Co-delivery of Cyclopamine and Doxorubicin Mediated by Bovine Serum Albumin Nanoparticles Reverses Doxorubicin Resistance in Breast Cancer by Down-regulating P-glycoprotein Expression

Abstract

Combination chemotherapy is considered to be one of the most effective treatments for breast cancer by reducing the emergence of drug resistance. In this study, a novel drug delivery system based on bovine serum albumin nanoparticles (BSA NPs) was successfully developed. Doxorubicin (DOX) and cyclopamine (CYC), a potential anti-cancer agent that inhibits the hedgehog signaling pathway were entrapped into BSA NPs through electrostatic interactions and hydrophobic interactions, respectively. Rather than simple combination of two different chemotherapeutics, the CYC also increased the intracellular DOX accumulation by decreasing the expression of P-glycoprotein (P-gp), which could thus reverse the DOX resistance. Tumor-targeting property of nanoparticles was the prerequisite for its further application. Interestingly, retention of fluorescently-labeled particles in vivo indicated that the dual-drug-loaded BSA NPs could not only target the primary tumors, but also target the metastatic lymph nodes, which would simultaneously inhibit the tumor growth and distant metastasis. Taken together, this study provides a promising strategy for co-delivery of drugs, tumor and metastatic lymph node targeting, and DOX resistance reversing in breast cancer chemotherapy.

Albumin-based nanoparticles: a promising strategy to overcome cancer drug resistance

“…The mixture was magnetically stirred at 750 rpm in a 65 °C water bath. Then, the colloidal solution was ultra-filtered to remove any excess buffer or drug [41] . Figure 2.…”

Natural Ingredient-Based Polymeric Nanoparticles for Cancer Treatment

“…As a result, any doxorubicin taken up by the cancer cells would be moved out [81]. Another DDS based on bovine serum albumin nanoparticles for codelivery of doxorubicin and cyclopamine was developed by Lu et al Similar to curcumin, cyclopamine can increase doxorubicin accumulation by inhibiting P-glycoprotein expression [84,85]. Antitumor activity of the formulation was evaluated in doxorubicin-resistant breast cancer cells (MDA-MB-231 cells) and tumor-bearing mice.…”

“…The nanoformulation significantly reversed the drug resistance in the cancer cell model. It could distribute at the tumor sites and metastatic lymph nodes in the xenograft model, inhibiting tumor growth and reducing distant metastasis [84]. Human serum albumin was also employed for the development of nanoparticle-based DDSs.…”

“… Materials Composition of Nanoparticles Significances Ref. Albumin Bovine serum albumin, piceatannol, glutaraldehyde Improved anticancer activity of piceatannol [ 77 ] Bovine serum albumin, curcumin Enhanced dissolution rate, solubility, bioavailability and antitumor activity of curcumin [ 80 ] Bovine serum albumin, curcumin, doxorubicin Controlled release in an acidic environment; decreased the adaptive treatment tolerance effect [ 81 ] Bovine serum albumin, doxorubicin, cyclopamine Reversed drug resistance in cancer cells model; distributed at the tumor sites; reduced distant metastasis [ 84 ] Human serum albumin, doxorubicin Increased the anticancer activity of doxorubicin in the drug-resistant cell lines [ 86 ] Human serum albumin, doxorubicin Weaker cytotoxicity in vitro; opposite in vivo results; suppressed tumor metastasis [ 88 ] Human serum albumin, doxorubicin prodrug Stronger cellular uptake; improved cytotoxicity in vitro; lower cardiotoxicity [ 89 ] Human serum albumin, derivative of maytansine Improved safety profile; controllable release; protected drug molecules from body clearance [ 90 ] …”

Nanoparticles as Tools to Target Redox Homeostasis in Cancer Cells

“…To overcome the problem of acquired resistance to doxorubicin [55] due to increased extrusion by the ATP-binding cassette (ABC) proteins, doxorubicin was conjugated with bovine serum albumin (BSA) NPs in association with cyclopamine, an inhibitor of the hedgehog pathway, which decreases the expression of ABC proteins. This approach led to the intracellular accumulation of doxorubicin and restored the sensitivity of breast cancer cells to doxorubicin [56]. In a recent work, Yang and colleagues [57] used mesoporous silica NPs (MSNPs), which are internalized by endocytosis, to target a human acute lymphoblastic leukemia (ALL) cell line.…”