Enhancing Targeted Therapy in Breast Cancer by Ultrasound-Responsive Nanocarriers (original) (raw)
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Ultrasound in Medicine & Biology
Compared with conventional chemotherapy, encapsulation of drugs in nanoparticles can improve efficacy and reduce toxicity. However, delivery of nanoparticles is often insufficient and heterogeneous because of various biological barriers and uneven tumor perfusion. We investigated a unique multifunctional drug delivery system consisting of microbubbles stabilized by polymeric nanoparticles (NPMBs), enabling ultrasound-mediated drug delivery. The aim was to examine mechanisms of ultrasound-mediated delivery and to determine if increased tumor uptake had a therapeutic benefit. Cellular uptake and toxicity, circulation and biodistribution were characterized. After intravenous injection of NPMBs into mice, tumors were treated with ultrasound of various pressures and pulse lengths, and distribution of nanoparticles was imaged on tumor sections. No effects of low pressures were observed, whereas complete bubble destruction at higher pressures improved tumor uptake 2.3 times, without tissue damage. An enhanced therapeutic effect was illustrated in a promising proof-of-concept study, in which all tumors exhibited regression into complete remission.
Nanocarriers are heavily researched as drug delivery vehicles capable of sequestering anti-neoplastic agents and then releasing their contents at the desired location. The feasibility of using such carriers stems from their ability to produce a multimodel delivery system whereby passive, ligand and triggered targeting can be applied in the fight against cancer. Passive targeting capitalizes on the leaky nature of tumor tissue which allows for the extravasation of particles with a size smaller than 0.5 m into the tumors. Ligand targeting utilizes the concept of receptor-mediated endocytosis and involves the conjugation of ligands onto the surface of nanoparticles, while triggered targeting involves the use of external and internal stimuli to release the carriers contents upon reaching the diseased location. In this review, micelles and liposomes have been considered due to the promising results they have shown in vivo and in vitro and their potential for advancements into clinical tr...
Ultrasound-Responsive Nanocarriers in Cancer Treatment: A Review
ACS Pharmacology & Translational Science
The safe and effective delivery of anticancer agents to diseased tissues is one of the significant challenges in cancer therapy. Conventional anticancer agents are generally cytotoxins with poor pharmacokinetics and bioavailability. Nanocarriers are nanosized particles, a few of which have received clinical approval, which increase the selectivity of anticancer drugs and genes transport to tumors. They are small enough to extravasate into solid tumors where they slowly release their therapeutic load by passive leakage or by biodegradation. Using smart nanocarriers, the rate of release of the entrapped therapeutic(s) can be increased, and greater exposure of the tumor cells to the therapeutics can be achieved when the nanocarriers are exposed to certain internally (enzymes, pH and temperature) or externally applied (light, magnetic field, and ultrasound) stimuli that trigger the release of their load in a safe and controlled manner, spatially and temporally. This review gives a comprehensive overview of recent research findings on the different types of stimuliresponsive nanocarriers and their application in cancer treatment, with a particular focus on ultrasound.
Materials, 2020
High doses of chemotherapy agents can cause adverse effects. To address this issue, drug-loaded vesicles with minimum drug loss, guided by an external element for precise delivery, are desired. Combinational therapy of both a focused ultrasound-induced drug delivery method and membrane fusogenic liposomes (MFLs) as drug delivery vehicles can satisfy such premises. In this study, we confirmed that the use of a small quantity of docetaxel-loaded membrane fusogenic liposomes (DTX-MFL) with focused ultrasound can induce better antitumor response in a xenograft mouse model compared to conventional docetaxel monotherapy and DTX-MFL only.
European Journal of Pharmaceutics and Biopharmaceutics, 2019
Mastectomy is common surgical treatment used in the management of breast cancer but has associated physical and psychological consequences for the patient. Breast conservation surgery (BCS) is an alternative to mastectomy but is only possible when the tumour is of an appropriate size. Neo-adjuvant chemotherapy has been successfully used to downstage tumours and increase the number of patients eligible for BCS. However, the chemotherapies used in this approach are non-targeted and often result in significant side effects to the patient. In this manuscript, we evaluate the potential of ultrasound targeted microbubble destruction (UTMD) to deliver Rose Bengal-mediated sonodynamic therapy (SDT) in combination with paclitaxel (PTX) and doxorubicin (Dox) chemotherapy as a potential treatment for breast cancer. Efficacy of the combined treatment was determined in a threedimensional (3D) spheroid model of human breast cancer and in a murine model of the disease bearing subcutaneous MCF-7 tumours. The results demonstrated a significant reduction in both the cell viability of spheroids and tumour volume following treatment with the drug loaded microbubbles and ultrasound compared to targets treated with the drug loaded microbubbles alone or a Cremophor EL suspension of PTX and Dox. In addition, the weight of animals that received the microbubble treatment was unchanged throughout the study while a reduction of 12.1% was observed for animals treated with a Cremophor suspension of PTX/Dox. These results suggest that UTMD-mediated chemo-sonodynamic therapy is an efficacious and well tolerated approach for the treatment of breast cancer.
Pharmaceuticals, 2020
Because chemotherapeutic drugs are often associated with serious side effects, the central topic in modern drug delivery is maximizing the localization of drugs at the target while minimizing non-specific drug interactions at unwanted regions. To address this issue, biocompatible nanoparticles have been developed to enhance the drug half-life while minimizing the associated toxicity. Nevertheless, relying solely on the enhanced half-life and enhanced permeability and retention (EPR) effects has been ineffective, and designing stimulus-sensitive nanoparticles to introduce the precise control of drug release has been desired. In this paper, we introduce a pH-sensitive, reduced albumin nanoparticle in combination with focused ultrasound treatment. Not only did these nanoparticles have superior therapeutic efficacy and toxicity profiles when compared to the free drugs in xenograft mouse models, but we were also able to show that the albumin nanoparticles reported in this paper were more...
Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles
Journal of Controlled Release, 2009
The paper reports the results of nanotherapy of ovarian, breast, and pancreatic cancerous tumors by paclitaxel-loaded nanoemulsions that convert into microbubbles locally in tumor tissue under the action of tumor-directed therapeutic ultrasound. Tumor accumulation of nanoemulsions was confirmed by ultrasound imaging. Dramatic regression of ovarian, breast, and orthotopic pancreatic tumors was observed in tumor therapy through systemic injections of drug-loaded nanoemulsions combined with therapeutic ultrasound, signifying efficient ultrasound-triggered drug release from tumor-accumulated nanodroplets. The mechanism of drug release in the process of droplet-to-bubble conversion is discussed. No therapeutic effect from the nanodroplet/ultrasound combination was observed without the drug, indicating that therapeutic effect was caused by the ultrasound-enhanced chemotherapeutic action of the tumor-targeted drug, rather than the mechanical or thermal action of ultrasound itself. Tumor recurrence was observed after the completion of the first treatment round; a second treatment round with the same regimen proved less effective, suggesting that drug resistant cells were either developed or selected during the first treatment round.
Stimuli-responsive Drug Delivery Nanocarriers in the Treatment of Breast Cancer
Stimuli-responsive drug-delivery nanocarriers (DDNs) have been increasingly reported in the literature as an alternative for breast cancer therapy. Stimuli-responsive DDNs are developed with materials that present a drastic change in response to intrinsic/chemical stimuli (pH, redox and enzyme) and extrinsic/physical stimuli (ultrasound, light, magnetic field and electric current). In addition, they can be developed using different strategies, such as functionalization with signaling molecules, leading to several advantages, such as (a) improved pharmaceutical properties of liposoluble drugs, (b) selectivity with the tumor tissue decreasing systemic toxic effects, (c) controlled release upon different stimuli, which are all fundamental to improving the therapeutic effectiveness of breast cancer treatment. Therefore, this review summarizes the use of stimuli-responsive DDNs in the treatment of breast cancer. We have divided the discussions into intrinsic and extrinsic stimuli and have separately detailed them regarding their definitions and applications. Finally, we aim to address the ability of these stimuli-responsive DDNs to control the drug release in vitro and the influence on breast cancer therapy, evaluated in vivo in breast cancer models.
Application of Ultrasound for Targeted Nanotherapy of Malignant Tumors
Acoustical physics, 2009
The article describes the study of targeted chemotherapeutic intervention on solid tumors by means of ultrasound and doxorubicin- or paclitaxel-loaded perfluoropentane nanoemulsions. Nanodroplets of the emulsions accumulated in a tumor by passive targeting. Under the action of a tumor-directed therapeutic ultrasound, the nanodroplets converted into vapor microbubbles. In vivo, the nanodroplets strongly retained the loaded drugs; yet, under ultrasound-mediated vaporization they released the drugs into the tumor tissue, thereby implementing effective targeting into the tumor. The tumors subjected to this treatment regressed effectively; however, after some time they recurred. The recurring tumors were more resistant to the repeated therapy than the primary ones. At present, the causes of of the resistance development and methods for its elimination are unclear and they are under investigation.
The Potential of Ultrasound Technology and Chemotherapy Carriers in Breast Cancer Treatment
Al Qasimi Foundation Policy Paper Series , 2018
In the United Arab Emirates (UAE), breast cancer is the leading cause of death among women, and chemotherapy is widely used to treat it. However, chemotherapy drugs are not able to differentiate between the cancerous and healthy tissues. This leads to the well-known, harmful side effects of this treatment, which include hair loss, fatigue, nausea, and a weakened immune system. This paper argues for the potential effectiveness of delivering chemotherapy drugs to tumors in protective barriers (drug encapsulation in a nano-carrier) that isolate the drug from healthy tissues, minimizing side effects and increasing the quality of life of patients and their families. When injected into the bloodstream, these nanocarriers will diffuse into the tumor and ultrasonic waves can then be administered at the tumor site in order to release the chemotherapy drug from its capsule. This will restrict the drug to the physical location of the cancerous cells. This policy paper offers a number of recommendations related to furthering cancer research in the UAE and Gulf region for the benefit of citizens, residents, and those impacted by breast cancer around the world.