Receptor-Mediated Targeted Delivery of Surface-ModifiedNanomedicine in Breast Cancer: Recent Update and Challenges

Abstract

Breast cancer therapeutic intervention continues to be ambiguous owing to the lack of strategies for targeted transport and receptor-mediated uptake of drugs by cancer cells. In addition to this, sporadic tumor microenvironment, prominent restrictions with conventional chemotherapy, and multidrug-resistant mechanisms of breast cancer cells possess a big challenge to even otherwise optimal and efficacious breast cancer treatment strategies. Surface-modified nanomedicines can expedite the cellular uptake and delivery of drug-loaded nanoparticulate constructs through binding with specific receptors overexpressed aberrantly on the tumor cell. The present review elucidates the interesting yet challenging concept of targeted delivery approaches by exploiting different types of nanoparticulate systems with multiple targeting ligands to target overexpressed receptors of breast cancer cells. The therapeutic efficacy of these novel approaches in preclinical models is also comprehensively discussed in this review. It is concluded from critical analysis of related literature that insight into the translational gap between laboratories and clinical settings would provide the possible future directions to plug the loopholes in the process of development of these receptor-targeted nanomedicines for the treatment of breast cancer.

Keywords: breast cancer; multidrug resistance; nanoparticle; receptor-mediated; surface-modification; targeted delivery.

Figure 1

Illustrate the common structure of the ABC transporters and their subfamily. (a) ABC transporter with 2 sets of transmembrane domains and 2 nucleotide-binding domains. Orange color structure in the inner membrane indicates substrate molecules. (b) The binding of ATP caused the joining of NBD which ultimately leads to a conformational change and transfer of the substrate molecule out of the membrane. (c) Common structure of P-glycoprotein (P-gp) as one of the ABC transporters contains 12 TMD and 2 sites for ATP binding. (d) Another ABC transporter as Multidrug Resistance Protein 1 (MRP1) also contains 12 TMD and 2 sites for ATP binding similar to the P-gp transport system but also contains an extra 5 TMD at the amino-terminal end. (e) Another ABC transporter as Breast Cancer Resistance Protein (BCRP) contains 6 TMD and only 1 site for ATP binding at the amino-terminal end of the TMD. TMD: Transmembrane domain; NBD: Nucleotide-binding domains.

Figure 2

Different ABC transporter overexpressed in breast cancer cells responsible for MDR and failure of chemotherapy.

Figure 3

Different types of nanoparticulate systems utilized in receptor-mediated targeted drug delivery in breast cancer.

Figure 4

Schematic presentation of different types of targeted nanomedicine mediated through overexpressed receptors in breast cancer to induce cancer cell death/apoptosis. a. Oligoclonal antibody conjugated liposomes loaded with doxorubicin induce significant cell killing in HER2-overexpressed BT-474 breast cancer cells. b. GE11 peptides conjugated PEGylated PLGA nanoparticles loaded with curcumin induce significant cell killing in EGFR-overexpressed MCF-7 breast cancer cells c. Folate conjugated nanostructured lipid carriers loaded with curcumin induce significant inhibition of tumor growth compared to nontargeted nanomedicine in MCF-7 xenograft mice model. d. Doxorubicin-loaded liposomes surface-grafted with tamoxifen (ER antagonist) cause increased cellular/nuclear uptake of loaded therapeutics and induce more cell death compared to plain liposomes in ER overexpressed MCF-7 cells. e. PLGA/HA copolymers nanoparticles loaded with docetaxel causes increased cellular uptake and cytotoxicity in MDA-MB-231 breast cancer cells through CD44-mediated endocytosis. f. LHRH-conjugated PEGylated magnetite nanoparticles exhibited enhanced uptake in triple-negative breast cancer cells. g. Transferrin-capped mesoporous silica nanoparticles loaded with doxorubicin cause increased internalization in MCF-7 cells through transferrin-mediated endocytosis. h. Doxorubicin-loaded leukocyte mimicking nanoformulation (leukosomes) exhibited enhanced accumulation in tumor and significantly reduces the tumor volume. i. VIP functionalized phospholipid micelles loaded with pararubicin cause increased anticancer activity in MCF- 7 cells. HER2—Human Epidermal Growth Factor Receptor2; EGFR—Epidermal Growth Factor Receptor (HER1); FR—Folate Receptor; ER—Estrogen Receptor; HR—CD44/Hyaluronan Receptor; LHRH—Luteinizing Hormone-Releasing Hormone Receptor; IR—Integrin Receptor; VIP—Vasoactive Intestinal Peptide Receptor.

Figure 5

Image showing the tumor growth inhibition and impact on bodyweight of female Balb/c mice with MDR breast tumor (n = 5 ± SE) upon various treatment. Tumor-bearing mice were intravenously treated with normal saline (●), Pluronic (■), pure DOX (▲), and FA/DOX micelles (_Χ) (dose of DOX = 4 mg/kg) at days 0, 4, and 8 (indicated by arrows). It indicated changes in (A) tumor volume; (B) body weight and (C) image showing MDR breast tumor-bearing Balb/c mice. The photographs of all the treated tumor-bearing mice were taken after 22 days of treatment. The tumors are indicated with yellow dotted circles. Reproduced with permission of Nguyen et al., Int. J. Pharm, published by Elsevier, 2015 [86].

Figure 6

The photomicrograph showing the imaging of MCF-7 tumor-bearing Balb/c nude mice after intravenous administration of free DiR and DiR-labeled liposomes. (A) The in vivo imaging of Balb/c nude mice at predetermined time points; (B) The ex vivo imaging of different organs of Balb/c mice that were dissected just after 12 h of intravenous administration. The antitumor effect of ES-SSL-EPI/PTX in MCF-7 tumor-bearing Balb/c nude mice (n = 4). (C) Impact on body weights upon treatment; (D) Tumor volume after intravenous administration of free drugs and liposomal formulations; (E) The photomicrographs of MCF-7 tumors after intravenous administration of free drugs and liposomal formulations. ‘*’, ‘**’ represents the comparison with other treated groups, p < 0.05 and p < 0.01 respectively. Reproduced with permission of Tang et al., Int. J. Pharm, published by Elsevier, 2019 [93].