78 research outputs found
Three dimensional spheroids and gold nanoparticles in combined cancer therapy
No full textOne of the major issues in cancer radiotherapy (RT) is normal tissue toxicity.
Introduction of radiosensitizers like gold nanoparticles (GNPs) into cancer cells to
enhance the local RT dose is a promising technique that is being explored. However,
a large portion of experimentation involving GNPs has been done in simple two-dimensional (2D) monolayer models that cannot properly encapsulate the complex
heterogeneous interactions that occur in vivo. By introducing an in vitro three-dimensional (3D) model that better mimics the tumour microenvironment (TME),
we can more rapidly facilitate a quicker translation of various treatment technologies
like GNPs to the clinic. Further, clinical trials show that the chemotherapy drug
docetaxel (DTX) given in conjunction with RT can improve survival in high-risk
cancers. Addition of GNPs to this current DTX/RT protocol is expected to further
improve therapeutic benefits. Elucidation of a combined therapy of GNPs, DTX, and
RT to optimize treatment can better improve patient outcome and reduce normal
tissue toxicity by specifically targeting tumours and is completely novel research.
The work in this dissertation explores the application of GNPs to various elements
that are present in a TME. Many cell types are present in TME and contribute in
different ways to the proliferation of cancer. One of these cell lines, cancer associated
fibroblasts (CAFs), which can promote tumour growth and metastasis, was compared
to cancer epithelial cells and normal fibroblasts (FBs). Hence, we used FBs and CAFs
to evaluate the differences in GNP uptake and resulting radiation induced damage.
It was found that the CAFs had a much larger uptake of GNPs relative to the other
cells, with on average 265% more GNPs relative to cervical cancer cells while FBs
had only 7.55% the uptake of the tumour cells and 2.87% the uptake of CAFs. This
translated to increases in 53BP1-related DNA damage foci in CAFs (13.5%) and
tumour cells (9.8%) along with FBs (8.8%), compared to control with RT treatment.
This difference in DNA damage due to selective targeting of cancer associated cells
over normal cells may allow GNPs to be an effective tool in future cancer RT to battle
normal tissue toxicity while improving local RT dose to the tumour.
To expedite a quicker clinical translation, 3D tumor spheroid models were optimized and compared to 2D monolayer. The uptake of various sizes of GNPs was
tested on monolayer and spheroids to evaluate the differences between a 2D and 3D
model in similar conditions. Moreover, combined treatment of GNPs with DTX was
introduced and how they effect the uptake of the GNPs was elucidated.iv
In the 2D monolayer model, the addition of DTX induced a small increase of
uptake of GNPs of between 13% and 24%, while in the 3D spheroid model, DTX
increased uptake by between 47% and 186%. It was observed that the more complex
spheroid, which introduces an extracellular matrix, had larger uptake and penetration
of smaller GNPs (15 nm) relative to larger GNPs (50 nm). Moreover, while the
addition of DTX had a beneficial effect on the uptake of GNPs into cells, it also
synchronized the cells into a radiosensitive cell cycle phase. This translated to a larger
effect when radiation was introduced, in a combined treatment modality with GNP,
DTX, and RT. In spheroids, the addition of GNPs to the treatment regime decreased
the surviving tumour cells by 16-32% compared to samples not treated with GNPs.
Further, the addition of DTX seems to synergistically increase damage in some cancer
cell lines. This work highlights the necessity to optimize GNP treatment conditions in
a more realistic tumor-like environment. A 3D spheroid model can capture important
details which are absent from a simple 2D monolayer model.Graduat
Optimization of Bio-Nano Interface Using Gold Nanostructures as a Model Nanoparticle System
No full text
Colloidal Gold-Mediated Delivery of Bleomycin for Improved Outcome in Chemotherapy
No full textNanoparticles (NPs) can be used to overcome the side effects of poor distribution of anticancer drugs. Among other NPs, colloidal gold nanoparticles (GNPs) offer the possibility of transporting major quantities of drugs due to their large surface-to-volume ratio. This is while confining these anticancer drugs as closely as possible to their biological targets through passive and active targeting, thus ensuring limited harmful systemic distribution. In this study, we chose to use bleomycin (BLM) as the anticancer drug due to its limited therapeutic efficiency (harmful side effects). BLM was conjugated onto GNPs through a thiol bond. The effectiveness of the chemotherapeutic drug, BLM, is observed by visualizing DNA double strand breaks and by calculating the survival fraction. The action of the drug (where the drug takes effect) is known to be in the nucleus, and our experiments have shown that some of the GNPs carrying BLM were present in the nucleus. The use of GNPs to deliver BLM increased the delivery and therapeutic efficacy of the drug. Having a better control over delivery of anticancer drugs using GNPs will establish a more successful NP-based platform for a combined therapeutic approach. This is due to the fact that GNPs can also be used as radiation dose enhancers in cancer research
Advances in Gold Nanoparticle-Based Combined Cancer Therapy
No full textAccording to the global cancer observatory (GLOBOCAN), there are approximately 18 million new cancer cases per year worldwide. Cancer therapies are largely limited to surgery, radiotherapy, and chemotherapy. In radiotherapy and chemotherapy, the maximum tolerated dose is presently being used to treat cancer patients. The integrated development of innovative nanoparticle (NP) based approaches will be a key to address one of the main issues in both radiotherapy and chemotherapy: normal tissue toxicity. Among other inorganic NP systems, gold nanoparticle (GNP) based systems offer the means to further improve chemotherapy through controlled delivery of chemotherapeutics, while local radiotherapy dose can be enhanced by targeting the GNPs to the tumor. There have been over 20 nanotechnology-based therapeutic products approved for clinical use in the past two decades. Hence, the goal of this review is to understand what we have achieved so far and what else we can do to accelerate clinical use of GNP-based therapeutic platforms to minimize normal tissue toxicity while increasing the efficacy of the treatment. Nanomedicine will revolutionize future cancer treatment options and our ultimate goal should be to develop treatments that have minimum side effects, for improving the quality of life of all cancer patients.The authors would like to acknowledge Canada Foundation for Innovation (CFI), the British
Columbia government, Natural Sciences and Engineering Research Council of Canada (NSERC), British Columbia
Cancer, Vancouver Island (BCC), Centre for Advanced Materials and Related Technologies (CAMTEC),
and University of Victoria for their financial support.FacultyReviewe
Nuclear Targeting Dynamics of Gold Nanoclusters for Enhanced Therapy of HER2(+) Breast Cancer
No full textRecent advances in fluorescent metal nanoclusters have spurred tremendous interest In nanomedicine due to the ease of fabrication, excellent biocompatibility, and, more Importantly, excellent wavelength-dependent tunability. Herein, we report our findings on fluorescent BSA-protected gold nanoclusters (AuNCs), similar to 2 nm in size conjugated with Herceptin (AuNCs-Her), for specific targeting and nuclear localization in ErbB2 over-expressing breast cancer cells and tumor tissue as a novel fluorescent agent for simultaneous imaging and cancer therapy. More interestingly, we found that AuNCs-Her could escape the endolysosomal pathway and enter the nucleus of cancer cells to enhance the therapeutic efficacy of Herceptin. We elucidate the diffusion characteristics (diffusion time and number of diffusers) and concentration of the fluorescing dusters in the nucleus of live cells. Our findings also suggest that the nuclear localization effect of AuNCs-Her enhances the anticancer therapeutic efficacy of Herceptin as evidenced by the induction of DNA damage. This study not only discusses a new nanomaterial platform for nuclear delivery of drugs but also provides important insights on nuclear targeting for enhanced therapy
Gold Nanostructures as a Platform for Combinational Therapy in Future Cancer Therapeutics
No full textThe field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research
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