Double-Coated Poly(butyl Cyanoacrylate) Nanoparticles as a Potential Carrier for Overcoming P-Gp- and BCRP-Mediated Multidrug Resistance in Cancer Cells

The present study evaluates poly (butyl cyanoacrylate) nanoparticles (PBCA-NPs), double-coated with Tween 80 and polyethylene glycol (PEG) 20,000 as a potential carrier system for overcoming P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)-mediated multidrug resistance (MDR) in cancer cell lines. Doxorubicin-loaded PBCA-NPs were prepared by the anionic polymerization method and were successively double-coated with Tween 80 and PEG 20000 at varied concentrations. MDR reversing potential was investigated by cellular uptake in P-gp overexpressing cell line. And, the outcomes were verified by modified MTT assay in P-gp or BCRP overexpressing cell lines. The findings from the cell uptake study indicate that double-coated PBCA-NPs significantly enhanced doxorubicin accumulation within the cells. MTT assays revealed that double-coated PBCA-NPs significantly potentiated the sensitivity of doxorubicin in P-gp overexpressing cells, in comparison to free doxorubicin, single-, and un-coated PBCA-NPs, respectively. Moreover, further increase in concentration with Tween 80, double-coated PBCA-NPs significantly enhanced the sensitivity of doxorubicin in BCRP overexpressing cell line, in comparison to single- and double-coated formulations (with lower concentration of Tween 80). Hence, it could be concluded that double-coated PBCA-NPs can be used as a potential carrier for enhancing doxorubicin accumulation in MDR cancer cells.

State-of-the-Art of the Major Nanopharmaceuticals Treatments in Breast Cancer: A Systematic Review

Introduction: Breast cancer is the most frequently detected cancer in women worldwide, its metastasis is responsible for 90% of deaths. Breast carcinoma is the most common cancer in women worldwide and the most common cause of deaths associated with malignancies. Hyaluronic acid (HA) is the main molecule binding to CD44 and has proved to be a significant ally in the development of nanotransporters that demonstrate preferential accumulation of tumors and increased cellular uptake. Objective: Carry out a systematic review of the main treatments to reduce or prevent the proliferation of breast cancer. Methods: A total of 59 articles have found and after the selection process 20 articles have included and discussed in this study. PUBMED, EMBASE, OVID, AND COCHRANE LIBRARY databases were searched. Results: cationic liposomes containing the conjugate hyaluronic acid-dioleoylphosphatidylethanolamine (HA-DOPE) mediated good transfection in cell lines that express CD44 in culture. Still, other results suggested that the formulation of lapatinib (LPT) coated with HA increases the activity of LPT against triple-negative breast cancer. In addition, compared to free doxorubicin (DOX), superior in vivo antitumor efficacy of modified carbon spots (HA HA-CD) and (p-CBA-DOX) was observed in heterotopic and orthotopic 4T1 cell tumor models. In addition, hematological and biochemical analysis of blood showed that HA-CD and p-CBA-DOX did not induce noticeable toxicity, which further confirmed the good biocompatibility of HA-CD and p-CBA-DOX. Also, it was found that CD44v expression can negatively influence HA uptake and, instead, when cells expressed mainly CD44s, a positive correlation between expression and uptake was observed. Other findings point to the potential clinical utility of recombinant human proteoglycan 4 (rhPRG4) as a therapeutic treatment for invasive and metastatic breast cancer. Conclusion: The development of nanopharmaceuticals delivery systems are able to control the development of tumors and represent a promising strategy to overcome issues related to the non-specific effects of conventional anticancer therapies.

Cell-Penetrating Doxorubicin Released from Elastin-Like Polypeptide Kills Doxorubicin-Resistant Cancer Cells in In Vitro Study

Elastin-like polypeptides (ELPs) undergo a characteristic phase transition in response to ambient temperature. Therefore, it has been be used as a thermosensitive vector for the delivery of chemotherapy agents since it can be used to target hyperthermic tumors. This novel strategy introduces unprecedented options for treating cancer with fewer concerns about side effects. In this study, the ELP system was further modified with an enzyme-cleavable linker in order to release drugs within tumors. This system consists of an ELP, a matrix metalloproteinase (MMP) substrate, a cell-penetrating peptide (CPP), and a 6-maleimidocaproyl amide derivative of doxorubicin (Dox). This strategy shows up to a 4-fold increase in cell penetration and results in more death in breast cancer cells compared to ELP-Dox. Even in doxorubicin-resistant cells (NCI/ADR and MES-SA/Dx5), ELP-released cell-penetrating doxorubicin demonstrated better membrane penetration, leading to at least twice the killing of resistant cells compared to ELP-Dox and free Dox. MMP-digested CPP-Dox showed better membrane penetration and induced more cancer cell death in vitro. This CPP-complexed Dox released from the ELP killed even Dox-resistant cells more efficiently than both free doxorubicin and non-cleaved ELP-CPP-Dox.

Multiresponsive Hybrid Microparticles for Stimuli-Responsive Delivery of Bioactive Compounds

Hybrid microparticles based on an iron core and an amphiphilic polymeric shell have been prepared to respond simultaneously to magnetic and ultrasonic fields and variation in the surrounding pH to trigger and modulate the delivery of doxorubicin. The microparticles have been developed in four steps: (i) synthesis of the iron core; (ii) surface modification of the core; (iii) conjugation with the amphiphilic poly(lactic acid)-grafted chitosan; and (iv) doxorubicin loading. The particles demonstrate spherical shape, a size in the range of 1–3 µm and surface charge that is tuneable by changing the pH of the environment. The microparticles demonstrate good stability in simulated physiological solutions and are able to hold up to 400 µg of doxorubicin per mg of dried particles. The response to ultrasound and the changes in the shell structure during exposure to different pH levels allows the control of the burst intensity and release rate of the payload. Additionally, the magnetic response of the iron core is preserved despite the polymer coat. In vitro cytotoxicity tests performed on fibroblast NIH/3T3 demonstrate a reduction in the cell viability after administration of doxorubicin-loaded microparticles compared to the administration of free doxorubicin. The application of ultrasound causes a burst in the release of the doxorubicin from the carrier, causing a decrease in cell viability. The microparticles demonstrate in vitro cytocompatibility and hemocompatibility at concentrations of up to 50 and 60 µg/mL, respectively.

Effects of Focused-Ultrasound-and-Microbubble-Induced Blood-Brain Barrier Disruption on Drug Transport under Liposome-Mediated Delivery in Brain Tumour: A Pilot Numerical Simulation Study

Focused ultrasound (FUS) coupled with microbubbles (MB) has been found to be a promising approach to disrupt the blood-brain barrier (BBB). However, how this disruption affects drug transport remains unclear. In this study, drug transport in combination therapy of liposomes and FUS-MB-induced BBB disruption (BBBD) was investigated based on a multiphysics model. A realistic 3D brain tumour model extracted from MR images was applied. The results demonstrated the advantage of liposomes compared to free doxorubicin injection in further improving treatment when the BBB is opened under the same delivery conditions using burst sonication. This improvement was mainly due to the BBBD-enhanced transvascular transport of free doxorubicin and the sustainable supply of the drug by long-circulating liposomes. Treatment efficacy can be improved in different ways. Disrupting the BBB simultaneously with liposome bolus injection enables more free drug molecules to cross the vessel wall, while prolonging the BBBD duration could accelerate liposome transvascular transport for more effective drug release. However, the drug release rate needs to be well controlled to balance the trade-off among drug release, transvascular exchange and elimination. The results obtained in this study could provide suggestions for the future optimisation of this FUS-MB–liposome combination therapy against brain cancer.

PEG-DOX, novel pH responsive prodrug nanoparticles

pH responsive prodrug nanoparticles (PEG-DOX) were prepared by attaching free Doxorubicin ( DOX) onto the amphipathic polyethylene glycol-aldehyde (PEG-CHO). The hydrophobic core of PEG-CHO enabled free DOX to be attached, while the hydrophilic outer layer of the carrier enabled the water solubility of the entire structure. This nanocarrier enabled a greater carrying capacity than free DOX, making its circulation time longer. The prodrug remained stable within neutral pH, ensuring its prolonged circulation time, but disassembled rapidly when reaching in the acidic environment of tumor tissues to release the free DOX. The newly designed nanocarriers have the potential to be applied clinically as a future DOX formulation in cancer chemotherapy.

Tumor Drug Distribution after Local Drug Delivery by Hyperthermia, In Vivo

Tumor drug distribution and concentration are important factors for effective tumor treatment. A promising method to enhance the distribution and the concentration of the drug in the tumor is to encapsulate the drug in a temperature sensitive liposome. The aim of this study was to investigate the tumor drug distribution after treatment with various injected doses of different liposomal formulations of doxorubicin, ThermoDox (temperature sensitive liposomes) and DOXIL (non-temperature sensitive liposomes), and free doxorubicin at macroscopic and microscopic levels. Only ThermoDox treatment was combined with hyperthermia. Experiments were performed in mice bearing a human fibrosarcoma. At low and intermediate doses, the largest growth delay was obtained with ThermoDox, and at the largest dose, the largest growth delay was obtained with DOXIL. On histology, tumor areas with increased doxorubicin concentration correlated with decreased cell proliferation, and substantial variations in doxorubicin heterogeneity were observed. ThermoDox treatment resulted in higher tissue drug levels than DOXIL and free doxorubicin for the same dose. A relation with the distance to the vasculature was shown, but vessel perfusion was not always sufficient to determine doxorubicin delivery. Our results indicate that tumor drug distribution is an important factor for effective tumor treatment and that its dependence on delivery formulation merits further systemic investigation.

Amylase-Sensitive Polymeric Nanoparticles Based on Dextran Sulfate and Doxorubicin with Anticoagulant Activity

This study looked into the synthesis and study of Dextrane Sulfate–Doxorubicin Nanoparticles (DS–Dox NP) that are sensitive to amylase and show anticoagulant properties. The particles were obtained by the method of solvent replacement. They had a size of 305 ± 58 nm, with a mass ratio of DS:Dox = 3.3:1. On heating to 37 °C, the release of Dox from the particles was equal to 24.2% of the drug contained. In the presence of amylase, this ratio had increased to 42.1%. The study of the biological activity of the particles included an assessment of the cytotoxicity and the effect on hemostasis and antitumor activity. In a study of cytotoxicity on the L929 cell culture, it was found that the synthesized particles had less toxicity, compared to free doxorubicin. However, in the presence of amylase, their cytotoxicity was higher than the traditional forms of the drug. In a study of the effect of DS–Dox NP on hemostasis, it was found that the particles had a heparin-like anticoagulant effect. Antitumor activity was studied on the model of ascitic Zaidel hepatoma in rats. The frequency of complete cure in animals treated with the DS–Dox nanoparticles was higher, compared to animals receiving the traditional form of the drug.