Crimson Publishers Publish With Us Reprints e-Books Video articles

Full Text

Modern Applications in Pharmacy & Pharmacology

Active Targeting of Breast Cancer Cells Using Nanocarriers

Marina Santiago Franco*, Marjorie Coimbra Roque and Monica Cristina Oliveira

Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Brazil

*Corresponding author:Marina Santiago Franco, Department of Pharmaceutical Products, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, Postal code: 3127-0901, Belo Horizonte, Minas Gerais, Brazil

Submission: November 17, 2017;Published: December 18, 2017

DOI: 10.31031/MAPP.2017.01.000507

ISSN 2637-7756
Volume1 Issue2


Breast cancer is the most common and lethal cancer type in women worldwide. Therapeutic strategies with better selectivity, such as active targeting by nanocarriers, are highly desirable. In this mini review, we briefly outline the evolution of nanocarriers culminating in actively targeted systems, the challenges faced when designing such carriers and, finally, the most promising breast cancer targets and possible ligands that can be coupled to the nanocarriers.

Keywords:Drug delivery systems; Active target; Breast cancer


The treatments currently available for breast cancer treatment are allowing for the long-term survival rates to rise after a diagnosis of the disease. In 2012, around 6.2 million of women were accounted as breast cancer survivors, which represented 36.4% of the total estimated cancer survivors among women [1]. Nevertheless, the available chemotherapy schemes lead not only to severe side effects during the treatment, but also to potential long term medical issues. These challenges highlight the need of searching for new therapeutic strategies, especially ones with better selectivity [2,3]. Nanocarriers have the potential to circumvent the toxicity problems of anticancer drugs by increasing cancer cell targeting in comparison to conventional formulations. Since the approval of Doxil®, a PEGylated liposomal formulation of doxorubicin in 1995, great advances on understanding both nano systems and the molecular biology of breast cancer were made. This knowledge allow for the development of new promising nanotherapeutic strategies and devices [4].

The Evolution of Nanocarriers for Breast Cancer Treatment

The first generation of anticancer nanocarrries was planned based on the concept of passive targeting [5]. This is a size-dependent process and may occur as a result of the pathophysiological characteristics of the tumor vessels, which present a leaky vasculature and poor lymphatic drainage. These two characteristics together lead to an effect known as “enhanced permeability and retention (EPR) effect” [6]. This effect may be responsible for an increased accumulation of the nanocarrier in the tumor site compared to normal tissues, which allows higher efficacy and lower side effects [7].

Table 1:Nanocarriers currently on the market for breast cancer treatment.

DSPE-PEG: N-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine; EPC: Egg phosphatidylcholine; HSPC: Hydrogenated soyphosphatidylcholine; mPEG-PLA: Monomethoxypoly(ethyleneglycol)-block-poly(D,Llactide).

To better explore the passive targeting, the possibilities of enhancing the bloodstream circulation time of the nanocarriers started being explored. A successful method to obtain longcirculating nanocarriers is coating them with hydrophilic and flexible polymers such as poly(ethylene glycol) (PEG).This polymers create a sterical barrier so that interactions with blood components are reduced. Since the interaction of the nanosystems with opsonins is reduced, their uptake by the reticulo endothelial system is also decreased allowing them to achieve a longer blood circulation time [7]. All nanocarriers approved for breast cancer treatment are listed on Table 1, [8-11] and, except of Doxil®, belong to the first generation of nanosystems.

Despite of the advances concerning toxicity management, formulations with a greater impact on the overall survival rate of patients with breast cancer are still necessary. This fact encouraged the search for new strategies on nanocarriers development such as triggered drug delivery. This strategy theoretically allows the formulations to be triggered to release their contents upon the exposure to specific stimuli. These stimuli can be something such as heat, light, ultrasound, magnetic fields, low pH or enzymes [12]. ThermoDox®, a new formulation of thermo-sensitive PEGylated liposomes encapsulating doxorubicin was based on this concept. It presented encouraging efficacy results for patients with breast cancer on a Phase I clinical trial and is now undergoing a Phase III clinical trial [13]. Although they play an important role in the treatment of breast cancer, the formulations presented in Table 1 are generic anticancer products. The next step on the evolution of nanocarriers for treating breast cancer is to tailor the nanocarriers based on specific characteristics of the disease [4].

A strategy that rises from the idea of building nanocarriers to treat patients with a specific type of cancer is the active targeting. The careful selection of ligands to target surface molecules or receptors overexpressed by cancer cells leads to specific retention and uptake on tumor tissue [6]. No active targeted nanocarrier is commercially available for breast cancer treatment yet. Possible targets to be explored in breast cancer cell lines are the focus of this mini-review and will be further presented.

Passive versus active targeting

As previously mentioned, passive targeting occurs as a result of EPR effect and was the main driving force supporting the first generation of nanocarriers. However, it is known that EPR is a highly variable phenomenon and large inter- and intra-individual differences are observed. Parameters such as vascular volume, perfusion, permeability, penetration, and retention of the EPR effect differ quite significantly not only between different types of tumors, but also between different tumors within the same patient [14,15]. Active targeting, or ligand-mediated targeting, consists on binding ligands to the surface of the nanocarriers so that it can bind specifically to surface molecules or receptors overexpressed in the targeted tissue. It not only allows an accumulation of the nanocarrier at the targeted site, but also might induce receptormediated endocytosis, improving the intracellular delivery of the carried content [14]. A major drawback on this strategy is that the actively targeted carrier needs to be in the proximity of their target to benefit from this increased affinity. For this reason, actively targeted carriers are envisioned as a promising complementary strategy to EPR, to further augment the efficiency of the designed nanocarriers [6].

Designing actively-targeted nanocarriers

The first step when designing an actively-targeted nanocarrier is to select the target. One should consider 1) the relative degree of overexpression or selective expression on the target, 2) the ability to internalize the ligand-targeted formulation and 3) if the population that would benefit from that treatment is really significant. Then, it is necessary to think about the formulation development, considering 1) the ligand conjugation strategy to the nanocarrier (before or after nanocarrier formation, 2) the need of a linker to maximize targeting efficiency (e.g. PEG), 3) the ligand density and 4) the costs of the scaling up the formulation, as the development of targeted nanocarriers is much more expensive than that of non-targeted ones [6,14,16,17].

Table 1:Breast cancer targets, their reported prevalence of expression and possible ligands to couple to nanocarriers

Active targeting to breast cancer cells

Many different receptors have been investigated for their potential to be targeted in breast cancer cells. The most relevant receptors and their reported prevalence in breast tumors are listed in Table 2. Similarly, many different nanocarriers such as liposomes, lipid nanoparticles, micelles, silica nanoparticles and gold nanorods have had their surface modified with ligands for those receptors. The ligands usually fall on one of the following categories: antibodies, peptides, aptamers or small molecules. Antibodies present high selectivity and binding affinity for the target as a direct result of the presence of two epitope binding sites in a single molecule. As limitations one can count the high cost of manufacturing, high molecular weight and batch-to-batch variation with the potential to induce an immunogenic response. Peptides have small size, low immunogenicity, easier and less expensive manufacture compared to antibodies. However, they have limitations such as a low target affinity and susceptibility to proteolytic cleavage. Aptamers have high specificity to target but might suffer from rapid clearance from the blood circulation due to nuclease degradation. Small molecules are relatively inexpensive to manufacture and versatile on structures and properties. However, they must have high specificity and affinity towards cellular receptors, what has proven to be a challenging task [18-36].

The promising in vitro and in vivo results observed to date for active-targeted nanocarriers allowed some of them to progress to clinical trials [18]. To the best of our knowledge, only one formulation designed specifically for breast cancer active targeting made its way into clinical trials. This formulation, called MM-302, is a HER2-targeted antibody-liposomal doxorubicin conjugate. In preclinical models, MM-302 had superior efficacy compared with both free doxorubicin and Doxil®. Its combination with trastuzumab also demonstrated better efficacy compared to either agent alone in HER2¬ over expressing tumor xenograft models. These findings provided support for starting the Phase Iclinical trial. This study suggested the promising efficacy of MM-302 alone or in combination with trastuzumab as well as a manageable safety profile in patients with advanced HER2-positive breast cancer. MM-302 progressed then to a Phase II study (HERmione) [37]. However, this study was halted after the observation of a shorter than expected median progression-free survival [38].


Active targeting is envisioned as a strategy that allows the accumulation of the nanocarrier at the targeted site and also might induce receptor-mediated endocytosis. Concerning breast cancer, some targets herein mentioned have raised special interest for active target. To date, many promising in vitro and in vivo results have been observed for nanocarriers directed to these targets. However, only one liposomal formulation designed specifically for breast cancer active targeting made its way into clinical trials. The many challenges behind this strategy might be responsible for the low translation of these formulations to the clinics. However, the need for treatments with better selectivity and efficacy should boost the research efforts based on this promising approach.


  1. Accessed.
  2. Bodai BI, Tuso P (2015) Breast Cancer Survivorship: A Comprehensive Review of Long-Term Medical Issues and Lifestyle Recommendations. Perm J 19(2): 48-79.
  3. Tao JJ, Visvanathan K, Wolff AC (2015) Long term side effects of adjuvant chemotherapy in patients with early breast cancer. Breast 24(Suppl 2): 149-153.
  4. Wu D, Si M, Xue H, Wong HL (2017) Nanomedicine applications in the treatment of breast cancer: current state of the art. International Journal of Nanomedicine 12: 5879-5892.
  5. Zamboni WC, Torchilin V, Patri AK, Hrkach JS, Lee R, et al. (2012) Best practices in cancer nanotechnology: perspective from NCI nanotechnology alliance. Clin Cancer Res 18 (12): 3229-3241.
  6. Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC (2014) Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev 66: 2-25.
  7. Torchilin VP (2010) Passive and active drug targeting: drug delivery to tumors as an example. In: Korting MS (Ed.), Handb Exp Pharmacol, USA, pp. 3-53.
  8. Barenholz Y (2012) Doxil®-the first FDA-approved nano-drug: lessons learned. J Controlled Release 160(2): 117-134.
  9. Accessed November 2017.
  12. Huo M, Chen Y, Shi J (2016) Triggered-release drug delivery nanosystems for cancer therapy by intravenous injection: where are we now? Expert Opinion Drug Delivery 13(9): 1195-1198.
  13. Boissenot T, Bordat A, Fattal E, Tsapis N (2016) Ultrasound-triggered drug delivery for cancer treatment using drug delivery systems: from theoretical considerations to practical applications. J Controlled Release 10(241): 144-163.
  14. Sawant RR, Torchilin VP (2012) Challenges in development of targeted liposomal therapeutics. AAPS J 14(2): 303-315.
  15. Kunjachan S, Pola R, Gremse F, Theek B, Ehling J, et al. (2014) Passive vs. active tumor targeting using RGD-and NGR-modified polymeric nanomedicines. Nano Lett 14(2): 972-981.
  16. Yu B, Tai HC, Xue W, Lee LJ, Lee RJ (2010) Receptor-targeted nanocarriers for therapeutic delivery to cancer. Mol Membr Biol 27(7): 286-298.
  17. Noble GT, Stefanick JF, Ashley JD, Kiziltepe T, Bilgicer B (2014) Ligandtargeted liposome design: challenges and fundamental considerations. Trends Biotechnol 32(1): 32-45.
  18. Sanna V, Pala N, Sechi M (2014) Targeted therapy using nanotechnology: focus on cancer. Int J Nanomedicine 9: 467-483.
  19. Glasgow MDK, Chougule MB (2015) Recent Developments in Active Tumor Targeted Multifunctional Nanoparticles for Combination Chemotherapy in Cancer Treatment and Imaging. J Biomed Nanotechnol 11(11): 1859-1898.
  20. Dai X, Xiang L, Li T, Bai Z (2016) Cancer Hallmarks, Biomarkers and Breast Cancer Molecular Subtypes. J Cancer 7(10): 1281-1294.
  21. Sadat SMA, Saeidnia S, Nazarali AJ, Haddadi A (2015) Nanopharmaceutical Formulations for Targeted Drug Delivery against HER2 in Breast Cancer. Curr Cancer Drug Targets 15(1): 71- 86.
  22. Wang K, Yao H, Meng Y, Wang Y, Yan X, et al. (2015 ) Specific aptamerconjugated mesoporous silica-carbon nanoparticles for HER2-targeted chemo-photothermal combined therapy. Acta Biomater 16: 196-205.
  23. Paliwal SR, Paliwal R, Pal HC, Saxena AK, Sharma PR, et al. (2012) Estrogen-anchored pH-sensitive liposomes as nanomodule designed for site-specific delivery of doxorubicin in breast cancer therapy. Mol Pharm 9(1): 176-186.
  24. Jain AS, Goel PN, Shah SM, Dhawan VV, Nikam Y, et al. (2014) Tamoxifen guided liposomes for targeting encapsulated anticancer agent to estrogen receptor positive breast cancer cells: in vitro and in vivo evaluation. Biomed Pharmacother 68(4): 429-438.
  25. O’Shannessy DJ, Somers EB, Maltzman J, Smale R, Fu Y (2012) Folate receptor alpha (FRA) expression in breast cancer: identification of a new molecular subtype and association with triple negative disease. Springerplus 1: 22.
  26. Khosravian P, Shafiee Ardestani M, Khoobi M, Ostad SN, Dorkoosh FA, et al. (2016) Mesoporous silica nanoparticles functionalized with folic acid/methionine for active targeted delivery of docetaxel. Onco Targets Ther 9: 7315-7330.
  27. Högemann Savellano D, Bos E, Blondet C, Sato F, Abe T, et al. (2003) The transferrin receptor: a potential molecular imaging marker for human cancer. Neoplasia 5(6): 495-506.
  28. Gao W, Ye G, Duan X, Yang X, Yang VC (2017) Transferrin receptortargeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer. Int J Nanomedicine 12: 1047-1064.
  29. Taherian A, Li X, Liu Y, Haas TA (2011) Differences in integrin expression and signaling within human breast cancer cells. BMC Cancer. 11: 293.
  30. Zhao N, Yang Z, Li B, Meng J, Shi Z, et al. (2016) RGD-conjugated mesoporous silica-encapsulated gold nanorods enhance the sensitization of triple-negative breast cancer to megavoltage radiation therapy. Int J Nanomedicine 11: 5595-5610.
  31. Kufe DW (2013) MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene 32(9): 1073-1081.
  32. Lozano N, Al Ahmady ZS, Beziere NS, Ntziachristos V, Kostarelos K (2015) Monoclonal antibody-targeted PEGylated liposome-ICG encapsulating doxorubicin as a potential theranostic agent. Int J Pharm 482: 2-10.
  33. Hanafi Bojd MY, Kalat SAM, Taghdisi SM, Ansari L, Abnous K, et al. (2017) MUC1 Aptamer-conjugated mesoporous silica nanoparticles effectively target breast cancer cells. Drug Dev Ind Pharm 44(1): 13-18.
  34. Rimawi MF, Shetty PB, Weiss HL, Schiff R, Osborne CK, et al. (2010) Epidermal growth factor receptor expression in breast cancer association with biologic phenotype and clinical outcomes. Cancer 116(5): 1234-1242.
  35. Jin H, Pi J, Zhao Y, Jiang J, Li T, et al. (2017) EGFR-targeting PLGA-PEG nanoparticles as a curcumin delivery system for breast cancer therapy. Nanoscale 9(42): 16365-16374.
  36. Zhang XQ, Lam R, Xu X, Chow EK, Kim HJ, Ho D (2011) Multimodal nanodiamond drug delivery carriers for selective targeting, imaging, and enhanced chemotherapeutic efficacy. Adv Mater 23(41): 4770-4775.
  37. Miller K, Cortes J, Hurvitz SA, Krop IE, Tripathy D, et al. (2016) HERMIONE: A randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer. BMC Cancer 16: 352.
  38. trial-of-mm-302.

© 2018 Marina Santiago Franco. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and build upon your work non-commercially.