Accurin
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Accurin is a nanomedicine of which there are many specific targeted nanoparticles that deliver different medications and target different receptors. Nanomedicine is a field of drug delivery that hopes to use nanotechnology, such as nanoparticles, in medical treatment. Nanoparticles used in this manner typically have specific properties and range from 1-100 nm in diameter. Nanoparticles such as Accurin are used in specifying drug delivery to certain cells. Nanoparticles are also usually associated with lower side effects and lower drug consumption. Accurins were developed with the intention of specific targeting of tumor cells and offer a possible future treatment of cancers with a safer and more effective method of treatment.
Accurins include:
- BIND-014, targeting PSMA delivering docetaxel, in phase 2 clinical trials
- BIND-510, targeting PSMA delivering vincristine.[1] IND soon.
- BIND-2206 containing the AKT inhibitor MK-2206.[2]
Workflow[edit]
Accurins are made up of four layers that contribute to their therapeutic function. The first layer is a controlled-release polymer matrix. [3] This layer ensures that the therapeutic agent of choice is released at the site of diseased tissue. The second layer incorporates polyethylene glycol onto polylactic acid in nanoparticles in order to supply a conjugation location for the chemotherapeutic agent of choice. [4][5]Third, another layer of just polyethylene glycol is used to prevent the immune system from recognizing the molecule and therefore prevents immune clearance of the treatment allowing for a greater circulation in the system.[3] The final layer of Accurins is a series of ligands that facilitate the selective binding to diseased cells that allows for targeted accumulation of the chemotherapeutic in cancerous tissue. [3]
History and Applications[edit]
Bind Therapeutics was the biopharmaceutical company responsible for the development of Accurins. The company was founded by Professor Robert Langer from the Massachusetts Institute of Technology and by Omid Farokhzad from Harvard Medical School. The clinical-stage company’s lead product was BIND-014. BIND-014 was a nanoparticle developed to specifically select upregulated surface proteins found on a variety of solid tumors. BIND-014 progressed to Phase 2 clinical trials involving cancer patients. Before their bankruptcy in 2016, BIND was funded by Polaris Venture Partners, Flagship Ventures, ARCH Venture Partners, NanoDimension, DHK Investments, EndeavourVision and Rusnano. [6]
In 2013, Bind Therapeutics announced an official collaboration with Pfizer, a pharmaceutical industry company. The aim of the collaboration was to commercialize Accurins. The agreement stipulated that Pfizer would have the exclusive ability to commercialize their choice of Accurins. The companies agreed to collaborate on preclinical research, though Pfizer maintained responsibility for development and commercialization responsibilities. In 2016 Bind Therapeutics declared bankruptcy and was officially acquired in full by Pfizer. [6]
Accurin was originally developed by Bind Therapeutics in order to treat various cancers. At the time of development Accurin was described to implement highly selective targeting and was viewed to have a high potential for improvement in treatment for oncology, inflammatory diseases and cardiovascular disorders. Accurins were thought to have the potential to outperform current treatments by selective accumulation in specific sites of diseased cells, thus allowing for a greater drug concentration at the site of action and a lessened chance for off-target exposure. This combination would create a remarkably improved treatment efficacy and safety wise. [6]
Methods[edit]
There are three primary Accurin nanoparticles that met with the most success in clinical trials: BIND-014, BIND-510, and BIND-2206. Each Accurin differs in either or both the target molecule or the delivered drug, though the mechanism of action remains the same. Of these, Bind-014 was considered the most successful and the most likely to undergo commercial development by Pfizer.
BIND-014[edit]
BIND-014 was an Accurin developed with the investigated application of treating prostate cancer. The nanoparticle’s target was prostate-specific membrane antigen (PSMA) and the delivered drug was docetaxel. PSMA was the chosen target as it is an established tumor marker that is often overexpressed in prostate cancers as well as solid tumors. Docetaxel was the chosen agent as it is an existing chemotherapeutic drug used in popularity for cancer treatment. [7]
Clinical trials exemplified BIND-014’s tumor shrinking abilities. The nanoparticle was even able to shrink tumors that were otherwise resistant to docetaxel. [8]In comparison to free drug dosage, BIND-014 has proven to be up to ten times more effective at docetaxel delivery. For this increase in efficacy there is no associated toxicity increase. In direct comparison to Taxotere, a popular intravenous docetaxel treatment, BIND-014 is a more effective treatment method. [7] Despite the specific target being PSMA, BIND-014 has demonstrated an ability to attribute anti-tumor activity in a variety of tumor types.
Studies conducted investigating BIND-014’s efficacy in docetaxel delivery in mutated tumors further proved the Accurin’s increased chemotherapeutic ability. Mutated kirsten ras oncogene was the investigated mutation; KRAS mutations are established to have a poorer than normal response to chemotherapeutics. Docetaxel treatment is one of the therapeutics that often has a lessened efficacy on KRAS mutated tumors. One way through which KRAS mutated tumors function is macropinocytosis. When investigating treatment of mutated tumors with BIND-014 it was discovered that BIND-014 has increased affinity for cells that have high levels of macropinocytosis and markers of the process. Therefore, BIND-014 may possibly accumulate in KRAS mutated tumors and in doing so may supply anti-tumor activity for the mutated tumors that are otherwise difficult to treat. [9]
Though similar docetaxel treatments are associated with defects in the cardiovascular system, BIND-014 was free from association with any cardiac abnormalities. [10] Side effects that were observed include: fatigue, nausea, and diarrhea. [11] Other than the listed side effects, patients were found to exhibit tolerance for BIND-014 treatment with minimal safety concerns.
BIND-510[edit]
BIND-510 was an Accurin developed with the investigated application of treating prostate cancer. Similar to BIND-014, the nanoparticle’s target was prostate-specific membrane antigen (PSMA), though the Accurins differ in the delivered drug which was vincristine for BIND-510. Vincristine is a chemotherapy drug used to treat a variety of cancers and has an anti-mitotic function, meaning it prevents cancer cells from dividing and therefore stops cancer growth. [12]
Clinical trials evaluating BIND-510 supported its efficacy in comparison to free drug vincristine. In comparison to free dosage, BIND-510 was eight times more effective. Additionally, BIND-510 was associated with a decreased clearance, longer delay in tumor growth, a greater tolerability, and increased anti tumor behavior. [12] When toxicity was investigated BIND-510 also demonstrated a decreased toxicity. While vincristine often has neurotoxic effects involving peripheral sensory or motor neuropathies, BIND-510 delivery had no associated neurotoxicities. [13]
BIND-2206[edit]
BIND-2206 was another Accurin developed for the purpose of treating various cancer lines. Unlike previous Accurins, BIND-2206 targets the protein kinase AKT. Additionally, BIND-2206 delivered primarily MK-2206 and possibly AZD2811. AKT was targeted as it is one of the most active protein kinases in most cancers. [14] Overactivation of AKT is associated with uncontrollable cell growth. Unlike BIND-014 and BIND-510, BIND-2206 delivers drugs that have yet to be used in commonplace for cancer treatment.
MK-2206 and AZD2811 are AKT inhibitors that have yet to be approved for patient use. AKT, also known as protein kinase B, is an aurora kinase whose overexpression is strongly related to drug-resistant cancers that often have poor prognosis. [15] The drugs MK-2206 and AZD2811 function by inhibiting AKT signaling. However, free drug dosage of MK-2206 and AZD2811 appear to have high toxicity as mice trials involving the drugs resulted in death after three treatments. Therefore, since Accurins have previously demonstrated an ability to target agents with a reduced toxicity as compared to free drug dosage, BIND-2206 was hypothesized to reduce toxicity levels and increase the possible usage of AKT inhibitors as viable cancer treatments. [14]
Similarly to previous BIND molecules, clinical trials demonstrated a higher efficacy for drug delivery with BIND-2206 as opposed to free drug dosage. In freely delivered MK-2206 there was an associated 300% increase in blood glucose levels as opposed to no increase in BIND-2206 delivered. Furthermore, the drug demonstrated an increase in tumor exposure, longer inhibition duration, increased tolerability, and increased efficacy. The dose dependent toxicity levels associated with MK-2206 were not present with BIND-2206. [16]
Other Applications[edit]
As a targeted therapy, Accurin holds great prospects for the personalized cancer treatment’s future. Additionally, there lies a possibility for utilizing Accurins for treatments beyond cancer.
Personalized Medicine[edit]
Nanoparticle medicine enhances the possibilities for personalization as it allows for individualized prediction, treatment, and prevention of disease and disorder. As a nanoparticle treatment Accurins are no exception to this and are significant for the personalization of cancer treatment. Since the target and drug can be changed in Accurins the treatment can be personalized depending on the severity of the patient’s cancer and the type of cancer the patient suffers. Furthermore, it was discovered that certain patients may benefit more from Accurin treatment depending on their expression of the target molecule. For BIND-014 patients who expressed more PSMA experienced more benefits from treatment. This implies that analysis of patients’ expression of the target in disease would be a possible screening process for prediction of treatment efficacy. As a patient’s disease progresses biological profiling may be used to keep track of developments that may evaluate a patient’s response to Accurins. [11]
Anti-Infection[edit]
Though Accurins were developed with the intention of cancer treatment, there is a possibility for use in other therapeutic areas such as infection treatment. As bacteria gain multi-drug resistance the possibilities for therapeutic treatment decrease and the clinical use of colistin is increasing. Colistin is a strong antibiotic usually reserved as a last-resort effort due to high associated toxicity levels and associated nephrotoxicity, however as its usage rate increases a need for reducing this toxicity also increases. Accurin has been suggested as a possible solution for colistin delivery. Encapsulation of colistin in Accurin was studied and results showed a decrease in toxicity levels as no nephrotoxicity was discovered. Additionally, the efficacy remained high as colistin release rate was increased as well as bacterial elimination. [17]
Advantages and Limitations[edit]
Though Accurin treatments have many associated advantages related to their safety profiles and reduced toxicity of the delivered drug, no Accurins were ever made commercially available due to limitations in efficacy.
Advantages[edit]
As mentioned, Accurin treatment is advantageous due to the associated lowered risk with toxicity and drug clearance. Since Accurin uses an encapsulation technique, toxicity is reduced and slow-releasing Accurins especially are highly associated with better safety profiles. Furthermore, Accurins are able to avoid clearance from the immune system which allows for longer systemic circulation of the drug and thus an increased treatment efficacy. [18]
Limitations[edit]
There are associated limitations to Accurin usage that may possibly explain why Accurin therapeutics were never actually commercialized. While Accurin therapeutics demonstrated high efficacy rates in early studies, as the treatment progressed to Phase III clinical trials the success rate was measured at only 14%. [19]
References[edit]
- ↑ name=R2015>BIND Therapeutics Presents Positive Phase 2 Results Highlighting Potential of BIND-014 as Novel Anti-Cancer Treatment at Q3W Dosing Schedule for Patients with Non-small Cell Lung Cancer at 26th EORTC-NCI-AACR Annual Symposium[dead link]
- ↑ name=bw2015>BIND Presents Data Demonstrating Ability of Accurins to Improve Efficacy and Tolerability of Multiple Anti-Cancer Agents
- ↑ 3.0 3.1 3.2 “Bind Therapeutics, Inc. Form S-1 for Fiscal Year Ended August 12, 2013.” EDGAR. Securities and Change Commission, 2013, https://www.sec.gov/Archives/edgar/data/1385228/000119312513330904/d555506ds1.htm
- ↑ Cole J. Batty, Eric M. Bachelder, Kristy M. Ainslie, Historical Perspective of Clinical Nano and Microparticle Formulations for Delivery of Therapeutics, Trends in Molecular Medicine, Volume 27, Issue 6, 2021, Pages 516-519, ISSN 1471-4914, https://doi.org/10.1016/j.molmed.2021.04.002.
- ↑ Betancourt T, Byrne JD, Sunaryo N, Crowder SW, Kadapakkam M, Patel S, Casciato S, Brannon-Peppas L. PEGylation strategies for active targeting of PLA/PLGA nanoparticles. J Biomed Mater Res A. 2009 Oct;91(1):263-76. doi: 10.1002/jbm.a.32247. PMID: 18980197.
- ↑ 6.0 6.1 6.2 Morris, Kathryn. BIND Eligible to Receive Approximately $50 ... - Pfizer. https://cdn.pfizer.com/pfizercom/partnering/040313_bind_press_release.pdf.
- ↑ 7.0 7.1 Sechi, Mario, et al. “Targeted Therapy Using Nanotechnology: Focus on Cancer.” International Journal of Nanomedicine, 2014, p. 467., https://doi.org/10.2147/ijn.s36654.
- ↑ Anselmo, Aaron C., and Samir Mitragotri. “Nanoparticles in the Clinic.” Bioengineering & Translational Medicine, vol. 1, no. 1, 2016, pp. 10–29., https://doi.org/10.1002/btm2.10003.
- ↑ Cullis, Jane E., et al. “Abstract 3001: Accurins Are Endocytosed by Kras-Mutant Cells via Macropinocytosis.” Experimental and Molecular Therapeutics, 2016, https://doi.org/10.1158/1538-7445.am2016-3001.
- ↑ Summa, Jason, et al. “Abstract A161: Cardiovascular Safety Profile of Bind-014 (Docetaxel Nanoparticles for Injectable Suspension) Evaluated in Phase 1 and 2 Studies.” Therapeutic Agents: Other, 2015, https://doi.org/10.1158/1535-7163.targ-15-a161.
- ↑ 11.0 11.1 Autio, Karen A., et al. “Safety and Efficacy of BIND-014, a Docetaxel Nanoparticle Targeting Prostate-Specific Membrane Antigen for Patients with Metastatic Castration-Resistant Prostate Cancer.” JAMA Oncology, vol. 4, no. 10, 2018, p. 1344., https://doi.org/10.1001/jamaoncol.2018.2168.
- ↑ 12.0 12.1 Cadzow, Louise, et al. “Abstract c197: Accurins Improve the Pharmacokinetics, Pharmacodynamics, Tolerability and Anti-Tumor Activity of the AKT Inhibitor MK-2206.” Therapeutic Agents: Small Molecule Kinase Inhibitors, 2015, https://doi.org/10.1158/1535-7163.targ-15-c197.
- ↑ Shahin, Mostafa, et al. “Current Development in Vincristine Nanoformulations.” International Journal of Medicine in Developing Countries, 2020, pp. 1292–1300., https://doi.org/10.24911/ijmdc.51-1591859609.
- ↑ 14.0 14.1 Sangai, Takafumi, et al. “Biomarkers of Response to AKT Inhibitor MK-2206 in Breast Cancer.” Clinical Cancer Research, vol. 18, no. 20, 2012, pp. 5816–5828., https://doi.org/10.1158/1078-0432.ccr-12-1141.
- ↑ Tang, Anqun, et al. “Aurora Kinases: Novel Therapy Targets in Cancers.” Oncotarget, vol. 8, no. 14, 2017, pp. 23937–23954., https://doi.org/10.18632/oncotarget.14893.
- ↑ Cadzow, Louise, et al. “Abstract c197: Accurins Improve the Pharmacokinetics, Pharmacodynamics, Tolerability and Anti-Tumor Activity of the AKT Inhibitor MK-2206.” Therapeutic Agents: Small Molecule Kinase Inhibitors, 2015, https://doi.org/10.1158/1535-7163.targ-15-c197.
- ↑ “This Is the Peer Reviewed Version of ... - Researchgate.net.” ACCURIN® NANOPARTICLES IMPROVE THE THERAPEUTIC INDEX OF COLISTIN IN PRECLINICAL MODELS OF INFECTION, Daria Zaytseva-Zotova 1 , A. Zinchenko 1 , T. Levada 1 , D. Andreev 1 , Y. Shilov 1 , E. Safarova 1 , G. Troiano, https://www.researchgate.net/profile/Daria-Zaytseva-Zotova/publication/50305635_Polyelectrolyte_microcapsules_with_entrapped_multicellular_tumor_spheroids_as_a_novel_tool_to_study_the_effects_of_photodynamic_therapy/links/586ead8008ae8fce491c8da6/Polyelectrolyte-microcapsules-with-entrapped-multicellular-tumor-spheroids-as-a-novel-tool-to-study-the-effects-of-photodynamic-therapy.pdf.
- ↑ Cully, Megan. “Nanoparticles Improve Profile of Molecularly Targeted Cancer Drug.” Nature Reviews Drug Discovery, vol. 15, no. 4, 2016, pp. 231–231., https://doi.org/10.1038/nrd.2016.60.
- ↑ Salama, Lavinia, et al. “Emerging Nanopharmaceuticals and Nanonutraceuticals in Cancer Management.” Biomedicines, vol. 8, no. 9, 2020, p. 347., https://doi.org/10.3390/biomedicines8090347.
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