Much has been made of the promise of nanoscale anticancer drugs for improved targeting and penetration of tumors, circumvention of their drug-resistance mechanisms, and the potential to reduce toxic side effects. Thanks to the reduced toxicities from nanopharmaceutical formulations, newly widespread adoption of old anticancer agents may be possible.

A nanometer is 1-billionth of a meter (10-9) and nanoparticles are smaller than 100 nm in diameter.1 Nanopharmaceutical agents tend to be between 10 and 100 nm in diameter, because particles smaller than that are filtered from the blood into the kidneys and excreted.2 At this scale, particles’ interactions with cell membranes and other molecules are distinct from those seen among larger particles, thus opening the door to development of new diagnostic and therapeutic applications for the war on cancer.

Importantly, nanoscale formulations might also allow the resurrection of long-abandoned anticancer agents that have previously been found, in their non-nanoscale formulations, to be unacceptably toxic to patients. One such example of “putting old wine in new bottles”3 is the nanopharmaceutical formulation of camptothecin, an analog of topotecan and irinotecan. Early clinical development of this highly cytotoxic topoisomerase-1 inhibitor and hypoxia-inducible factor 1 alpha (HIF-1α)-inhibiting agent was discontinued after its discovery in the mid-1960s, because of a high incidence of hemorrhagic cystitis, severe bone marrow suppression, and bladder cell toxicity among participants in clinical trials.4

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But now, an investigational anticancer nanopharmaceutical, CRLX101—which carries a payload of camptothecin—has shown encouraging safety, pharmacokinetic, and efficacy profiles in a clinical phase 1/2a trial, and is now undergoing phase 2 clinical study among patients with multiple tumor types.4

CRLX101 is 30 to 40 nm in diameter.4 That size makes it small enough to pass through tumors’ neovasculature, which has larger pores and enhanced permeability compared with normal blood vessels.4 The camptothecin in CRLX101 is conjugated to cyclodextrin-containing polymer; it concentrates differentially in tumor cells, where it releases its camptothecin payload.4

Nanoscale liposomal vincristine sulfate also exhibits promising efficacy and tolerability, particularly in Ph-negative acute lymphoblastic leukemia (ALL), “demonstrating that 50 years after the first clinical investigations, there is still plenty of room for significant improvement at the bedside through the development of innovative drug-loaded systems.”3

Familiar nano-oncology agents include liposome-formulation doxorubicin (Doxil®), which has been approved for treating ovarian cancer and multiple myeloma, and nab-paclitaxel (Abraxane®), approved for breast cancer, non-small cell lung cancer, and metastatic pancreatic cancer.2,5-7 Recently, nab-paclitaxel was spotlighted as a promising therapy for metastatic breast cancer; it is associated with superior overall response rates and longer progression-free and overall survival times.8

Other approved cancer nanopharmaceuticals include liposomal daunorubicin (DaunoXome®) for HIV-related Kaposi sarcoma, liposomal cytarabine (DepoCyt®) for intrathecal lymphomatous meningitis, and anti-ALL agents liposomal vincristine sulphate (Marqibo®) and polymeric PEG-L-asparaginase (Oncaspar®).9

More than 150 other diagnostic and therapeutic anticancer nanopharmaceuticals are also under development, though few have yet reached clinical evaluation.7

Although most approved and investigational anticancer nanopharmaceuticals self-assemble into relatively simple lipid- or polymer-encapsulated or bound nanoparticles, as doxorubicin and CRLX101 do, others under development represent more complex nanobiotechnologies.

“Nanoparticles are being used to deliver increasingly sophisticated cargoes including small molecules, nucleic acids, peptides, proteins, and combinations of these molecules to cancer cells in vitro and in vivo,” according to Jonathan S. Rink, MD and colleagues of the Feinberg School of Medicine at Northwestern University, in Chicago, IL.2