Novel Delivery Systems: Competitive Landscape

Part
01
of four
Part
01

Novel Delivery Systems: Polymeric Nanoparticle Companies

At present, there appear to be only two companies actively and openly working on developing a polymeric nanoparticle delivery system for drugs, Cristal Therapeutics and Samyang Biopharmaceuticals Corp. However, public records do not verify whether these projects involve the treatment types of disulfiram, quercetin, dasatinib, or salinomycin. In addition, it appears that BIND Therapeutics was working on polymeric nanoparticle until it filed for bankruptcy in 2016. While most of its assets appear to have been purchased by Pfizer, the current status of BIND's project is unknown.

Below are our findings and a detailed research strategy which explains why the expected minimum of five companies could not be located.


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

We began our research with a broad search for sources linking polymeric nanoparticles with disulfiram, quercetin, dasatinib, and salinomycin. We soon found that the number of research papers on the subject overwhelmed any instances of companies boasting of their treatments. We, therefore, took a roundabout route and sought out research papers which mentioned specific treatments and/or companies offering this type of treatment. Due to the complexity of the papers involved, we pulled multiple sources to verify that the drugs in question do indeed provide polymeric nanoparticle treatment within one of the four specified treatment types. However, this method ultimately provided only a single company, Cristal Therapeutics.

Therefore, we changed strategies. We next went to the Clinical Trials government database and conducted a search for any that included "polymeric nanoparticle" in the description of the trial. This yielded only three results, two of which had been sponsored by the same company, Samyang Biopharmaceuticals Corporation. This proved to be only a possible hit, as explained in the findings above, but which we included due to the dearth of other candidates.

As this fell well short of the project criteria, as a final effort, we pulled a list of nanobiotechnology and nanomedicine companies from NanoWerk. We then conducted a quick search of each company's name in conjunction with the relevant key terms. Due to the need to quickly assess 54 companies while staying within the scope of a single Wonder request, we did not attempt to read the large number of scientific papers that this produced, instead seeking press releases, hits on the actual company websites, patent filings, and/or other news sources. While this did not yield any direct results, following references through Google's patent database led us to a patent by the now-defunct BIND Biosciences, but as explained in our findings, BIND's bankruptcy has put the status of that technology in doubt. Nevertheless, and again due to a dearth of findings, we have included BIND and the primary owner of its assets, Pfizer, in our findings.

Given the sheer number of academic works on this technology that we encountered in our research, it seems incredible that more companies are not working on polymeric nanoparticle treatments. Based on the lack of clinical trials, we hypothesize that any other companies currently working on this technology are not yet at the trial phase and so are playing their cards close to their chests lest they lose a competitive advantage, but could not confirm our hypothesis from records in the public domain.
Part
02
of four
Part
02

Novel Delivery Systems: Medical Research Report

In looking for medical research reports on the efficacy of polymeric nanoparticles that help in the delivery of chemotherapy, your research team was able to find three reports that were done in the past year. These studies all show improvement over current methods, with lower toxicity. These articles are summarized below.

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:

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.
Part
03
of four
Part
03

Novel Delivery Systems: Liposomal Treatment

Four key brands of liposomal treatment are Doxil, Adriamycin, Lipodox, and Nudoxa.

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

We selected four key brands of liposomal treatment from market research reports on the global liposomal doxorubicin market. We chose Doxil, Adriamycin, Lipodox, and Nudoxa (manufactured by Johnson & Johnson, Pfizer, Sun Pharmaceutical, and Cadila respectively), after reviewing five market research reports from Grand View Research, Mordor Intelligence, The Market Reports, Research Reports World, and QY Research. Each of the brands was selected because its manufacturer was mentioned in at least four of the five reports.

Part
04
of four
Part
04

Novel Delivery Systems: Polymeric Nanoparticle Treatment Types.

Polymeric nanoparticle treatment types resemble each other in routes of administration and treatment aim, while differing in terms of major application.

POLYMERIC NANOPARTICLES ROUTES OF ADMINISTRATION AND AIM

MAJOR APPLICATIONS

TREATMENT TYPE EXAMPLES


RESEARCH STRATEGY

We began our research with the study "Nanotechnology And Nanocarrier-Based Approaches On Treatment Of Degenerative Diseases," published in the 2017 issue of International Nano Letters journal. The source provided a broad overview of polymeric nanoparticle treatments along with their system components, aim, major applications, and routes of administration.

However, outside of the source provided in the Strategy document (Nanotechnology for Cancer Therapy Based on Chemotherapy), we found no head-on comparison for the polymeric nanoparticle treatments disulfiram, quercetin, dasatinib, and salinomycin. Therefore, we proceeded to research each example separately and found that these are used in different cancer types for which they have various specific applications. Due to the broad range of diseases to which they were applied, we could not determine an exact and in-depth set of similarities and differences. Nevertheless, we followed the pattern given in the International Nano Letters article and provided available information from the locked study previews including routes of administration and aim (i.e. similarities) as well as major applications (differences).
Sources
Sources

From Part 03
From Part 04
Quotes
  • "Table 1 (See Polymeric Nanoparticles): Examples of nanotechnology and nanocarrier-based drug delivery systems, compositions, aims, applications and route of administrations for degenerative disease treatment"
Quotes
  • "Quercetin nanoparticles accumulated in tumour site through enhanced permeability and retention effect"
  • "Quercetin nanoparticles exhibited improved anti-tumour effect in tumour bearing mice compared to free quercetin"
  • "Researchers are working on the application of nanotechnology to target chemotherapeutic drugs to the tumour site. The aim of the present study was to develop quercetin loaded chitosan nanoparticles (QCT-CS NPs) with enhanced encapsulation efficiency and sustained release property. "
  • "In summary, the recent investigations reported successful encapsulation of QCT in chitosan (CS) NPs to target the tumour microenvironment and exhibited enhanced efficacy of QCT-CS NPs in cancer therapy."
Quotes
  • "Paclitaxel, a conventional chemotherapeutic agent was used to kill cancer cells. Salinomycin was selected as cancer stem cell inhibitor."
  • "Both the anticancer drugs were delivered through polymeric nanoparticles."
  • "Combination of HA coated SLM nanoparticles and PTX nanoparticles showed the highest cytotoxicity against CD44+ cells. "
  • "Hence combinational therapy using conventional chemotherapeutic drug and cancer stem cell inhibitor could be a promising approach in overcoming cancer recurrence due to resistant cell population."
Quotes
  • "Dasatinib (DAS)-loaded magnetic micelles were prepared for magnetically guided drug delivery. The magnetic nanoplatform is composed of hydrophobic oleic acid–coated magnetite (Fe3O4) core along with DAS encapsulated in amphiphilic zein-lactoferrin self-assembled polymeric micelles. "
  • "They also showed good in vitro serum stability and hemocompatibility accompanied with a sustained release of DAS in acidic pH. "
  • "More importantly, they exhibited 1.35-fold increase in their in vitro cytotoxicity against triple-negative human breast cancer cell line (MDA-MB-231) using an external magnetic field compared to drug-loaded magnetic micelles in the absence of a magnetic field. "
  • "Taken all together, these results suggest that DAS-loaded magnetic micelles possess a great potential for targeted therapy of breast cancer."
Quotes
  • "Disulfiram (DSF), an FDA approved drug for the treatment of alcoholism, degrades to therapeutically active diethyldithiocarbamate (DDTC) in the body by reduction. Hereby, we developed a redox sensitive DDTC-polymer conjugate for targeted cancer therapy. "
  • " It was found that the DDTC-polymer conjugate modified with a β-d-galactose receptor targeting ligand can self-assemble into LDNP nanoparticle and efficiently enter cancer cells by receptor-mediated endocytosis. "
  • "Upon cellular uptake, the LDNP nanoparticle degrades and releases DDTC due to the cleavage of disulfide bonds, and subsequently forms copper (II) DDTC complex to kill a broad spectrum of cancer cells. "
  • "3D cell culture revealed that this nanoparticle shows much stronger tumor mass penetrating and destructive capacity."
Quotes
  • "Polymeric nanoparticles protect drugs against chemical degradation; physically stabilize the drugs; have high EPR effects, high drug loading, and the possibility of binding substances to cells and tissues through targeted delivery;"