CRISTAL THERAPEUTICS

• Based in the Netherlands, Cristal Therapeutics "is a clinical stage pharmaceutical company" which is attempting to develop "the next generation of targeted nanomedicines for improving the treatment of cancer and other diseases."
• The company was founded in 2011 and has raised a total of €23.8 million in venture capital, mostly from grants and an investment round in 2017.
• Cristal is developing a "passively-targeted polymeric nanoparticle"-based drug named CPC634, which is built on Cristal's CriPec nanoparticle technology.
• According to the most recent press release, "CPC634 was specifically designed to overcome the toxic systemic side effects associated with current docetaxel products by enabling enhanced accumulation and ensure sustained release at the tumor site to optimize the therapeutic/safety balance."
• However, we are unable to find references to disulfiram, quercetin, dasatinib, or salinomycin in conjunction with Cristal's nanoparticle technology, and so cannot verify whether this company is a true fit for the criteria.

SAMYANG BIOPHARMACEUTICAL CORP.

• Samyang Biopharmaceuticals Corp. split off from parent company Samyang in 2011 and has been based out of Pangyo Techno Valley since 2016.
• The company is heavily focused on the drug-delivery system (DDS) side of anti-cancer drugs, but also produces a number of other products, including smoking cessation patches and biodegradable surgical sutures.
• Samyang has conducted trials for a polymeric formulation of Docetaxel, but we find no reference connecting this to disulfiram, quercetin, dasatinib, or salinomycin.
• In addition, at the 2018 17th Annual World Preclinical Congress in Boston, Samyang representatives gave a presentation entitled, "Development and Validation of and bDNABased Hybridization Assay and qRT-PCT for the Quantification of Polymeric Nanoparticle." Again, we are unable to directly connect this essay to the four treatment types in the criteria.

BIND THERAPEUTICS / PFIZER

• In a page that has since been taken down but which was archived by Google, AstraZenica mentions collaborating "with BIND Therapeutics for its ACCURINS polymeric nanoparticle technology." However, that partnership appears to have been sundered when Pfizer bought out BIND's assets as part of a bankruptcy deal.
• As there are no references to polymeric nanoparticle technology on Pfizer's page or in its last three annual reports, the status of the technology and whether Pfizer is continuing to develop it is uncertain, as is whether it fits within the requisite treatment types.
•  BIND's patent for the process makes no mention of rights being transferred to Pfizer or any other entity; it is possible that the rights are in legal limbo due to the bankruptcy.

RESEARCH STRATEGY

ARTICLES

Polymer-Stabilized Micelles Reduce the Drug Rapid Clearance In Vivo

• Authors: Shan-Ni Wen, Chih-Hang Chu, Yu-Chao Wang, et al.
• FINDINGS:
• The three most common types of drug delivery systems are liposomes, micelles, and polymeric nanoparticles. Micelles are nanoscaled aggregates that can be used to encapsulate hydrophobic drugs, but the property of micelles that exchanges unimers between the micelles and bulk solutions causes leaking of the encapsulated substances.
• In this study, the researchers sought to incorporate a hydrophobic polymer into the micellar core in order to interlace the unimers and form polymer-stabilized micelles. They found that drugs delivered in polymer-stabilized micelles have a lower clearance rate than non-polymer-stabilized micelles, and are present in higher concentrations.
• Even though this study didn't mention chemotherapy treatments, the study cites studies dealing with chemotherapy delivery and clearance is a problem that scientists often look to solve.

Anti-tumor efficacy of hyaluronan-based nanoparticles for the co-delivery of drugs in lung cancer

• Authors: V. Jeannot, C. Gauche, S. Mazzaferro, et al.
• FINDINGS:
• In this study, the researchers used nanoparticles from self-assembled hyaluronan-based copolymer to house gefitinib and vorinostat to target CD44 receptors. The drugs were loaded into the nanoparticles using a process known as nanoprecipitation.
• The researchers used two- and three-dimensional lung adenocarcinoma cell cultures and found that there was a slow drug release after 5 days. Cell toxicity was about the same as drugs delivered in a free method, and the only toxicity found was due to apoptosis induction. They concluded that hyaluronan-based nanoparticles provide great active targeting, with a less-toxic drug release and improved efficiency against tumors.

Improvement of oral efficacy of Irinotecan through biodegradable polymeric nanoparticles through in vitro and in vivo investigations

• Authors: N. Ahmad, MA Alam, R. Ahmad, et al.
• FINDINGS:
• Oral formulations for Irinocetan (IRN) are very limited due to active efflux by intestinal P-glycoprotein receptors. In order to enhance the oral bioavailability of Irinocetan, the researchers sought to find a nanoformulation to solve this problem. The researchers came up with CS-IRN-PLGA-NPs, or Chitosan-coated-IRN-loaded-poly-lactic-co-glycolic acid nanoparticles.
• When cytotoxicity of this formulation was tested, they found that toxicity was less than free-IRN solution. They found that permeability was high when tested against the human colon adenocarcinoma cell line, as well as an increased improvement in oral bioavailability in the plasma as well as the brain.

DOXIL

• Doxil is used in the treatment of ovarian cancer if the “disease has progressed or recurred after platinum-based chemotherapy”. It is also used in the treatment of AIDS-related Kaposi's sarcoma if initial systemic chemotherapy has failed or patients don't tolerate such therapy.
• Doxil is manufactured by Johnson & Johnson.
• 25 milliliters of Doxil cost $3,268.29.

ADRIAMYCIN

• Adriamycin is used in the treatment of neoplastic conditions including acute leukemia, Wilms' tumor, and neuroblastoma. It is also used in the treatment “of non-metastatic carcinoma of the bladder.”
• Adriamycin is manufactured by Pfizer.
• 25 milliliters of Adriamycin cost $28.12.

LIPODOX

• Lipodox is a generic version of Doxil which was produced to enhance the access and affordability of the essential medication. It was approved by the US FDA in 2013.
• Lipodox is manufactured by Sun Pharmaceutical.
• 10 milliliters of Lipodox cost $814.34.
• Therefore, 25 milliliters of Lipodox cost $814.34 / 10 * 25 = $2035.85.

NUDOXA

• Nudoxa is used to treat leukemia, cancers of the ovaries, and Kaposi's sarcoma. It is also used in the treatment of HIV patients who have not responded positively to other cancer medications.
• Nudoxa is manufactured by Cadila.
• 10 milliliters of Nudoxa cost $138.93.
• Therefore, 25 milliliters of Nudoxa cost $138.93 / 10 * 25 = $347.325.

RESEARCH STRATEGY

POLYMERIC NANOPARTICLES ROUTES OF ADMINISTRATION AND AIM

•  Polymeric nanoparticles are used to stabilize drugs physically as well as protect them against chemical degradation.
• These are also used for potential binding of substances to tissues and cells through targeted delivery.
• Polymeric nanoparticles are also prized for their enhanced permeability and retention (EPR) effect as well as high drug loading.
• The typical routes of administration of polymeric nanoparticles are oral delivery, in vitro and in vivo.
• The aims of polymeric nanoparticles can be categorized into the following: improve/increase bioavailability, increase the drug's release and long-acting effect, improve solubility, and achieve pharmaceutical synergy.

MAJOR APPLICATIONS

• Polymeric nanoparticles differ in terms of major application based on the drug/active ingredient used.
• For example, while Quecertin and Ellipticine both aim to increase bioavailability, the former is used to reduce therapy while the latter is applied to increase cytotoxicity.
•  Amphotericin B is also used to increase bioavailability but is also applied to lessen nephrotoxicity.
•  Curcumin is also used to increase oral bioavailability as well as improve the drug's solubility.
•  Tamoxifen is used to promote synergistic effect as well as increase bioavailability.
• Both Exenatide and Rivastigmine are used to prolong the drug's release, but the former is applied to improve the drug's long-acting effect while the latter is applied to improve cognitive function and memory.
•  Cisplatin and Naringenin both increase bioavailability but Cisplatin is used reduce adverse effects while Naringenin is applied to heighten therapeutic effect.

TREATMENT TYPE EXAMPLES

•  Disulfiram was found to have strong tumor mass penetration and destruction capacity upon cellular uptake when administrated in vivo in a 2018 study.
•  Quercetin was found to exhibit anti-tumor effect as well as enhanced permeability and retention (EPR) effect when administrated in vitro in a 2018 study.
•  Dasatinib demonstrated high cytotoxicity, good stability and hemocompatibility when administered in vitro in a 2019 study.
•  Salinomycin together with Paclitaxel showed improved cellular uptake, increased binding efficacy, and higher cytotoxicity when administered in vitro in a 2016 study.

RESEARCH STRATEGY