Nanoparticles: Facilitating Targeted Drug Delivery in Cancer Therapy

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-03-02-2013, Volume 37, Issue 3

Engineering nanoparticles with optimal properties for use in cancer therapies.

PharmTech spoke to Robert Langer, professor at the Massachusetts Institute of Technology 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, Singapore, about engineering nanoparticles with optimal properties for use in cancer therapies.

Nanoparticles have significantly changed the scientific landscape of disease treatment, prevention, and diagnosis, generating a new wave of nanoscale drug-delivery strategies. From solubility/bioavailability enhancement (1, 2) and targeted drug delivery (3, 4) to controlled/sustained release (5, 6) and protection of labile molecules (e.g., proteins, peptides, and DNA) from enzymatic degradation (7, 8), these structures can be manufactured, controlled, and manipulated to take on novel properties and functions that have opened new doors in the biomedical arena.

Sciepro/Science Photo Library/Getty Images

While nanoparticles may vary in size ranging from 10 nm to 1000 nm, nanomedicines are typically less than 200 nm (9). Nanoparticles made from natural or synthetic polymers have gained popularity because of their stability and ease of surface modification. They can be engineered to achieve controlled drug release as well as specific localization at disease sites by modification of the polymer characteristics and surface chemistry. For example, it has been well established that nanoparticles accumulate preferentially at tumor and inflammatory sites due to the enhanced permeability and retention effect (EPR) of the vasculature (9–11). At the target site, the biodegrable polymeric nanoparticles can act as a local drug depot that provides continuous release of the encapsulated therapeutic agent.

These advantages offered by nano-particles for targeted drug delivery are a result of their small size and the use of biodegradable materials. The small size enables the nanoparticles to overcome biological barriers (e.g., gastro-intestinal epithelium, tumor vasculatures, and endothelium of inflammatory sites) and achieve cellular uptake while the use of biodegradable materials allows for sustained drug release at the target site (9–11).

Advances in the development of nanoparticles have seen these systems being translated into clinically useful medicines, particularly in the treatment of cancer. Examples of nanoparticle-based medicines approved by FDA and EMA as cancer therapies include Doxil and Myocet (liposomal formulations of doxorubicin), DepoCyt (liposomal cytarabine), Dauno-Xome (liposomal daunorubicin), Abraxane (an albumin-bound formulation of paclitaxel), and Genexol-PM (a polymeric-micelle formulation of paclitaxel).

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.

Building in optimal properties


PharmTech: What are the key considerations when designing nanoparticles for the delivery of cancer therapeutics? How do you engineer these nanoparticles to achieve targeted delivery?

Zale (BIND Biosciences): This is a complicated question because the effects of many characteristics on how nanoparticles behave in the human body are interdependent on one another. Broadly speaking though, for nanoparticles to be effective, they must be able to circulate in the bloodstream, extravasate into diseased tissues, and release their therapeutic payload at a rate that provides high concentrations at the target site.

We use particles based on copolymers of polylactic acid (PLA) or copolylactic/glycolic acid (PLGA) and PEG, and attach targeting ligands to the end of the PEG chain. We have developed a particle-manufacturing process that encapsulates the drug payload in the PLA/PLGA core of the particle and orients the PEG and the targeting ligand toward the surface of the particle. PEG gives the particle a water-like corona, which disguises the particle from the systems in the body that would otherwise remove them from the bloodstream within minutes after administration. As a result, our nanoparticles display circulation half-lives of nearly 24 hours and are able to concentrate drugs in tumors at levels typically 10 times greater than when the same dose is given as a solution.

Langer (MIT and BIND Biosciences): We have used a broad range of targeting ligands, including antibodies, antibody fragments, aptamers, peptides, and small molecules. We have studied a range of targets including, for example, well-established and clinically validated tumor targets such as the prostate-specific membrane antigen (PSMA) and human epidermal growth factor receptor 2 (HER2), and have discovered our own targets and ligands in areas such as cardiovascular disease. At BIND, rapid clinical translation is important, and therefore, the focus is on validated targets in areas of unmet clinical need such as cancer, and primarily using peptide and small-molecule ligands for targeting.

There are many antigens or receptors expressed by cancer cells or the surrounding tissue that can be targeted by peptide and small-molecule ligands, which are inherently more stable and less complex than macromolecular ligands such as antibodies and aptamers. For examle, while our initial studies employed an aptamer that targets PSMA, BIND switched to a PSMA-binding small molecule in BIND-014, which enabled them to quickly move into clinical development with a simple, pharmaceutically stable, and well-characterized targeted particle. This PSMA-targeted particle can be manufactured reproducibly at large scale and has been shown to be nontoxic in animal studies.

Zhao (NTU): Nanoparticles tend to aggregate as a result of their large surface-to-volume ratio in biological media. When nanoparticles agglo-merate, they not only lose their intended functionality, but are quickly recognized and effectively removed by the mononuclear phagocytic cells in the reticuloendothelial system (RES) of the liver and spleen. This sequestration is often increased by the surface coating of nanoparticles with a corona of proteins that leads to opsonization and enhanced phagocytosis by the RES.

A strategy to maintain good dispersion of drug-loaded nanoparticles in biological media is by surface modifications with PEG polymers. PEG has been known to prevent protein adsorption (opsonization) on the nanoparticle surfaces, enhance circulation time, reduce nonspecific RES uptake, and facilitate preferential accumulation at tumor sites through the EPR effect. Passive targeting in itself, however, is often not enough to eradicate the side effects of cytotoxic drugs and divert the anticancer therapy away from healthy cells to selectively target cancer cells.

To further enhance the targeting ability of drug-loaded nanoparticles, these systems must also be coupled with targeting agents that can actively bind to over-expressed antigens or receptors on the surface of cancer cells. Drug-loaded nanoparticles can be engineered to recognize and bind to cancer cells through ligand-receptor interactions and the bound nanoparticles are internalized before the loaded drug is released inside the cells. Finally, there is another concern that these drug-delivery systems should release the loaded drug rapidly upon accumulating at tumor sites and after being taken up by cancer cells.

Designing nanoparticles for selective targeting

PharmTech: Could you describe your research on nanoparticles as targeted drug delivery systems in the treatment of cancer?

Langer (MIT and BIND Biosciences): The idea of employing targeted nanoparticles to bring cancer drugs to the site of disease and increase their safety and effectiveness has been around for several decades, but until recently the solution has been elusive. A major obstacle has been the inability to achieve the optimal interplay of particle characteristics that confer targeting of diseased cells, evasion of particle clearance mechanisms, and controlled release of the encapsulated drug payload.

In the mid 2000s, Omid Farokhzad at Harvard Medical School and I developed a new approach for targeting of drug-loaded polymeric nanoparticles to disease sites, including cancer cells and diseased vasculature. The technology is based on a novel self-assembly process which allows formation of nanoparticle libraries consisting of hundreds or even thousands of distinct nanoparticle formulations. We developed methods to screen these particles to identify the ones with the optimal properties for diseased-tissue targeting and avoidance of off-target tissues. Importantly, the particles we developed are composed of biocompatible and biodegradable polymers that are commonly used in other pharmaceutical products such as biodegradable microspheres and PEGylated proteins.

Zale (BIND Biosciences): BIND is now using this platform to develop targeted nanoparticles called Accurins to treat cancer and other diseases. The company has set about developing Accurins for clinical evaluation. The most advanced of these nanoparticles is BIND-014, an Accurin targeted to a cell-surface receptor expressed in all major solid tumor types. BIND-014 contains the chemotherapeutic agent docetaxel, which is a blockbuster drug in its own right, with approvals in five solid tumor indications, including breast, lung, and prostate. BIND-014 has just completed a Phase I clinical trial and is advancing into Phase II. The early results for BIND-014 are very promising. We have seen that the drug behaves very differently from conventional docetaxel, including showing signs of activity at relatively low doses and in tumors where docetaxel is not normally used.

Zhao (NTU): Our multifunctional meso-porous silica nanoparticles for cancer-targeted and controlled drug delivery have three components—the mesoporous silica nanoparticle core, the amino-β-cyclodextrin, the PEG polymers functionalized with an adamantane (Ad) unit at one end and a folate (FA) unit at the other end (Ad-PEG-FA) (18). The surface of mesoporous silica nanoparticles is firstly functionalized with amino-β-cyclodextrin rings bridged by cleavable disulfide bonds, blocking drugs inside the mesopores of the nanoparticles. The Ad-PEG-FA polymers are immobilized onto the nanoparticle surface through strong -cyclodextrin/adamantane complexation. The multifunctional nanoparticles can be efficiently trapped by folate-receptor-rich cancer cells through receptor-mediated endocytosis, where they then rapidly release the loaded anticancer drug inside the cell when triggered by the acidic pH and intracellular glutathione.

Several functions are built onto the multifunctional nanoparticles to deliver drugs in an optimal fashion. These functions include:

  • PEGylated coating on the nanoparticle surface to enhance long-term stability of the nanoparticles under physiological conditions

  • Active cancer targeting by the folate ligands attached onto the nanoparticle surface

  • pH-triggered drug release to allow drug released within acidic intracellular compartments such as endosome and lysosome (pH 5.0–5.5)

  • Positively charged nanoparticle surface under acidic conditions to facilitate the transfer of the nanoparticles from endosome to cytoplasm

  • Glutathione-induced cleavage of the disulfide bonds to further enhance the drug release in the cytoplasm of cancer cells.

The engineering of these functions onto the single nanoparticle entities significantly enhances the efficacy of anticancer drug delivery to cancer cells, while reducing the cytotoxic effects on healthy cells. In vivo experiments demonstrate that doxorubicin-loaded multifunctional mesoporous silica nanoparticles could effectively release doxorubicin to tumor sites resulting in significant inhibition of the tumor growth.


1. M. Morgen et al., Pharm. Res. 29 (2) 427-440 (2012).

2. A. Siew et al., Mol. Pharm. 9 (1) 14-28 (2012).

3. C. Liu et al., Biomat. 34 (10) 2547-2564 (2013).

4. I. Altintas et al., J. Control. Rel. 165 (2) 110-118 (2013).

5. W.Y. Qian et al., Int. J. Nanomed. 7: 5781-5792 (2012).

6. J.H. Sung, D. Han, and J.B. Lee, Biotechnol. J. 8 (2) 215-220 (2013).

7. C.Y. Dombu and D. Betbeder, Biomat. 34 (2) 516-525 (2013).

8. S. Hauptstein and A. Bernkop-Schnurch, Expert. Opin. Drug Deliv. 9 (9) 1069-1081 (2012).

9. R. Singh and J.W. Lillard, Exp. Mol. Pathol. 86 (3) 215-223 (2009).

10. A.Z. Wang, R. Langer, and O.C. Farokhzad, Annu. Rev. Med. 63: 185-198 (2012).

11. A. Swami et al., "Nanoparticles for targeted and temporally controlled drug delivery," in Multifunctional Nanoparticles for Drug Delivery Applications, S. Svenson and R.K. Prud'homme, Eds. (Springer, US, 2012), pp. 9-29.

12. NanoCarrier, "NC-6004 Nanoplatin," accessed Feb. 8, 2013.

13. H. Uchino et al., Br. J. Cancer 93 (6) 678-687 (2005).

14. R. Plummer et al., Br. J. Cancer 104 (4) 593-598 (2011).

15. Cerulean, "CRLX101,", accessed Feb. 8, 2013.

16. Young et al., Curr. Bioact. Compd. 7 (1) 8-14 (2011).

17. T. Hamaguchi et al., Br. J. Cancer 92 (7) 1240-1246 (2005).

18. Zhang et al., Adv. Funct. Mat. 22 (24) 5144-5156 (2012).