Seyed Yazdan Madani

A new era of cancer treatment: carbon nanotubes as drug delivery tools

Cancer is a generic term that encompasses a group of diseases characterized by an uncontrolled proliferation of cells. There are over 200 different types of cancer, each of which gains its nomenclature according to the type of tissue the cell originates in. Many patients who succumb to cancer do not die as a result of the primary tumor, but because of the systemic effects of metastases on other regions away from the original site. One of the aims of cancer therapy is to prevent the metastatic process as early as possible. There are currently many therapies in clinical use, and recent advances in biotechnology lend credence to the potential of nanotechnology in the fight against cancer. Nanomaterials such as carbon nanotubes (CNTs), quantum dots, and dendrimers have unique properties that can be exploited for diagnostic purposes, thermal ablation, and drug delivery in cancer. CNTs are tubular materials with nanometer-sized diameters and axial symmetry, giving them unique properties that can be exploited in the diagnosis and treatment of cancer. In addition, CNTs have the potential to deliver drugs directly to targeted cells and tissues. Alongside the rapid advances in the development of nanotechnology-based materials, elucidating the toxicity of nanoparticles is also imperative. Hence, in this review, we seek to explore the biomedical applications of CNTs, with particular emphasis on their use as therapeutic platforms in oncology.

A concise review of carbon nanotube's toxicology.

Carbon nanotubes can be either single-walled or multi-walled, each of which is known to have a different electron arrangement and as a result have different properties. However, the shared unique properties of both types of carbon nanotubes (CNT) allow for their potential use in various biomedical devices and therapies. Some of the most common properties of these materials include the ability to absorb near-infra-red light and generate heat, the ability to deliver drugs in a cellular environment, their light weight, and chemical stability. These properties have encouraged scientists to further investigate CNTs as a tool for thermal treatment of cancer and drug delivery agents. Various promising data have so far been obtained about the usage of CNTs for cancer treatment; however, toxicity of pure CNTs represents a major challenge for clinical application. Various techniques both in vivo and in in vitro have been conducted by a number of different research groups to establish the factors which have a direct effect on CNT-mediated cytotoxicity. The main analysis techniques include using Alamar blue, MTT, and Trypan blue assays. Successful interpretation of these results is difficult because the CNTs can significantly disrupt the emission of the certain particles, which these assays detect. In contrast, in vivo studies allow for the measurement of toxicity and pathology caused by CNTs on an organismal level. Despite the drawbacks of in vitro studies, they have been invaluable in identifying important toxicity factors, such as size, shape, purity, and functionalisation, the latter of which can attenuate CNT toxicity.

Stem cell tracking using iron oxide nanoparticles

Superparamagnetic iron oxide nanoparticles (SPIONs) are an exciting advancement in the field of nanotechnology. They expand the possibilities of noninvasive analysis and have many useful properties, making them potential candidates for numerous novel applications. Notably, they have been shown that they can be tracked by magnetic resonance imaging (MRI) and are capable of conjugation with various cell types, including stem cells. In-depth research has been undertaken to establish these benefits, so that a deeper level of understanding of stem cell migratory pathways and differentiation, tumor migration, and improved drug delivery can be achieved. Stem cells have the ability to treat and cure many debilitating diseases with limited side effects, but a main problem that arises is in the noninvasive tracking and analysis of these stem cells. Recently, researchers have acknowledged the use of SPIONs for this purpose and have set out to establish suitable protocols for coating and attachment, so as to bring MRI tracking of SPION-labeled stem cells into common practice. This review paper explains the manner in which SPIONs are produced, conjugated, and tracked using MRI, as well as a discussion on their limitations. A concise summary of recently researched magnetic particle coatings is provided, and the effects of SPIONs on stem cells are evaluated, while animal and human studies investigating the role of SPIONs in stem cell tracking will be explored.

Functionalization of single-walled carbon nanotubes and their binding to cancer cells

Background Single-walled carbon nanotubes (SWCNTs) have novel properties including their nanoscale size and ease of cellular uptake. This makes them useful for drug delivery, and their photo-thermal effects make them potentially useful in a wide range of applications, particularly the treatment of solid tumors. The poor solubility of SWCNTs has, however, been an issue that may potentially limit the utility of SWCNTs for cancer treatment. Functionalization of the surface of the tubes may be an approach to overcome this problem. Methods SWCNTs were refluxed in HNO3/H2SO4 (1:3) at 120°C for 120 minutes. Transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), contact angle measurements, and near infrared (NIR) light exposure were used to assess the functionalization process. The attachment of a carbohydrate-binding protein (lectin) labeled with fluorescein isothiocyanate to the functionalized SWCNTs enabled evaluation of the functionalization step via confocal microscopy. The lectin from Helix pomatia, (Helix pomatia agglutinin [HPA]), can detect changes in protein glycosylation associated with aggressive metastatic cancer. The interaction between the lectin HPA alone and HPA conjugated to the functionalized SWCNTs with human breast cancer cells (MCF-7) was measured using a quartz crystal microbalance biosensor. Results Following the functionalization process, TEM images showed a layer had formed on the surface of the SWCNTs. In the FTIR experiment, results illustrated the presence of the −COOH group on the functionalized SWCNTs. Contact angle measurements showed that upon functionalization the hydrophilicity of the SWCNTs increased. The temperature increase in the liquid (supernatant) surrounding the functionalized SWCNTs following exposure to light in the NIR (808 nm) was greater than for non-functionalized SWCNTs. The biosensor work showed that HPA binds with high affinity (nanomolar range) to human breast cancer cells; HPA-binding properties to MCF-7 cells were retained following conjugation to the functionalized SWCNTs. Conclusion Treating pure SWCNTs with HNO3/H2SO4 (1:3) at 120°C for 120 minutes is an effective method for functionalization of SWCNTs. HPA linked to SWCNTs is a suitable candidate for the delivery of the functionalized SWCNTs to cancer cells.

Conjugation of quantum dots on carbon nanotubes for medical diagnosis and treatment

Cancer is one of the leading causes of death worldwide and early detection provides the best possible prognosis for cancer patients. Nanotechnology is the branch of engineering that deals with the manipulation of individual atoms and molecules. This area of science has the potential to help identify cancerous cells and to destroy them by various methods such as drug delivery or thermal treatment of cancer. Carbon nanotubes (CNT) and quantum dots (QDs) are the two nanoparticles, which have received considerable interest in view of their application for diagnosis and treatment of cancer. Fluorescent nanoparticles known as QDs are gaining momentum as imaging molecules with life science and clinical applications. Clinically they can be used for localization of cancer cells due to their nano size and ability to penetrate individual cancer cells and high-resolution imaging derived from their narrow emission bands compared with organic dyes. CNTs are of interest to the medical community due to their unique properties such as the ability to deliver drugs to a site of action or convert optical energy into thermal energy. By attaching antibodies that bind specifically to tumor cells, CNTs can navigate to malignant tumors. Once at the tumor site, the CNTs enter into the cancer cells by penetration or endocytosis, allowing drug release, and resulting in specific cancer cell death. Alternatively, CNTs can be exposed to near-infrared light in order to thermally destroy the cancer cells. The amphiphilic nature of CNTs allows them to penetrate the cell membrane and their large surface area (in the order of 2600 m2/g) allows drugs to be loaded into the tube and released once inside the cancer cell. Many research laboratories, including our own, are investigating the conjugation of QDs to CNTs to allow localization of the cancer cells in the patient, by imaging with QDs, and subsequent cell killing, via drug release or thermal treatment. This is an area of huge interest and future research and therapy will focus on the multimodality of nanoparticles. In this review, we seek to explore the biomedical applications of QDs conjugated to CNTs, with a particular emphasis on their use as therapeutic platforms in oncology.

Synergistic photothermal ablative effects of functionalizing carbon nanotubes with a POSS-PCU nanocomposite polymer

BackgroundThe application of nanotechnology in biology and medicine represents a significant paradigm shift in the approach to the treatment of cancer. Evidence suggests that when exposed to near-infrared radiation (NIR), carbon nanotubes (CNTs) dissipate a substantial amount of heat energy. We have developed a novel nanocomposite polymer, polyhedral oligomeric silsesquioxane poly (carbonate-urea) urethane (POSS-PCU). POSS-PCU displays excellent biocompatibility and has been used in making artificial organs as well as protective coatings for medical devices.ResultsFunctionalizing (or “coating”) CNTs with POSS-PCU confers biocompatibility and increase the amount of heat energy generated, by enhancing dispersion. Here we demonstrate that POSS-PCU-functionalized multi-walled CNTs (MWNTs) act synergistically together when exposed to NIR to thermally ablate cancer cells.ConclusionGiven that POSS-PCU has already been used in human in first-in-man studies as trachea, lacrimal duct, bypass graft and other organs, our long-term goal is to take POSS-PCU coated CNTs to clinical studies to address the treatment of cancer by optimizing its therapeutic index and increasing its specificity via antibody conjugation.

Carbon Nanotubes in the Diagnosis and Treatment of Malignant Melanoma

The potential role of carbon nanotubes (CNTs) in the diagnosis and treatment of malignant melanoma (MM) is still an emerging area of research. To date, there is strong evidence for the efficiency of CNTs in this therapeutic area, despite their unique physical, mechanical and biological properties. In this review, the application of CNTs in cancer diagnostics and treatment is reviewed, and consideration is given to the toxicity issues associated with their use.

Octa-ammonium POSS-conjugated single-walled carbon nanotubes as vehicles for targeted delivery of paclitaxel

Background Carbon nanotubes (CNTs) have unique physical and chemical properties. Furthermore, novel properties can be developed by attachment or encapsulation of functional groups. These unique properties facilitate the use of CNTs in drug delivery. We developed a new nanomedicine consisting of a nanocarrier, cell-targeting molecule, and chemotherapeutic drug and assessed its efficacy in vitro. Methods The efficacy of a single-walled carbon nanotubes (SWCNTs)-based nanoconjugate system is assessed in the targeted delivery of paclitaxel (PTX) to cancer cells. SWCNTs were oxidized and reacted with octa-ammonium polyhedral oligomeric silsesquioxanes (octa-ammonium POSS) to render them biocompatible and water dispersable. The functionalized SWCNTs were loaded with PTX, a chemotherapeutic agent toxic to cancer cells, and Tn218 antibodies for cancer cell targeting. The nanohybrid composites were characterized with transmission electron microscopy (TEM), Fourier transform infrared (FTIR), and ultraviolet–visible–near-infrared (UV–Vis–NIR). Additionally, their cytotoxic effects on Colon cancer cell (HT-29) and Breast cancer cell (MCF-7) lines were assessed in vitro. Results TEM, FTIR, and UV–Vis–NIR studies confirmed side-wall functionalization of SWCNT with COOH-groups, PTX, POSS, and antibodies. Increased cell death was observed with PTX–POSS–SWCNT, PTX–POSS–Ab–SWCNT, and free PTX compared to functionalized-SWCNT (f-SWCNT), POSS–SWCNT, and cell-only controls at 48 and 72 h time intervals in both cell lines. At all time intervals, there was no significant cell death in the POSS–SWCNT samples compared to cell-only controls. Conclusion The PTX-based nanocomposites were shown to be as cytotoxic as free PTX. This important finding indicates successful release of PTX from the nanocomposites and further reiterates the potential of SWCNTs to deliver drugs directly to targeted cells and tissues.

Cancer Antibody Enhanced Real Time Imaging Cell Probes - a Novel Theranostic Tool using Polymer Linked Carbon Nanotubes and Quantum Dots

BACKGROUND Cancer is a potentially fatal diagnosis, but due to modern medicine there is a potential cure in many of these cases. The rate of treatment success depends on early disease detection and timely, effective delivery of tumour specific treatment. There are many ongoing researches aimed to improve diagnostics or treatment, but the option to use both modalities concomitantly is deficient. In this project we are using the advances in nanotechnology to develop new theranostic tool using single walled carbon nanotubes (SWCNT) and Quantum dots (QDs) for early cancer cell detection, and option to deliver targeted treatment. METHOD SWCNTs were refluxed in HNO3/H2SO4 (1:3) at 120ºC for 120 minutes. Functionalised SWCNT was then covalently attached to octa-ammonium polyhedral oligomeric silsesquioxane (POSS), QDs and conjugated with antibodies for targeted cell detection. Fourier transforms infrared spectroscopy (FTIR), Transmission electron microscopy (TEM), UV/NIR analysis, Raman and UV-VIS spectroscopy were used in order to prove the successful conjugation. Toxicology study using alamar blue analysis and DNA assay was conducted in order to choose the best concentration of SWCNT, octa-ammonium-POSS and QDs before commencing the conjugation process. Human colorectal cancer cell line HT29, pancreas cancer cell line PANC-1 and mouse fibroblasts 3T3 were then treated with or without antibody conjugated SWCNT-POSS-QDs (CPQ) compound solution. The cell response was observed under the microscope after 24, 48 and 72 hours. RESULTS FTIR and Raman spectroscopies confirmed covalent binding of the SWCNTs to Octa-Ammonium-POSS. This was supported by TEM images and photos obtained, which showed well dispersed SWCNTs following its treatment with Octa-Ammonium-POSS compared to pristine SWCNT samples. UV-VIS graphs determined the presence of antibody within the compound. UV/NIR demonstrated QD fluorescence even after attachment of SWCNT-POSS. The cellular behaviour revealed high CPQ-antibody complex affinity towards cancer cells when compared to healthy cell line which internalised the complex only on day three. The pancreas cancer cell line had appearance of lysed pulp after 72 hours of incubation. Colonic cancer cells seemed to regain ability to populate from day three signifying that higher treatment payload is necessary. CONCLUSION We have successfully manufactured novel compound consisting of Octa-Ammonium-POSS linked SWCNTs, QDs, and tumour specific antibodies. The complex has proven its potential as cell probing tool, and the attachment of antibodies has shown high affinity to cancer cells rendering this an attractive model for further theranostic developments.

Biological dosimetry for breast cancer radiotherapy: a comparison of external beam and intraoperative radiotherapy

PurposeExternal beam radiotherapy (EBRT) is the gold standard adjuvant treatment after breast conserving surgery although a recent phase 3 trial has shown the non-inferiority of intraoperative radiotherapy (IORT).Radiation exposure of the heart and cardiac vessels causes an increase in morbidity and mortality following EBRT for breast cancer.We have used γ-H2AX foci formation in peripheral blood lymphocytes as a surrogate marker of dose delivered to the heart and great vessels and have assessed the feasibility of using this technique for biological dosimetry.Methods34 patients were recruited, having either EBRT or IORT as part of a randomised controlled trial (TARGIT). Blood samples were taken prior to and after first fraction of radiotherapy, and the γ-H2AX biomarker then quantified.ResultsData were available for 31 patients. Following TARGIT-IORT there was an increase of 0.203 foci per cell (range −1.436 to 1.275) compared with 0.935 foci per cell (range −0.679 to 2.216) in the EBRT group; this difference was highly significant (p = 0.009). As TARGIT-IORT treatment is completed with a single fraction, whilst EBRT requires at least 15 fractions, the actual difference is estimated to be many times more.ConclusionsThese data show a significantly greater change in γ-H2AX foci number per cell following one fraction of EBRT compared to TARGIT-IORT. This is the first study to demonstrate this effect using a biomarker and demonstrates a proof of concept methodology for similar applications.