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Medicinal Chemistry
News & Analysis Highlighting the latest news and research in medicinal chemistry
Novel nanoparticles possess triple threat Researchers design nanosystems capable of carrying and releasing multiple therapeutic agents A team of scientists, from the Massachusetts Institute of Technology (MA, USA), has designed and synthesized a polymer nanoparticle (NP) capable of carrying precise molar ratios of three different anticancer drugs, doxorubicin, camptothecin and cisplatin. The researchers demonstrated that these NPs were more effective at killing ovarian cancer cells compared with nanoparticles carrying only one or two drugs. Jeremiah Johnson, senior author of the recent study detailing these findings, explained to Nanomedicine the rationale behind the work, “The application of this strategy to cancer drug delivery is a natural choice, because chemotherapeutics are typically administered as drug combinations in the clinic but there are relatively few exam-
ples of nanoparticles for combination drug delivery.” Johnson’s team used a new approach towards designing these triple-threat NPs, creating polymer building blocks that already included the drug. This approach overcame the limitations of previously explored strategies, such as encapsulation of a drug within a particle or attaching the drug to the particle’s surface. “They provide a new synthetic platform for rapidly and efficiently making nanoparticles with any desired combination and ratio of drugs. These combinations can then be screened for activity in various biological assays. The hope is that such a strategy can rapidly lead to new therapeutic formulations,” commented Johnson.
Cisplatin
Doxorubicin
Camptothecin Brush-first ROMP
Fast and simple nanoparticle synthesis, tunable size, precise drug ratios, synchronized release, biodegradable
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The combination of three drug-conjugated monomers that carry camptothecin, doxorubicin and cisplatin leads to a new platform for single-nanoparticle combination cancer therapy. Figure courtesy of Jeremiah Johnson (Massachusetts Institute of Technology [MA, USA]).
Future Med. Chem. (2014) 6(10), 1105–1107
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News & Views The research has now moved into animal models and the team are also working on particles that can carry four drugs. Johnson explained that the system will need further testing, “We need to very thor-
oughly understand the toxicity, pharmacokinetics, and biodistribution behavior of these new particles. The ultimate goal is to translate this technology to the clinic.”
– Written by Hannah Stanwix Source: Liao L, Liu J, Dreaden EC et al. A convergent synthetic platform for single-nanoparticle combination cancer therapy: ratiometric loading and controlled release of cisplatin, doxorubicin, and camptothecin. J. Am. Chem. Soc. 136(16), 5896–5899 (2014).
Expansion of manufacturing agreement Bristol-Myers Squibb (NY, USA) and SamsungBioLogics (Seoul, South Korea) have recently announced that they will expand their existing manufacturing agreement. Under the expansion, commercial drug substances and drug products for a selection of Bristol-Myers Squibb biologic medicines will be manufactured by Samsung at its manufacturing site based in Incheon, South Korea. Lou Schmukler, President of Global Manufacturing and Supply at Bristol-Myers Squibb commented on the expansion of their collaboration, “Biologic medicines that treat serious diseases are an integral part of Bristol-Myers Squibb’s specialty care portfolio and R&D pipeline. The expanded relationship with Samsung will increase our biologics manufacturing capability and give us the flexibility to respond to increased demand in order to meet the global needs of patients.”
TH Kim, President and Chief Executive Officer of Samsung BioLogics added, “Samsung is delighted to reach the second manufacturing agreement with Bristol-Myers Squibb and we look forward to delivering top quality GMP production. It represents another significant step for Samsung and Bristol-Myers Squibb in strengthening our biopharmaceutical manufacturing relationship.” This recent agreement will expand their collaboration further, with the companies first collaborating in July 2013 with a manufacturing agreement for the production of a single commercial antibody cancer drug substance. Samsung are currently building a second manufacturing facility in Incheon, which is expected to be completed in early 2015.
– Written by Lisa Parks Source: Bristol-Myers Squibb and Samsung BioLogics expand manufacturing agreement: http://news.bms.com/press-release/ bristol-myers-squibb-and-samsung-biologics-expand-manufacturing-agreement
CPhI report looks to a revolution in manufacturing A recent CPhIPharma Insights report on manufacturing demonstrated the need for improved global manufacturing efficiency to meet rising demands from emerging economies. The annual report provides perspectives from CPhI exhibitors and the wider industry, overall concluding that industry must drive these changes and not the regulators, as this will only increase costs. It was revealed in the report that 70% of industry executives interviewed said that they were actively investing in manufacturing techniques and technologies, and 59% were hiring more staff. Other findings included 41% outsourcing more of their manufacturing, and nearly 50% of the industry stated they introduced more than three products last year, with a further 41% adding one to three products to their portfolio.
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Chris Kilbee, Group Director of UBMPharma, commented, “With the majority of the industry now committed to process improvements and increased product quality the next few years will hopefully see more new manufacturing methods coming to market, with tighter process controls — these should ultimately reduce costs and increase profits for the industry.” The report found that the biggest manufacturing goals are to ‘increase efficiencies’ and ‘safety’. In the press release reporting the findings, it was stated, “CPhI believes we may be at the cusp of a revolution and if one major Pharma company starts reaping the benefits of implementing process perfection from initial development to commercialization others will follow.” Kilbee added, “The desire to modernize processes across the industry is clearly there and taking a longterm view we can see that the way we conduct devel-
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opment work right through to commercialization has the chance to revolutionize the business model. Patented products will be opened up to a wider number of the globe’s seven billion inhabitants, which is a real human goal, but also one that will see the indus-
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try become more sustainable and increase profits. I believe that with these commitments we see a situation where industry actively drives improvements and takes these new methods to the regulator cost savings and improved quality should go hand in hand.”
–Written by Lisa Parks Sources: Pharma manufacturing: analyzing pharma industry trends and techniques: www.cphi.com/documents/129623/1317492/ CPhI±Pharma±Insights±Report-±Manufacturing.pdf/2fe19c18--9641--4a60--9846--4fbb561cb8a6%20; CPhI report warns industry must actively drive process improvements itself to meet growing global demand: http://cphi-online.com/News/ Show/18316/CPhI_Report_Warns_Industry_Must_ Actively_Drive_Process_Improvemen_e2_80_8bts_itself_to_Meet_Growing_Global_Demand#.U2Nhh_Nwau4
Researchers elucidate the uptake mechanism of single-walled carbon nanotubes A team from Stanford University (CA, USA), in collaboration with the University of California (CA, USA), has provided an insight into the uptake mechanism of single-walled carbon nanotubes, which may be significant in achieving targeted drug delivery to tumor cells. It is generally assumed that nanoparticles accumulate in tumor cells via several targeting mechanisms, the primary route being extravasation. In this report the team demonstrates that, in addition to conventional nanoparticle-uptake mechanisms, single-walled carbon nanotubes are almost exclusively taken up by a single immune cell subset, Ly-6Chi monocytes (almost 100% uptake in Ly-6Chi monocytes, below 3% in all other circulating cells), and delivered to tumor cells in mice. The group, which was led by Sanjiv Sam Gambhir, a scientist at Stanford University, also found that when the targeting ligand (RGD) was conjugated to the nanotubes the number of single-walled carbon
nanotube-loaded monocytes reaching the tumor was significantly enhanced. Speaking to Nanomedicine, co-leader of the study, Bryan Ronain Smith, from Stanford University, commented: “The vast majority of work in this field relies upon the leakage of nanoparticles into the tumor bed for delivery, but our work shows that you can have specific cells actively transport nanoparticles into the tumor regardless of the nanoparticles’ ability to ‘leak’.” Smith envisages that this will be a considerable advantage when translating a nanoparticle to the clinic for diagnostic or therapeutic medicine. In terms of future work, Gambhir commented that the team now intends to “test other nanoparticles to see if they also are naturally delivered by specific cells into the tumor.” In addition, the group will study the use of specific cell types as delivery vehicles for one or more nanoparticle types by loading the cells ex vivo and injecting the cells into living subjects.
– Hannah Coaker Source: Smith, BR, Ghosn EEB, Rallapalli H et al. Selective uptake of single-walled carbon nanotubes by circulating monocytes for enhanced tumor delivery. Nat. Nanotechnol. doi:10.1038/nnano.2014.62. (2014) (Epub ahead of print).
The editorial team welcomes suggestions for timely, relevant items for inclusion in the news. If you have newsworthy information, please contact: Hannah Coaker, Commissioning Editor, Future Medicinal Chemistry E-mail:
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