StemCell Therapy

AI-generated image using Midjourney depicting scientists inventing new medicines

In 1998 I was exposed to the term disruptive innovation for the first time. I read a wonderful book, The Innovators Dilemma by Clayton Christensen, where I learned the difference between incremental innovation and disruptive innovation. He analyzed the hard drive industry and showed that while many companies were trying to increase the capacity of the drives, other companies changed the form factor and made the drives smaller. This resulted in disruptive progress in the industry. We also recently witnessed dramatic advances in artificial intelligence (AI), where in 2013/2014 AI systems started outperforming humans in image recognition. This was made possible by taking several existing technologies, deep neural networks (DNNs) and GPU computing, and training DNN on really big data sets. In fact, disruptive innovation often results from the combination of already existing technologies to make them work to address a massive unmet need.

Over past decades, the field of nanomedicine, mostly characterized by the targeted delivery of drugs for numerous types of diseases, has gained a special attention in oncology research. While some anti-cancer drugs work well when administered to the right patient and in the right dose, no drug is perfect, and no dose fits all. One of the most frequently used classes of anti-cancer drugs is platinum-based compounds, such as carboplatin, oxaliplatin, and cisplatin (one of the most effective anti-cancer drugs for the treatment of solid malignancies). Chemotherapeutic agents are necessarily toxic, as from a therapeutic stance, we need to kill the rapidly dividing cancer cells. However, as these drugs are nonselective (targeting both healthy and malignant tissues), patients often suffer the unfortunate combination of substantial side effects and low efficacy at the target site when these compounds are administered systemically via traditional routes (orally or intravenously).

Enhancing the accumulation of these drugs locally at the tumor site may significantly reduce the systemic toxicities and adverse side effects, while simultaneously improving treatment efficacy substantially. The major limitation is that these drugs do not penetrate very well, and so enhancing penetration has become a necessary goal in the optimization of delivering these agents. One technology that can help with this task is encapsulating the chemotherapeutic agents in nanoparticles (NPs). During the last decade, a wide range of nano-based drug delivery systems has been explored as alternative cisplatin delivery methods that may promote its accumulation and retention in cancer cells. While some of these NP formulations have demonstrated promising preclinical results and a few have entered clinical trials, none have been approved for the treatment of human cancers. Targeted accumulation of the drug can be further optimized through topical delivery of NPs in the form of gels and film composites, which may also increase the local and precise administration of chemotherapeutic drugs to accessible tumors (such as cancers arising in the oral cavity). Therefore, disruptive innovation has originated from merging these approaches and generating topical NP-based drug delivery platforms that primarily intend to ameliorate the adverse effects of systemically administered treatment and maximize the total dose and retention of the carried therapeutic agent at the local site, improving treatment efficacy.

Manijeh Goldberg, PhD, MBA, CEO of Privo Technologies

A multidisciplinary group led by Dr. Manijeh Goldberg, founder and CEO of Privo Technologies, together with Dr. Nishant Agrawal and Dr. Evgeny Izumchenko, Chief of Head and Neck Surgery and Professor of Hematology and Oncology at the University of Chicago, respectively, recently published the results of Privos preclinical and clinical studies using PRV111 treatment. This treatment is a topical mucoadhesive cisplatin delivery system that has the potential to revolutionize the field.

A screen capture of the header of the Nature Communications paper titled "A nanoengineered topical ... [+] transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer" https://doi.org/10.1038/s41467-022-31859-3

In the recent Nature Communications paper titled A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer, the scientists describe a nanotechnology-based patch system for non-invasive, local delivery of cisplatin-loaded chitosan particles that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. The system was used in both animal models (mice and hamsters) and patients with oral cancer and demonstrated promising, potentially disruptive, results.

Professor Nishant Agrawal, MD, Director, Head and Neck Surgical Oncology Chief, Section of ... [+] Otolaryngology-Head and Neck Surgery, University of Chicago

The hamster cheek model is a well-characterized system for studying oral cancer because of the similarities between the tissue in the pouch and the tissue in the human mouth. In the clinical trial, patients were treated with PRV111 as long as a week before undergoing surgery (surgery is standard for all patients with oral cancer). 87% of patients responded to treatment and showed decreased tumor volume, with an average decrease of 70% of tumor volume across all patients. As further confirmation of PRV111s efficacy, examination of the tumor tissue after surgery demonstrated that treatment also stimulated the patients innate immune system. Thus, the results from PRV111 use in humans suggest that PRV111 has shown a one-two punch therapeutic effect, simultaneously killing tumor cells and recruiting immune cells to attack the tumor site.

Briefly, in the PRV111 platform, chitosan (a non-toxic, biocompatible, and biodegradable polysaccharide derived from natural chitin), is used as a polymer for both the NPs and the porous matrix. As such, matrix-based water-soluble chitosan acts as a bioadhesive since the positively-charged chitosan can bind to negatively-charged mucoproteins, allowing the electrostatic interaction with mucin proteins in the oral cavity. Each cisplatin-loaded chitosan NPs containing patch covers a tumor region of 4 cm2, and incorporates a permeation enhancer that allows optimal penetration and absorption of the NPs released from the patch. When exposed to moisture, the NPs swell, allowing them to diffuse across the porous matrix and into the tumor tissue. However, these particles are too large to penetrate into the vasculature, and therefore prevent systemic cisplatin exposure.

Professor Evgeny Izumchenko, PhD

Since I made a tiny and insignificant contribution to the paper, and I am familiar with the leading authors. I got a chance to ask them a few questions about this possibly groundbreaking work.

Alex: I consider cisplatin to be one of the ancient uber-toxic cancer drugs that are responsible for the many misconceptions about modern cancer treatments. Why did you choose cisplatin for this study?

Cisplatin is one of the most potent anti-cancer agents. It has been studied and used in the field of oncology for decades. However, its dose-limiting systemic toxicities such as nephrotoxicity, ototoxicity and neurotoxicity can be severe and many times irreversible. In its early days, Privo discussed the best choice for its active ingredient with its advisor at the time, Dr. Jos Baselga at Bostons Mass General Hospital (MGH). Dr. Baselga, a renowned cancer researcher and the chief of hematology/oncology at MGH, recommended using cisplatin. He noted that cisplatin is a beast of a cancer drug and if tamed, it can be extremely effective in destroying cancer cells. Privo optimized the use of cisplatin to reduce its nasty systemic side effects while significantly improving its efficacy by its ability to directly deliver high concentrations of cisplatin to the tumor. This is like an atomic bomb applied specifically to the tumor, sparing the patients healthy tissues.

Alex: Nanomedicine is a frequently overused word, and it defines a very broad field. How do your group and your consortium of collaborators fit into this field?

We use both nano- and micro-particles in our matrix as part of our two-stage release platform technology. We design the particles with specific properties such as surface chemistry and size. The nano- and micro-particles can be programmed to control the release of the active ingredient based on the treatment requirements. In addition, the particle-containing polymeric matrix further protects the particles, allowing for longer lasting drugs following administration. For example, cisplatin is a very volatile drug which rapidly binds to proteins in the body, causing its deactivation before it can even reach the tumor site and have the chance to destroy cancer cells. Privos PRV111 is designed to protect and effectively insulate the drug for much longer, serving to decrease side effects and increase cellular uptake of the drug. The surface chemistry of the particles can also be optimized to increase cellular uptake further.

Alex: Can you tell me the story behind this paper - how did it come together?

Privo has been collaborating with Dr. Nishant Agrawal from Chicago Medicine since its early development days. I was introduced to Dr. Agrawal via a mutual friend, who was an oncologist that had lost a friend to oral cancer. He saw the potential of our research helping patients suffering from head and neck cancers. Dr. Agrawal is the chief of head and neck surgical oncology team at UChicago Medicine and has been a great mentor to our Privo team in addition to being a champion of our platform technology. Once Privo had successful preclinical data followed by phase 1 / 2 clinical study, the team agreed to publish the results. During the several years of research, Dr. Agrawal has made several introductions to other key opinion leaders such as Dr. Evgeny Izumchenko, an expert head and neck researcher at the University of Chicago who has been instrumental in compiling and publishing the data.

Alex: How much impact will this study have on patient lives once the technology reaches the market?

I think Privos technology has the potential to disrupt the treatment paradigm for several cancers starting with mucosal cancers such as oral, lung, cervical, and even brain tumors.

In todays world, social media has provided an unbiased, uncomfortable, and often raw insight into what a cancer patients journey is like. Over the past several years, we have followed a few oral cancer patients on their journey from initial diagnosis, treatment, surgery, physical therapy in addition to their mental health journey at each step of the road. Oral cancer has one of the highest suicide rates among cancers, and is second only to pancreatic cancer in terms of quality of life. Considering the accessibility of oral cancer, we aim to provide patients with a better alternative that offers them a better quality of life. Our data collected to date has shown that PRV111 has significantly reduced tumor volume for patients with T1/T2 stage tumors. In our Phase 3 design, we aim to target an early form of oral cancer, carcinoma in situ, where our goal is to eliminate the need for surgery indefinitely.

Alex: Are you planning to commercialize the technology and what are your plans to take it to market?

We are planning to commercialize the technology, especially after the successful first-in-human trial, which showed that PRV111 treatment performed better than expected, leading to early completion of the study. On average, PRV111 treatment decreased tumor volume by about 70% in just one week. Privo has successfully received support and collaboration from the FDA-OOPD, the NIH-NCI, the NIH-NIDCR, and the NSF. Their guidance and support is helping us be well on our way toward market approval.

In principle, this novel mucoadhesive system can be engineered to deliver virtually any chemotherapy and non-chemotherapy agent with a particular drug release profile, making it customizable for specific clinical applications. The unique properties of this carefully designed nanomedicine provide a promising framework and holds potential for the improved treatment of not only oral accessible cancers but also other solid malignancies.

Professor Alexander T Pearson, MD, PhD, Professor Evgeny Izumchenko, PhD, Alex Zhavoronkov, PhD at ... [+] the University of Chicago

Link:
Going Beyond Target Or Mechanism Of Disease: Disruptive Innovation In Drug Delivery Systems - Forbes

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