Nanotechnology is the use of nanosized particles for medical applications that originated in the 1960s with the discovery of liposomes—lipids that self-assemble into nanoparticulate spheres when exposed to water.1

These spheres can encapsulate small molecule pharmaceuticals, including the chemotherapeutic agents doxorubicin (Doxil®) and paclitaxel (Abraxane®), which have been formulated into several marketed liposome-based nanopharmaceuticals. The technology is constantly evolving, with other nanopharmaceuticals in development; two drug candidates are also in the pipeline.   

“Nanotechnology is the next chapter in the fight against cancer, and it is an exciting chapter, especially relative to some of the other chapters that have not really delivered on their promise,” says Chris Guiffre, JD, MBA, Chief Business Officer, Cerulean Pharma, Cambridge, MA. Cerulean Pharma has a liposomal nanopharmaceutical, CRLX101, currently in development.  

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Nanotechnology in the Pipeline

In CRLX101, Cerulean’s phase 2 clinical candidate, the payload (or deliverable chemotherapeutic agent) is a compound called camptothecin, the original member of the camptothecin class—the same class that irinotecan and topotecan belong to—which has a notorious toxicity profile.2 In fact, the toxicity of this class of drugs was so significant that camptothecin was discontinued in development, while its two analogs—irinotecan and topotecan—were marketed due to their greater effectiveness compared to camptothecin.

During the development of nanopharmaceuticals, Cerulean Pharma recognizes the importance of nanoparticle size in their formulation. According to Guiffre, the nanoparticles should be larger than 10 to 15 nanometers (nm) in diameter so that they do not pass through the normal pores of the healthy vasculature, which are about 10 nm in diameter.

“If a nanoparticle is any smaller than that, you will lose the preferential targeting,” says Guiffre. “At the same time, you do not want them to be so large that they cannot take advantage of the leaky neovasulature of tumors, which contains pore sizes that are considerably larger than the healthy vasculature.” For CRLX101, the diameter is 20 to 30 nm, which is well suited to take advantage of the leaky vasculature. The leaky nature of tumor vasculature allows for the passage of nanoparticles into the tumor, and, consequently, delivery of the chemotherapeutic agent to tumor cells.

“Camptothecin is a good payload for our technology because we concentrate the drug inside the tumor cells and spare the healthy tissue, so targeting its delivery by way of a nanoparticle is the only way to avoid its high toxicity,” says Guiffre. “We have seen evidence that the technology is doing exactly what it is supposed to because our safety profile with CRLX101 is one of its strengths.” (See the box to the right for details on the delivery of CRLX101.)

Delivery of CRLX101

CRLX101’s payload is delivered in a three-step process.

Step 1: the nanoparticles stay intact in the bloodstream and circulate until they concentrate in tumors through the tumors’ leaky neovasculature.
Step 2: the nanoparticles are actually taken up into the tumor cells through a process called macropinocytosis.
Step 3: conjugation of camptothecin to the nanoparticle backbone using linkers allows for sustained release of the drug over an extended period of time.

The controlled release feature enables a sustained inhibition of the tumor target as opposed to a burst release followed by a rest period; the latter is more likely to breed resistance than the former. By using this slow release, the payload stays inside the tumor cells for at least 2 weeks after the dose, creating a much more durable inhibition.

The controlled release feature enables a sustained inhibition of the tumor target as opposed to a burst release followed by a rest period; the latter is more likely to breed resistance than the former. By using this slow release, the payload stays inside the tumor cells for at least 2 weeks after the dose, creating a much more durable inhibition.

The type of nanoparticle delivery used by CRLX101 targets topoisomerase 1 as well as a previously undruggable target known as hypoxia-inducible factor 1-alpha (HIF-1α). HIF-1α is a master regulator of tumor survival mechanisms that is upregulated under hypoxic conditions created by antiangiogenic drugs and by radiation.

“The perfect HIF-1α drugs have to create durable inhibition, not transient, and you get this by having sustained release of the payload over time,” says Guiffre.

CRLX101 achieves this type of inhibition. “So we can use our product in combination with an antiangiogenic agent such as bevacizumab to prevent the upregulation of HIF-1α that normally happens with these agents.”

CRLX101 is currently being investigated in four phase 2 trials, three of which are in monotherapy, and one of which is in combination therapy. In clinical trials, CRLX101 has had an excellent safety profile, with a maximum tolerated dose of 15 mg/m2.

“Right now, we have one combination trial going forward. That is a renal cell carcinoma trial where we are using our drug in combination with Avastin®,” says Guiffre. In this trial, Cerulean Pharma has observed results that principal investigators characterize as better than they would have expected with Avastin alone. As a result, Cerulean is planning to start two other combination trials at the end of this year, one in refractory ovarian cancer and the other in rectal cancer.

Antibody-based Nanopharmaceuticals

“We have been fighting cancer for over 100 years with limited success. We have made some great strides in some limited areas, but largely we are losing the fight,” says Guiffre. “I think the newest and most exciting chapter involves ‘smart bombs’ such as antibody-drug conjugates (Related Video: Antibody Drug Conjugates: TDM-1) and nanoparticles. All of them have the benefit of targeting potent payloads at the site of the tumor or in the tumor cells. And they do so while sparing the healthy tissue.”  

For Immune Pharmaceuticals (New York, NY), their brand of nanotechnology comes in the form of antibody-drug conjugates called nanoMabs.3 These nanoparticles have a structure of antibodies that are attached by linkers to the nanoparticle. The antibodies help to target the nanoparticle to a specific molecule based on the antibody. The molecular targets of nanoMabs include growth factor receptors, such as epidermal growth factor receptor (EGFR) or HER2-neu.

“These targets are commonly known because antibodies to them have been successful in clinical trials and are already commercialized…examples include cetuximab and panitumumab against EGFR and trastuzumab against HER2-neu,” says David Sidransky, MD, Vice Chair of Immune Pharmaceuticals and Director of the Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD. 

“Standard nanoparticles have probably been more successful because they just leach out of the vasculature in tumors, yielding higher concentrations of chemotherapeutic agent in the tumor microenvironment than you get systemically,” says Dr. Sidransky. In general, this feature leads to reduced toxicity and increased efficacy of the chemotherapeutic agent. “NanoMabs are going to be more specifically bound, so they should deliver more specificity and less toxicity.”

“You can load nanoparticles with almost anything, not just with single drugs but also with combos of drugs,” says Dr. Sidransky. “So the nanoparticle is quite a little soldier in the sense that it has a targeting mechanism; it has the ability to get out of the vasculature and attach specifically, and then deliver the chemotherapy inside it.” In pre-clinical studies, nanoMabs have resulted in tumor shrinkage and low toxicity in mouse models. There have been no clinical trials yet.

Areas being explored for nanoMabs include pancreatic cancer and breast cancer. Immune Pharmaceuticals is planning to create nanoMabs that contain gemcitabine plus docetaxel, a combination that has been successful in treating pancreatic cancer. “By putting these two drugs into the same particle, you will get better targeting, so that both drugs will have less toxicity and greater efficacy,” says Dr. Sidransky.


In summary, nanotechnology is at the leading edge of cancer drug delivery due to its emerging features of controlled release and antibody-driven specificity. While this type of drug delivery system may still be in its infancy, particularly since some of them haven’t been tested in clinical trials yet, there is definite promise for their use in effectively treating many cancers.


1. Bangham AD, Horne RW. Negative Staining of Phospholipids and Their Structural Modification by Surface-Active Agents As Observed in the Electron Microscope. J Mol Bio. 1964 May; 8:660–668.

2. Cerulean. CRLX101. Accessed at

3. Immune Pharmaceuticals. NanomAbs Platform. Accessed at