Big Moment for Nanotech: Oncology Therapeutics Poised for a Leap

This image depicts nanowire arrays synthesized by researchers at Emory/Georgia Tech Center of Cancer Nanotechnology Excellence. The arrays can be used for biosensing, manipulation of cells, and converting mechanical energy into electricity for powering nanodevices.

Illustration courtesy Z.L. Wang, PhD/ NCI Nanotechnology Image Library

Research Advances Are Flowing Along With Investments

The first proof of the cancer-fighting potential of nanotechnology in the United States came in 1995, when the FDA approved the use of an encapsulated liposome to deliver a more heart-friendly form of the chemotherapy doxorubicin.

Yet despite the relative triumphs of doxorubicin liposomal (Doxil), including a sharply lower risk of congestive heart failure in patients with breast cancer and $402 million in 2011 sales, problems ranging from adverse events to manufacturing difficulties have helped slow the development of anticancer therapeutics using nanotechnology.

Until now.

The translation of scientific advances in nanotechnology into cancer therapies, in vitro assays, and imaging tools is poised for takeoff, amid fresh excitement among investors and a mushrooming of findings from leading research institutions.

Key developments include the continuing expansion of the oncology uses for albumin-bound paclitaxel (Abraxane) since the FDA initially approved the drug in 2005 for the treatment of breast cancer after prior chemotherapy. Last October, the agent was approved as a first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC); it is now undergoing a priority review as a first-line treatment in combination with gemcitabine for patients with advanced pancreatic cancer.

Another nano-chemotherapy combination, a liposomal formulation of vincristine sulfate called Marqibo, won expedited FDA approval in August 2012 as a third-line treatment for patients with Philadelphia chromosome- negative acute lymphoblastic leukemia (Ph- ALL).

Meanwhile, Nippon Kayaku’s NK105, which delivers paclitaxel in a polymer micelle, has reached a phase III trial in metastatic or recurrent breast cancer (NCT01644890). American biotech companies have advanced other compounds to later-stage clinical trials. And, global pharmaceutical companies have signed deals that could bring more than $1 billion to a tiny Boston-area biotech that recently announced results from its first-ever phase I trial.

Table. Nanotherapeutics Approved for Oncological Applications

Category

Agent

Description

Tumor Type

Approval/ Status

Albumin

Abraxane (albumin-bound paclitaxel)

Microtubule inhibitor that is an albumin-bound form of paclitaxel with a mean particle size of about 130 nm

Metastatic breast cancer, locally advanced or metastatic non-small cell lung cancer

FDA approval in 2005

Liposomal

Doxil

(doxorubicin HCI liposome injection)

Doxorubicin hydrochloride encapsulated in liposomes

Recurrent ovarian cancer, AIDS-related Kaposi sarcoma, multiple myeloma

FDA approval in 1995; approved in Europe for metastatic breast cancer

DaunoXome

(liposomal daunorubicin)

An aqueous solution of the citrate salt of daunorubicin encapsulated within lipid vesicles

Advanced HIV-associated Kaposi sarcoma

FDA approval in 1996

Myocet

(liposomal doxorubicin)

Liposome-encapsulated doxorubicincitrate corresponding to 50-mg doxorubicin hydrochloride

Metastatic breast cancer

FDA fast track designation for HER2- positive metastatic breast cancer; approved in Europe and Canada

Mepact

(muramyl tripeptide phosphatidyl-ethanolamine)

Synthetic derivative of muramyl dipeptide in a liposomal formulation

Nonmetastatic, resectable osteosarcoma

Approved in Europe; phase III trials in United States

DepoCyt

(liposomal cytarabine)

Injectable suspension of the antimetabolite cytarabine, encapsulated into multivesicular lipid-based particles

Lymphomatous meningitis

FDA granted accelerated approval in 1999 and full approval in 2007

Marqibo

(liposomal vincristine sulfate)

Vinca alkaloid antimitotic, encapsulated in the aqueous core of sphingomyelin-based liposomes

Philadelphia chromosome-negative acute lymphoblastic leukemia

FDA approval in 2012

Polymeric

Genexol-PM

(Methoxy-PEG-poly[D, L-lactide] taxol)

Copolymer miceller nanoparticleentrapped formulation of paclitaxel

Metastatic breast cancer; pancreatic cancer

Approved in South Korea for breast cancer; phase II in the United States for pancreatic cancer

Oncaspar

(PEG--L-asparaginase)

L-asparaginase covalently conjugated to monomethoxypolyethylene glycol

Acute lymphoblastic leukemia

FDA approval in limited setting in 1994, expanded to first line in 2006

Zinostatin stimalamer

(styrene maleic anhydrideneocarzinostatin)

Conjugate protein or copolymer of styrene-maleic acid (SMA) and an antitumor protein neocarzinostatin (NCS)^a

Primary unresectable hepatocellular carcinoma

Approved agent in Japan since 1994

Neulasta

(pegfilgrastim)

Covalent conjugate of recombinant methionyl human G-CSF (filgrastim) and monomethoxypolyethylene glycol

Reduce the risk of infection in patients with nonmyeloid malignancies receiving myelosuppressive anticancer therapy associated with febrile neutropenia

FDA approval in 2002

Hyperthermia

NanoTherm

(superparamagnetic iron oxide nanoparticles)

Nanoparticle-drug conjugates inside tumor heated selectively by a magnetic field, resulting in temperature-dependent release of drug

Local ablation in glioblastoma multiforme; prostate and pancreatic cancers

Marketing approval in Europe for glioblastoma; phase I/II trials in other tumor types

^aIshii H, et al. Jpn J Clin Oncol. 2003;33(11):570-573.

Sources: NCI Alliance for Nanotechnology in Cancer list of oncologic nanotherapeutics, including approval status; descriptions from NCI Drug Dictionary, company websites, and label information for individual agents.

Building “Delivery Vehicles”

Although scientific interest in nanotechnology in oncology is in part an outgrowth of the century-old search for the “magic bullet” to employ against cancers, the field began to develop after Richard P. Feynman, PhD, a physicist at the California Institute of Technology (CalTech), discussed “the problem of manipulating and controlling things on a small scale” in a now classic 1959 speech. Feynman, who went on to win a Nobel Prize, asked the question: “Why cannot we write the entire 24 volumes of the Encyclopaedia Brittanica on the head of a pin?”

As researchers have sought to answer such questions in designing cancer therapeutics, the complexity of developing what some call biotargeted nanomedicines has emerged. In 2004, the National Cancer Institute (NCI) launched the Alliance for Nanotechnology in Cancer, a network of research centers focused on investigating and translating discoveries (nano.cancer.gov).

Piotr Grodzinski, PhD

Investigations currently under way include development of a bio-barcode assay to improve upon the sensitivity of the prostate-specific antigen to monitor disease relapse in patients with prostate cancer, a PET imaging agent to help monitor immunosuppressive therapies, and gold nanoshells for use in thermal ablation of tumors.

“Nanotechnology does not allow us to alter the shape, size, or any other characteristics of the actual drug molecules,” said Piotr Grodzinski, PhD, director of the NCI’s Office of Cancer Nanotechnology Research, in an interview. “It allows us to build tiny delivery vehicles that operate inside the body, guiding medication away from healthy cells, helping them reach their targets and, often, controlling the timing of their release.”

The term nanotechnology applies to any designed and manufactured object that measures 1 nm-100 nm. To put that in perspective with an analogy devised by CalTech Professor Mark E. Davis, PhD, a sphere with a diameter of 1 nm—or 1 billionth of a meter— is to a soccer ball as the soccer ball is to the Earth.

Mark E. Davis, PhD

The nanoparticles now used to deliver anticancer medications generally measure 30 nm-100 nm, which sounds tiny but is not. A 100-nm particle dwarfs a chemotherapy molecule to the degree that the Goodyear Blimp dwarfs that soccer ball, so there’s plenty of room inside it, both for medication and for other chemical compounds designed to target tumors.

Impact on Outcomes

Without such nanoparticles to guide them, all anticancer medications waste therapeutic potential and inflict adverse events by attacking healthy cells as well as tumors. Chemotherapies, tiny and utterly untargeted, stray the most, leaking from all blood vessels and assaulting everything from toenails to hair roots, but even so-called targeted therapies misfire to some degree.Nanoparticle carriers cannot eliminate drug delivery problems, but certain medications have demonstrated the ability to improve outcomes.

Doxil encapsulates tiny doxorubicin molecules in 100-nm lipid bubbles that are, in turn, coated with polyethylene glycol (PEG) to prevent attacks from white blood cells. Bubbles of Doxil are too big to escape coronary blood vessels but small enough to escape the hastily built (and very leaky) blood vessels in many tumors.

Trials comparing Doxil with older chemotherapy agents have generally found that the pegylated liposomal formulation reduces many adverse events. The FDA has approved the drug for patients with ovarian cancer that has progressed or recurred after platinum-based therapy, for the treatment of patients with multiple myeloma in combination with bortezomib, and in AIDS-related Kaposi sarcoma after failure or intolerance to prior chemotherapy. In Europe, the formulation also is approved as monotherapy for metastatic breast cancer.

Lao et al found that liposomal anthracyclines, including pegylated liposomal doxorubicin and liposomeencapsulated doxorubicin citrate (Myocet), were as effective and less toxic when compared with conventional anthracyclines in breast cancer. The combined analysis of five clinical trials indicated an overall reduction in risk in cardiotoxicity (response rate [RR]= 0.38; P <.0001) and in clinical heart failure (RR = 0.20; P = .02).

Such results have not been enough to win Doxil as many indications as doxorubicin, however, because Doxil has not cleared the additional hurdle of outperforming its parent drug, in part because of dosage caps necessitated by Doxil’s tendency to cause hand-foot syndrome.

Marqibo, a lipid-encased variant of vincristine, shields healthy cells enough for doses of 2.25 mg/m² vs 1.4 mg/m² for conventional vincristine—and no dosage caps. In addition to providing patients up to three times the medication per use, the higher doses can increase cumulative vincristine exposure 10-fold.

In some cases, the higher dosage allowed by the lipids appears effective. The FDA’s expedited approval of Marqibo for treatment of recurring Ph(-) ALL came after 10 of 65 trial patients experienced a median remission of 28 days. (Even with the nanoparticle carrier, though, the vincristine doses take their toll. Some 76% of test subjects suffered serious adverse events that ranged from fever to heart attack.)

In other cases, however, higher doses aren’t enough. In 2005, the FDA Oncologic Drugs Advisory Committee, citing poor response rate and duration, recommended against approving liposomal vincristine sulfate as a third-line treatment of aggressive non- Hodgkin’s lymphoma (NHL).

Other first-generation liposomal nanomedicines suffer the same problem: They steer medication away from healthy cells enough to reduce side effects, but they often don’t outperform existing formulations enough to win approvals.

Lipids also suffer other shortcomings. Engineers cannot manipulate their shape, attach molecules to their exterior, or control when they release their payloads. Manufacturing is also tricky.

Image courtesy of Victor Segura Ibarra and Rita Serda, PhD

Image courtesy of Tayyaba Hasan, PhD, Prakash Rai, PhD, Ramtin Rahmanzadeh, PhD, and Conor Evans, PhD

Image courtesy of James R. Heath, PhD, Leroy Hood, MD, PhD, and Michael Phelps, PhD

Images from the NCI Alliance for Nanotechnology in Cancer capture some of the groundbreaking research unfolding at affiliated centers. The left image shows particle-based vaccines using dendritic cells (colored green) that researchers at the Texas Center for Cancer Nanomedicine are exploring. In the center image, researchers at the Wellman Center for Photomedicine, Massachusetts General Hospital-Harvard Cancer Nanotechnology Platform Partnership are creating photoactivatable nanoparticles to detect and treat cancer simultaneously. The Ki-67 protein present in the nucleoli (yellow) is stained pink by a targeting antibody encapsulated in nanoparticles and conjugated to a fluorescent dye. The right image depicts a DNA-encoded barcode assay for serum and tissue-based biomarkers being developed at the Nanosystems Biology Cancer Center at CalTech.

New Nanoparticles Emerge

Such problems have led researchers to other types of nanoparticles.

For example, Abraxane combines the chemotherapy paclitaxel with 130 nm human serum albumin molecules to achieve two benefits. First, the albumin molecules do not bind with one another, which eliminates the risk of capillary obstruction and, thus, the need for infusion systems or steroid-antihistamine premedication. Second, the albumin replaces the toxic solvent used to combat the hydrophobia of standard paclitaxel and, thus, allows higher doses.

Abraxane, (formerly called nab-paclitaxel), was approved as treatment of locally advanced or metastatic NSCLC in combination with carboplatin after a phase III trial that found the drug outperformed paclitaxel, with an overall response rate (ORR) among clinical trial participants of 33% vs 25%, respectively. Notably, the ORR was higher for Abraxane than paclitaxel among subgroups of patients with squamous cell carcinoma (41% vs 24%) and large cell carcinoma (33% vs 15%). The most common adverse reactions (≥20%) reported were anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue.

Another phase III trial of 861 patients with metastatic pancreatic cancer found that adding Abraxane to the chemotherapy gemcitabine increased the median overall survival time to 8.5 months compared with 6.7 months for gemcitabine alone, according to data presented at the 2013 Gastrointestinal Cancers Symposium. Celgene Corporation, which is developing the drug, said Abraxane improved progression-free survival over dacarbazine in chemotherapy-naïve patients with metastatic melanoma during a phase III study; further details have not been announced. It also is being evaluated in bladder and ovarian cancers.

Abraxane is unusual among postlipid nanoparticle medicines, with its 130-nm human serum albumin (which acts as a solubilizer rather than carrying the chemo inside itself). Newer products in human trials use some form of polymer, allowing engineers to target cancer with more than just size alone.

Porous silicon-based particle wafers, shown in this false-colored scanning electron micrograph, are loaded with antigens in nanovaccines under study at The Methodist Hospital Research Institute in Houston, Texas.

Image courtesy of Ismail Meraz, PhD, Jianhua Gu, PhD, and Rita Serda, PhD

CRLX101, from Cerulean Pharma Inc. of Cambridge, Massachusetts, uses a pH-sensitive cyclodextrin-based polymer nanocarrier that slowly releases medication when it enters acidic places, like cancer cells. This timing mechanism, plus a 30 nm size that is still too large to escape normal blood vessels, shields healthy cells enough for CRLX101 to use camptothecin, a chemotherapy too potent for regular use.

Early trial results were promising. In a phase I/ IIa study, 21 heavily pretreated patients with NSCLC achieved a median PFS of 4.4 months, about 50% more than current standards would likely provide, according to data presented in a poster at the 2011 AACR-NCI-EORTC International Conference in San Francisco.

So Cerulean ran an aggressive phase II trial that compared best supportive care with best supportive care plus CRLX101 in 157 patients with once- or twice-treated NSCLC. Cerulean’s drug reduced tumor size and showed other activity, but despite its unusually potent chemotherapy and its sophisticated targeting and timing mechanisms, CRLX101 showed no survival benefit against pretreated NSCLC, the company said.

Elsewhere, CRLX101 is being studied in combination with bevacizumab (Avastin) as a treatment for renal cell carcinoma and as a monotherapy in ovarian cancer, gastric cancer, and small cell lung cancer.

Small Biotech Attracts Interest

“The CRLX101 combination with Avastin trial is particularly interesting because it is the first that uses the toxicity-reducing properties of nanoparticles to try a drug combination,” said Davis, the CalTech professor and the inventor of CRLX101. “This trial will probably be the first of many, though, because there are many theoretically complementary drugs we’ve never been able to combine at desired dosages due to additive toxicities, before the use of nanoparticles.”Another nanomedicine that has inspired much excitement is BIND-014, the lead candidate from another Cambridge-based company, Bind Therapeutics Inc.

Each 100-nm sphere of BIND-014 contains a payload of the chemotherapy docetaxel inside a polymer nanoparticle that controls the timing and speed of drug release and holds two things on its surface: enough PEG to elude the immune system and ligands that bind readily with the prostate-specific membrane antigen that is overexpressed on both the surface of prostate cancer cells and the abnormal vasculature of most solid tumors.

In April, Bind announced the results of the first phase I trial of its lead compound at the American Association for Cancer Research 2013 Annual Meeting in Washington, DC. BIND-014 was shown to be generally safe and well tolerated by 28 heavily pretreated patients with advanced or metastatic solid tumors. It also showed signs of antitumor activity: one complete response, three partial responses, and five patients with stable disease lasting at least four cycles ( >12 wk).

Greg Berk, MD

Even with so little data to show, Bind has signed three huge deals this year. In January, Amgen Inc said it would pay as much as $180.5 million to use Bind’s technology in cancer drugs. In April, AstraZeneca committed up to $199 million to use Bind-built nanoparticles to deliver a new, targeted kinase inhibitor. That same month, Pfizer Inc signed a multidrug development deal that would bring Bind $50 million up front and, potentially, more than $160 million in milestone payments and tiered royalties on each commercialized drug.

This torrent of investment reflects the belief that Bind has developed the world’s first process that can, with relative speed and economy, develop an easily manufactured nanoparticle carrier that goes where directed.

“Our technology can be programmed to target virtually anything, and the particles it produces all assemble themselves the exact same way every time,” said Greg Berk, MD, Bind’s chief medical officer, speaking of a platform originally developed at the Massachusetts Institute of Technology and Harvard Medical School.

Delivering Results

The big question, of course, is whether the nanotechnology that has already made it from university labs to clinical trials is effective enough to improve care significantly.

Only additional clinical trials will provide proof, but some observers see reason for skepticism.

Ennio Tasciotti, PhD

“Long term, I believe nanoparticles will make revolutionary improvements in medicine, but the science is moving so fast that the 15-year-old technologies we are currently using in the clinical setting are obsolete,” said Ennio Tasciotti, PhD, cochair of The Department of Nanomedicine at The Methodist Hospital Research Institute, in Houston, where investigators recently published papers arguing that particles for nanomedicines should be disc-shaped.

“For example, all the spherical nanoparticles in trials don’t circulate in the blood flow and bind to targets as well as shapes we can now make in the lab,” said Tasciotti. “Also, we now know how to make coatings that are far better than PEG, but they’re pushing ahead with PEG because they don’t want to start over with better coatings,”

“And these shortcomings are showing up in the trial results already,” he added. “The nanoparticles are not beating the status quo as much as you’d expect if they were targeting very effectively—and often they’re no better than chemotherapies from the 1960s.”

Others say there are far too little trial data for any firm conclusions yet and that the best available gauge— best, yet still highly imperfect&mdash;of the technology’s potential and its maturity is investment. BCC Research, has forecast that the global market for anticancer nanomedicine products will grow from $5.5 billion in 2011 to $12.7 billion by 2016.

The NCI’s Grodzinski said that the $120 million to $150 million that his organization spends annually on research is just the tip of the iceberg. “Add in research dollars from other nations, research universities, private grants, and business. I don’t know what it comes to, but many billions of dollars, certainly. All that obviously doesn’t guarantee success, but it does show that a lot of smart people think it worthwhile to maintain the investment and improve the technology while we gather trial data.”

Key Research

• Abraxane [prescribing information]. Summit, NJ: Celgene Corporation; 2012.
• Bourzac K. Carrying drugs. Nature. 2012;491:S58-S60. doi:10.1038/491S58a.
• Form 10-K annual report. Johnson & Johnson website. http://www.investor.jnj.com/governance/sec-filings.cfm?DocType=Annual&Year=. Filed February 22, 2013. Accessed June 8, 2013.
• Lao J, Madani J, Puértolas, et al. Liposomal doxorubicin in the treatment of breast cancer patients: a review [published online ahead of print March 26, 2013]. J Drug Delv. 2013;456409. doi: 10.1155/2013/456409.
• Marqibo: a novel, targeted, nanoparticle-encapsulated, anti-cancer compound for hematologic cancers. Talon Therapeutics website. http://www.talontx.com/pipeline.php?divid=marqibo. Accessed June 9, 2013.
• Miele E, Spinelli GP, Miele E, et al. Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer [published online ahead of print April 20, 2009]. Int J Nanomedicine. 2009;4:99-105.
• Monsky WL, Vien DS, Link DP. Nanotechnology development and utilization: a primer for diagnostic and interventional radiologists. Radiographics. 2011;31(5):1449-1462.
• Von Hoff DD, Ervin TJ, Arena FP, et al. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). J Clin Oncol. 2012;(suppl 34; abstr LBA 148).