” may be particularly susceptible to treatment by nanoparticle-based drug-delivery systems. These include inflammatory diseases (e.g., rheumatoid arthritis, atherosclerosis), infectious diseases (e.g., tuberculosis), and cancer. Once nanoparticles reach the affected area, they can passively diffuse from the bloodstream across the leaky vasculature to deliver drugs directly to the disease site.
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Frontiers of Engineering: Reports on Leading-Edge Engineering from the 2008 Symposium However, because nanoparticles are foreign bodies circulating in the bloodstream, the natural defense mechanisms of the body attempt to remove them. The way the body protects itself from nanoparticles or other foreign particulate matter circulating in the bloodstream is through the mononuclear phagocytic system (MPS), sometimes also called the reticuloendothelial system, in which phagocytic cells located primarily in the liver and spleen engulf the nanoparticles. High levels and fast rates of nanoparticle clearance by the MPS lead to an accumulation of nanoparticles in the liver and spleen, thus removing them from circulation before they are able to reach the site of disease and effectively deliver their therapeutic payloads. In addition, if the drug being delivered has potential specific toxicities in the liver or spleen, the clearance of nanoparticles by these organs may exacerbate those effects, making the drug less tolerable or more dangerous. The optimization of nanoparticle properties, therefore, is critical to the development of a safe nanoparticle drug-delivery system. Particle-surface characteristics (e.g., chemical composition, charge) have a strong influence on the detection of nanoparticles by the MPS. Therefore, one way to minimize MPS clearance is to construct nanoparticles with poly(ethylene glycol) (PEG), a biocompatible polymer, on the surface, a technique that has been successfully used to increase the circulation time of biodegradable polymeric nanoparticles (Gref et al., 1994). The hydrophilic, uncharged nature of PEG can interfere with phagocytic recognition and the uptake of nanoparticles or proteins resulting in prolonged circulation times and more opportunity for the drug to reach the intended disease target. DOXIL®, a liposomal formulation of the drug doxorubicin that uses a PEG surface to prolong circulation time,2 is approved for treatment of ovarian cancer, AIDS-related Kaposi’s sarcoma, and multiple myeloma. Doxorubicin, like many drugs, does not have a long circulation time in the bloodstream but instead can diffuse throughout the body in a way that can cause untoward side effects and that limits the amount of drug delivered to the tumor, thus decreasing its efficacy. By encapsulating doxorubicin in PEGylated liposome nanoparticles, DOXIL allows for longer circulation times than the drug has in its free, unencapsulated state, in fact long enough for the particles to diffuse into and deliver doxorubicin to the tumor vasculature. A potential downside of nanoparticle-based drug-delivery systems is that they can deliver more drug to certain parts of the body than the free drug would normally deliver, which can result in either new side effects or an exacerbation of existing side effects. For DOXIL, the result is an increase in the incidence of hand-foot syndrome (a skin irritation that usually occurs on the hands and feet) compared to doxorubicin alone. The apparent cause is that the long-circulating nanoparticles eventually land in the capillary beds of the hands and feet where they deliver liposome-encapsulated doxorubicin in greater amounts than would be delivered by free, unencapsulated doxorubicin. 2 See http://www.doxil.com/.
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Frontiers of Engineering: Reports on Leading-Edge Engineering from the 2008 Symposium To repeat, nanoparticles can passively diffuse from the circulating bloodstream through the leaky defects in tumors or areas of infection or inflammation to deliver their therapeutic payloads. Although effective, this passive targeting can have limitations in that nanoparticles may also diffuse out of the disease site through the defects back into circulation. Considerable research is being conducted to improve nanoparticle drug-delivery systems by trying to actively target the nanoparticles to diseased cells (Allen, 2002; Heidel et al., 2007; Peer et al., 2007). These approaches attempt to take advantage of the presence of unique or highly up-regulated cell-surface receptors on diseased cells by functionalizing the surface of nanoparticles with ligands that promote cell-specific recognition and binding. The intent is that once the particles successfully migrate through the bloodstream to the disease site, targeted nanoparticles will then anchor themselves to the disease cells, keeping the nanoparticles in place long enough to deliver their payloads. The choice and properties of the cell-surface receptor may even allow for the uptake of intact nanoparticles into the cell. The resulting intracellular drug delivery can greatly increase the effectiveness of the drug. For some drugs and therapeutic applications, intracellular delivery may be necessary, thus requiring intracellular nanoparticle trafficking. One example of this is the new class of short-interfering RNA (siRNA) drugs, which are being developed to inhibit the production of disease-causing proteins through RNA interference (RNAi). THE BIND TARGETED NANOPARTICLE BIND Biosciences Inc. (BIND), a biopharmaceutical company that was founded upon the research of two pioneers in nanoparticle drug delivery, Professor Robert Langer of MIT and Professor Omid Farokhzad of Brigham and Women’s Hospital of the Harvard Medical School, has developed methods of engineering targeted nanoparticles composed of biodegradable and biocompatible polymers with precise biophysicochemical properties optimized to deliver drugs for specific therapeutic applications (Gu et al., 2008). The foundational research by Langer and Farokhzad put BIND in a position to pursue the development of targeted polymeric nanotherapeutics for treating several diseases. BIND’s lead program is focused on translating their innovative academic findings into improved treatments for patients with cancer. The BIND technology offers a unique combination of long-circulating nanoparticles with the capability of targeting diseased cells specifically and releasing drugs from nanoparticles in a programmable, controlled way. Figure 1 is a schematic diagram of a BIND targeted nanoparticle. The targeting ligand enables the nanoparticle to recognize specific proteins or receptors on the surface of cells involved in disease, or in the surrounding extracellular matrix, and bind, with high specificity and avidity, to its intended cellular target
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Frontiers of Engineering: Reports on Leading-Edge Engineering from the 2008 Symposium FIGURE 1 Schematic diagram of a BIND targeted polymeric nanoparticle. site. Many types of cancer have been shown to have cell-surface receptors that are highly expressed on the cancer cells (e.g., prostate cancer [prostate-specific membrane antigen, PSMA], breast cancer [human epidermal growth factor receptor 2, HER-2], and lung cancer [epidermal growth factor receptor, EGFR]), and many drugs are being evaluated that might improve treatment outcomes. Surface Functionalization Surface functionalization imparted by a PEG component shields the targeted nanoparticles from MPS immune clearance, while providing an attachment site for the targeting ligand on the particle surface at precise, controlled levels through proprietary linkage strategies. A key to the successful development of BIND targeted nanoparticles is the optimization of the nanoparticle surface, which requires a precise balance between the targeting ligand and PEG coverage so the nanoparticle surface is masked enough to provide circulation times long enough to reach the disease site and enough targeting ligand on the surface to effectively bind to the target cell-surface receptors. This delicate balance requires precise control over the nanoparticle production process. It also requires the discovery and selection of ligands that are potent and specific enough to bind selectively to the targeted disease cells while remaining bound to the nanoparticle surface. The polymer matrix, the bulk of the nanoparticle composition, encapsulates the drug in a matrix of clinically safe, validated biodegradable and biocompatible polymers that can be designed to provide appropriate particle size, drug-loading level, drug-release profile, and other critical properties. A variety of drugs or therapeutic payloads can be incorporated into the targeted nanoparticles, including small molecules, peptides, proteins, and nucleic acids, such as siRNA.
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Frontiers of Engineering: Reports on Leading-Edge Engineering from the 2008 Symposium Drug-Release Profile The drug-release profile is a critical factor for the effective delivery of targeted nanoparticles. If the drug leaks out of the nanoparticle too quickly, it will be released into the bloodstream and essentially delivered as free, unencapsulated drug, thus losing the advantages of nanoparticle delivery. If the drug is not released in the appropriate time frame after the nanoparticles have reached the disease site, it may not reach an efficacious level. Thus it is critical that the right combination of polymer properties be tailored to ensure the optimal drug-release profile. BIND targeted polymeric nanotherapeutics can be engineered with different physicochemical properties, mechanisms of action, and dose requirements to provide effective drug delivery for a variety of diseases with different indications. REGULATORY REQUIREMENTS When a start-up company is founded based on academic research, the initial scientific efforts are focused on transferring the technology from academic laboratories to the company, where researchers can establish the capabilities of the technology and reproduce the results. Shortly thereafter, with a baseline understanding of the technology in hand, the translational aspects of the research begin. The company focuses on defining the most suitable disease indications to pursue and the specific characteristics required. At this point, the regulatory requirements dictated in the United States by the Food and Drug Administration (FDA) for pharmaceutical development of drug product candidates must be taken into consideration. Since its inception in early 2007, BIND has undertaken a combinatorial optimization approach resulting in a number of enabling improvements to nanoparticle formulation, as well as the nanoparticle production process to meet the needs of its lead targeted oncology candidate. The optimization approach includes evaluating the performance of nanoparticles using in vitro cell-based assays and in vivo preclinical testing, as well as several chemistry, manufacturing, and controls (CMC) requirements mandated by current manufacturing practices and the FDA to ensure, among other things, batch-to-batch reproducibility and shelf-life stability. Meeting these requirements entails testing a variety of properties, such as particle size, content of the targeting ligand, drug-loading level, and the stability of the nanoparticles and the drug under storage and in-use conditions. As pharmaceutical development progresses, the CMC requirements become more stringent. However, even at this early stage, the company begins testing critical parameters. To establish an acceptable level of safety and tolerability to support the initial evaluation of a candidate drug product in human clinical studies, the FDA requires formal safety testing in animal models. This is the first major step in the FDA-regulated area of pharmaceutical development. It also represents the
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Frontiers of Engineering: Reports on Leading-Edge Engineering from the 2008 Symposium company’s first efforts at scaling up the formulation and process capabilities of the drug. Whereas research at MIT/Harvard and initial efforts at BIND were conducted on nanoparticle batches prepared on the bench-top milligram scale, BIND nanoparticle production batch size has been scaled up three orders of magnitude for the animal safety and tolerability tests that support clinical studies. The critical, long-term stage of pharmaceutical development is clinical testing. Through a progression of studies, the safety, tolerability, and efficacy of a drug product candidate are established; the tests are accompanied by a series of submissions to and discussions with the FDA. For BIND targeted polymeric nanotherapeutic drug candidates based on improving the performance of existing marketed drugs, the clinical testing period is likely to be shorter than for a completely new drug candidate, because the history and data established for the existing drug provide valuable reference points for BIND and the FDA. Nevertheless, several clinical studies are required, all CMC requirements must be met, and the nanoparticle production process must be scaled up to the kilogram level to supply the drug for clinical studies and ultimately, if successful, to supply the approved, marketed drug to doctors and patients. Thus a long, challenging, very exciting pathway lies ahead for BIND Biosciences in translating the novel targeted polymeric nanoparticle drug-delivery research by Professors Langer and Farokhzad into medicines that can improve, and even save, the lives of patients suffering from serious diseases. REFERENCES Allen, T.M. 2002. Ligand-targeted therapeutics in anticancer therapy. Nature Reviews 2(10): 750–763. Gref. R., Y. Minamitake, M.T. Peracchia, V. Trubetskoy, V. Torchilin, and R. Langer. 1994. Biodegradable long-circulating polymeric nanospheres. Science 263(5153): 1600–1603. Gu, F., L. Zhang, B.A. Teply, N. Mann, A. Wang, A.F. Radovic-Moreno, R. Langer, and O.C. Farokhzad. 2008. Precise engineering of targeted nanoparticles by using self-assembled bio-integrated block copolymers. Proceedings of the National Academy of Sciences of the United States of America 105(7): 2586–2591. Heidel, J.D., Z. Yu, J.Y. Liu, S.M. Rele, Y. Liang, R.K. Zeidan, D.J. Kornbrust, and M.E. Davis. 2007. Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA. Proceedings of the National Academy of Sciences of the United States of America 104(14): 5715–5721. Peer, D., J.M. Karp, S. Hong, O.C. Farokhzad, R. Margalit, and R. Langer. 2007. Nanocarriers as an emerging platform for cancer therapy. Nature Nanotechnology 2(12): 751–760.
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