Nanomedicines in clinical evaluation
A number of nanoparticle-based formulations are in clinical development as potential treatments for cancer. NanoCarrier's
nanoplatin (NC-6004), which consists of cisplatin incorporated into micellar nanoparticles composed of polyethylene glycol
(PEG) and polyglutamic acid block copolymers, is undergoing Phase II evaluation in patients with advanced or metastatic pancreatic
cancer (12). Preclinical results showed that nanoplatin accumulated in cancer cells and had significantly lower nephro-toxicity
and neurotoxicity (13). In a Phase I study conducted in the UK, the formulation was well tolerated in patients with solid
tumors, providing sustained and prolonged release with minimal nephrotoxicity and no significant myelosuppression, ototoxicity,
emesis, or neurotoxicity (14).
Cerulean's CRLX101 consists of the topoisomerase-1 inhibitor, campto-thecin, covalently conjugated to a PEG-β-cyclodextrin
copolymer that self assembles into nanoparticles of approximately 30 nm in diameter (15). Unlike camptothecin, these nanoparticles
have a long circulation half-life, enabling them to accumulate in the tumors. Following uptake of CRLX101 into tumor cells,
the active camptothecin is gradually released from the nanoparticles, providing a sustained concentration of the drug in tumors.
It has been observed that this sustained concentration of camptothecin at the tumor site results in the inhibition of HIF-1
alpha, a hypoxia-induced transcription factor known to regulate cancer cell survival, metastasis and drug resistance. Studies
have demonstrated that CRLX101 nanoparticles augment camptothecin efficacy by facilitating localization and retention at the
target tissue, increasing intracellular drug deposition, providing a sustained supply of active camptothecin, and prolonging
drug activity at the target site (16). CRLX101 is in Phase II evaluation for the treatment of various tumor types (15).
Nippon Kayaku's NK105, a nanoparticle-based formulation of paclitaxel incorporated into block copolymers of PEG-polyaspartate,
was developed to enhance the antitumor activity of paclitaxel while reducing adverse effects such as neurotoxicity, myelosuppression,
and allergic reactions (17). NK105 is currently in Phase III development and studies are being conducted to investigate if
NK105 can improve progression-free survival in patients with metastatic or recurrent breast cancer.
Other examples of molecular-targeted nanoparticle-based cancer therapeutics in clinical development include BIND Biosciences'
BIND-014 (Phase I), Calando's CALAA-01 (Phase I), Mebiopharm's MBP-426 (Phase I/II), and SynerGene's SGT53-01 (Phase I).
Pharmaceutical Technology spoke to Robert Langer, professor at the Massachusetts Institute of Technology (MIT) and founder of BIND Biosciences; Stephen
Zale, vice-president of development at BIND Biosciences; and Yanli Zhao, assistant professor and national research foundation
fellow at Nanyang Technological University (NTU), Singapore, about engineering nanoparticles with optimal properties for use
as cancer therapies.