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Nanomaterials for Theranostics: Recent Advances and Future Challenges *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Eun-Kyung Lim, Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh, Kwangyeol Lee
Chemotherapy against tumor is widely used in clinical research but suffers from drawbacks such as the lack of selectivity, low response rates, and toxicities to normal tissue. In order to reduce nonspecific toxicity and further increase chemotherapeutic efficacy, antibodies have been recognized as tumor-specific markers [382]. In the early 1900s, Paul Ehrlich developed the concept of “magic bullets” to specifically target disease sites while sparing normal tissues. In the late 1970s, monoclonal antibodies (mAbs) were developed from mouse cells in the hope that they would specifically recognize and block the action of growth factors against cancer cells. However, these early-stage mAbs with a nonhuman origin failed as drugs in clinical trials since they could not specifically bind to tumor cells and were rejected by the patient immune systems [383, 384].
Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Other antibacterial agents are designed to act on the plasma membrane. The polypeptides valinomycin and gramicidin A cause the uncontrolled movement of ions across the cell membrane. Valinomycin acts as an inverted detergent and complexes a ‘naked’ potassium ion. The hydrophobic outer of the complex can pass the cell membrane and deposit the potassium ion outside the cell, resulting in fatality. Typically, K+ is in high concentration inside the cell and can only pass the membrane via specialised transport proteins and this equilibrium is disrupted by valinomycin. Valinomycin is selective towards K+, having the correct spatial arrangement of donor atoms to displace water ligands and form bonds to K+. Other ions, such as Na+, are not the correct size to fit and displacing water ligands is too difficult. Unfortunately, the toxicity is not selective to bacteria; affecting mammal cells as well. Gramicidin A is a peptide consisting of 15 amino acids, which coil into a helix where hydrophobic side chains point outwards and interact with the membrane. Two helices of gramicidin A must combine to span the membrane and the hydrophobic interior of the helix serves as a channel for the passage of ions. However, gramicidin A is also toxic to humans. Producing compounds to serve as drugs which employ the ‘magic bullet’ approach is a challenge for medicinal chemists. Compounds must be toxic to bacteria, but safe to use and to achieve this, target specificity is essential when developing effective antibiotics in the future.
The Golden Age of Medicine?
Published in Roger Cooter, John Pickstone, Medicine in the Twentieth Century, 2020
Allan M. Brandt, Martha Gardner
Secondly, the heavy emphasis on specialization, technology, and hospital care was seen as overshadowing the particular medical needs of those with chronic illness, now often the most prevalent category of disease. And finally, the very articulation of ‘magic bullet’ medicine, with its emphasis on basic science and specificity, directed resources away from social, behavioral, and preventive measures more likely to benefit populations at risk for disease. According to these critiques, the elegance of bioscience and its impressive technology had misdirected medicine, creating powerful professional interests that now worked against alternative visions of health care and public health.
Clinical development of an anti-GPC-1 antibody for the treatment of cancer
Published in Expert Opinion on Biological Therapy, 2022
Saikat Ghosh, Pie Huda, Nicholas Fletcher, Douglas Campbell, Kristofer J. Thurecht, Bradley Walsh
Synergizing the specificity of antibodies and the cytotoxicity of small molecule pharmaceutical drugs can greatly enhance the anti-cancer potency of the resulting conjugate in comparison to the individual components. Also, the very high potency of these cytotoxic agents limits their use as free drugs, requiring their delivery to be specifically targeted through the mAb component. These ‘magic bullets’ (a.k.a. ADCs) are an emerging class of onco-therapeutics (Figure 2b) with distinct clinical advantages over conventional pharmaceuticals, such as (i) reduced systemic toxicity and increased tolerability, since they are directed toward cancer cells only; (ii) increased potency due to the additional target neutralizing ability of the antibody component which could be promising against drug-resistant tumors; (iii) enhanced retention of bioactivity through an intravenous route of administration ensuring protection for both the antibody and the drug component from degradation in the gastrointestinal environment. Moreover, ADC therapy could be administered in patients with radiation-resistant and recurrent tumors who would not benefit from radiotherapy.
Multitargeting approaches involving carbonic anhydrase inhibitors: hybrid drugs against a variety of disorders
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
The central paradigm in drug design, at least for the last century, was the concept introduced by Paul Ehrlich of the “magic bullet”1. Considered the founder of chemotherapy, mainly due to his excellent work on the treatment of syphilis with arsphenamine (Salvarsan) and structurally related derivatives2, this scientist introduced the concept of drug target and pinpointed to the fact that an effective drug should specifically act on one target in order to manifest its therapeutic benefits. Furthermore, many of the side effects that a drug shows may be considered as being due to off-targeting, that is, interactions with diverse biomolecules than the real target, according to the magic bullet theory. As a consequence, most if not all modern drugs in clinical use were discovered considering these concepts, which continue to influence generations of medicinal chemists in the search of both new drug targets as well as compounds that should effectively, and possibly specifically interact with them for producing beneficial therapeutic effects3.
The Emerging Role of Oral Oncolytics
Published in Oncology Issues, 2020
The idea of a magic bullet—a single targeted drug that kills cells while minimizing the amount of toxicity to other areas of the body—was first hypothesized by Paul Erlich, an American biologist, on the eve of the 20th century. Since that time, new molecular targets have been discovered that regulate tumor cell growth and proliferation patterns. Drug candidates against these proteins have prompted a growth in research aimed at developing molecular drugs from the benchtop to the bedside. More than 3,500 novel approaches have been evaluated clinically or pre-clinically in the last decade.1 Currently, more than 10,000 clinical trials with novel and approved agents, alone or in combination, are ongoing, with over 12 percent having entered phase III status.1 Oral oncolytic agents are being approved rapidly. Of the more than 800 new oncology therapies currently in the pipeline, 25 to 35 percent are oral agents.1