Actively Targeted Nanomedicines in Breast Cancer: From Pre-Clinal Investigation to Clinic

Abstract

Breast cancer is one of the most frequently diagnosed tumors and the second leading cause of cancer death in women worldwide. The use of nanosystems specifically targeted to tumor cells (active targeting) can be an excellent therapeutic tool to improve and optimize current chemotherapy for this type of neoplasm, since they make it possible to reduce the toxicity and, in some cases, increase the efficacy of antineoplastic drugs. Currently, there are 14 nanomedicines that have reached the clinic for the treatment of breast cancer, 4 of which are already approved (Kadcyla®, Enhertu®, Trodelvy®, and Abraxane®). Most of these nanomedicines are antibody–drug conjugates. In the case of HER-2-positive breast cancer, these conjugates (Kadcyla®, Enhertu®, Trastuzumab-duocarmycin, RC48, and HT19-MMAF) target HER-2 receptors, and incorporate maytansinoid, deruxtecan, duocarmicyn, or auristatins as antineoplastics. In TNBC these conjugates (Trodelvy®, Glembatumumab-Vedotin, Ladiratuzumab-vedotin, Cofetuzumab-pelidotin, and PF-06647263) are directed against various targets, in particular Trop-2 glycoprotein, NMB glycoprotein, Zinc transporter LIV-1, and Ephrin receptor-4, to achieve this selective accumulation, and include campthotecins, calicheamins, or auristatins as drugs. Apart from the antibody–drug conjugates, there are other active targeted nanosystems that have reached the clinic for the treatment of these tumors such as Abraxane® and Nab-rapamicyn (albumin nanoparticles entrapping placlitaxel and rapamycin respectively) and various liposomes (MM-302, C225-ILS-Dox, and MM-310) loaded with doxorubicin or docetaxel and coated with ligands targeted to Ephrin A2, EPGF, or HER-2 receptors. In this work, all these active targeted nanomedicines are discussed, analyzing their advantages and disadvantages over conventional chemotherapy as well as the challenges involved in their lab to clinical translation. In addition, examples of formulations developed and evaluated at the preclinical level are also discussed.

Nano-Based Approved Pharmaceuticals for Cancer Treatment: Present and Future Challenges

“…It is a 30 nm protein-based nanocompound formed by Transtuzumab, an anti-HER-2 humanized monoclonal antibody that is bound to DM-1 (emtansine, an antimicrotubular agent that blocks cellular division) [ 110 ]. Kadcyla TM , as a single therapy, is indicated for the adjuvant treatment of adult patients with HER2-positive early breast cancer who have residual invasive disease [ 111 ]. It is commonly used in combination with other antineoplastics for the treatment of HER-2-positive breast tumors.…”

“…Furthermore, this binding also promotes HER-2 receptor degradation and activates the antibody-dependent cell-mediated cytotoxicity. It is used in combination with other antineoplastics for the treatment of HER-2-positive breast tumors [ 111 , 112 ].…”

Current landscape of personalized clinical treatments for triple-negative breast cancer

“…In this cohort of heavily treated m TNBC patients, sacituzumab govitecan was shown to be very well tolerated and to produce early and long-lasting therapeutic effects. PF-06647263, an ADC consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, was shown to exhibit preliminary effects in some xenograft models (Fraguas-Sánchez et al, 2022). Ignacio et al implemented a first-inhuman study of PF-06647263 using every 3 weeks and every week regimens in patients with TNBC, ovarian cancer, and other advanced solid tumors (Garrido-Laguna et al, 2019).…”

Challenges in Preparation of Albumin Nanoparticle-Based Radiopharmaceuticals

“…In addition to the phagocytosis-based localisation of HSA-NC, much of the localisation of albumin nanoparticle-based chemotherapy is attributed to enhanced permeability and retention (EPR), by which the higher permeability of the blood vessels in tumours allows the extravasation of the nanoparticles into the tumour microenvironment, where retention is further enhanced by the lack of efficient lymphatic drainage [ 30 ]. However, the EPR theory has recently been described as too simplistic, and it has been demonstrated that there can be the transport of nanoparticles across intact endothelium [ 31 ].…”

“…HSA-NC is highly amenable to modification for specific targeting [ 23 , 30 ]. The vast range of possibilities include folate [ 32 ], peptides (e.g., Arg-Gly-Asp RGD peptides which bind α V β 3 integrin in neoangiogenesis) [ 33 ], and monoclonal antibodies (e.g., trastuzumab to target HER2-overexpressing breast tumour cells) [ 34 ].…”