Recent advances in nanotheranostics for triple negative breast cancer treatment

Abstract

Triple-negative breast cancer (TNBC) is the most complex and aggressive type of breast cancer encountered world widely in women. Absence of hormonal receptors on breast cancer cells necessitates the chemotherapy as the only treatment regime. High propensity to metastasize and relapse in addition to poor prognosis and survival motivated the oncologist, nano-medical scientist to develop novel and efficient nanotherapies to solve such a big TNBC challenge. Recently, the focus for enhanced availability, targeted cellular uptake with minimal toxicity is achieved by nano-carriers. These smart nano-carriers carrying all the necessary arsenals (drugs, tracking probe, and ligand) designed in such a way that specifically targets the TNBC cells at site. Articulating the targeted delivery system with multifunctional molecules for high specificity, tracking, diagnosis, and treatment emerged as theranostic approach. In this review, in addition to classical treatment modalities, recent advances in nanotheranostics for early and effective diagnostic and treatment is discussed. This review highlighted the recently FDA approved immunotherapy and all the ongoing clinical trials for TNBC, in addition to nanoparticle assisted immunotherapy. Futuristic but realistic advancements in artificial intelligence (AI) and machine learning not only improve early diagnosis but also assist clinicians for their workup in TNBC. The novel concept of Nanoparticles induced endothelial leakiness (NanoEL) as a way of tumor invasion is also discussed in addition to classical EPR effect. This review intends to provide basic insight and understanding of the novel nano-therapeutic modalities in TNBC diagnosis and treatment and to sensitize the readers for continue designing the novel nanomedicine. This is the first time that designing nanoparticles with stoichiometric definable number of antibodies per nanoparticle now represents the next level of precision by design in nanomedicine.

Keywords: Breast Cancer; Immunotherapy; NanoEL; Nanomedicine; Nanotechnology; Theranostics.

Fig. 1

Diagrammatic representation of the concept of targeted theranostics: a Liposome cavity is loaded with the anti-cancerous drug and the surface of the liposomal nanoparticle is coated with ligand for the targeted and specific delivery of the drug. In addition to this, tracer helps in the accurate screening and diagnosis of cancer cells. b Transferrin is conjugated to vitamin-ED-alpha-tocopheryl polyethylene glycol succinate (TPGS) micelle for targeted co-delivery of therapeutic drug (docetaxel) and diagnostic agent (AuNC) as theranostic.

Fig. 2

Diagrammatic representation of ligands and their specific receptors: Folate receptor is targeted by folic acid-conjugated gold nanorod as nanotherapeutics. Similarly, various other receptors like CD44 and CXCR4 are identified by HA-PTX nanoconjugate and HA-PTX poly(lactide-co-glycolide) nanoparticle respectively increases the specificity and decrease the adverse effects of the cancer therapy.

Fig. 3

Brief representation of potential inhibitors of various pathways and receptors for the treatment of triple-negative breast cancer. Poly (ADP-ribose) polymerase (PARP) inhibitors like BSI-20I target ssDNA break repairing enzyme causing synthetic lethality resulting in control of cancer cell proliferation. Similarly, other class of inhibitors like tyrosine kinase (TK), EGFR, PI3K, angiogenesis, insulin-like growth factor (IGF), heat shock protein (Hsp90), histone deacetylase (HDAC), andmammalian target of rapamycin (mTOR) employ different mechanism to control and treat TNBC.

Fig. 4

Schematic representation of different routes followed by nanoparticles in cancer therapy. (1) In transcellular route, the drug carrying nanoparticle injected into the bloodstream passes through the endothelial cell and reaches as the cancer site. (2) Whereas in paracellular route, the nanoparticle passes through the inter-endothelial cell spaces and known as active targeting. These nanoparticles induce leakiness by widening the gap between the endothelial cells and enhance the cancer cell targeting also known as naoEL effect. (3) Passive targeting is the classical and common phenomenon where the nanoparticle transverse through the leaky vasculature by EPR effect to the site of cancer cells.

Fig. 5

Graphical Abstract: Advancements in the theranostics: Recent advancements like artificial intelligence, neural network and deep mind in addition to classical mammogram predict and improve the breast cancer diagnosis. Additionally, immunotherapies using immune checkpoint blockade, immunostimulatory cytokines, and adaptive cell therapy in addition to current combination therapy collectively improve the diagnosis and treatment when articulated in the form of theranostics.