Nanotechnology-Based Cancer Therapeutics-Promise and Challenge-Lessons Learned Through the NCI Alliance for Nanotechnology in Cancer
ABSTRACT The new generation of nanotechnology-based drug formulations is challenging the accepted ways of cancer treatment. Multi-functional nanomaterial constructs have the capability to be delivered directly to the tumor site and eradicate cancer cells selectively, while sparing healthy cells. Tailoring of the nano-construct design can result in enhanced drug efficacy at lower doses as compared to free drug treatment, wider therapeutic window, and lower side effects. Nanoparticle carriers can also address several drug delivery problems which could not be effectively solved in the past and include reduction of multi-drug resistance effects, delivery of siRNA, and penetration of the blood-brain-barrier. Although challenges in understanding toxicity, biodistribution, and paving an effective regulatory path must be met, nanoscale devices carry a formidable promise to change ways cancer is diagnosed and treated. This article summarizes current developments in nanotechnology-based drug delivery and discusses path forward in this field. The discussion is done in context of research and development occurring within the NCI Alliance for Nanotechnology in Cancer program.
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ABSTRACT: Glioblastoma (GBM) is simultaneously the most common and most malignant subtype tumor of the central nervous system. These are particularly dramatic diseases ranking first among all human tumor types for tumor-related average years of life lost and for which curative therapies are not available. Recently, the use of nanoparticles as drug delivery systems (DDS) for tumor treatment has gained particular interest. In an attempt to evaluate the potential of carboxymethylchitosan/poly(amidoamine) (CMCht/PAMAM) dendrimer nanoparticles as a DDS, we aimed to evaluate its cytotoxicity and internalization efficiency in GBM cell models. CMCht/PAMAM-mediated cytotoxicity was evaluated in a GBM cell line (U87MG) and in human immortalized astrocytes (hTERT/E6/E7) by MTS and double-stranded DNA quantification. CMCht/PAMAM internalization was assessed by double fluorescence staining. Both cells lines present similar internalization kinetics when exposed to a high dose (400 μg/mL) of these nanoparticles. However, the internalization rate was higher in tumor GBM cells as compared to immortalized astrocytes when cells were exposed to lower doses (200 μg/mL) of CMCht/PAMAM for short periods (<24 h). After 48 h of exposure, both cell lines present ~100 % of internalization efficiency for the tested concentrations. Importantly, short-term exposures (1, 6, 12, 24, and 48 h) did not show cytotoxicity, and long-term exposures (7 days) to CMCht/PAMAM induced only low levels of cytotoxicity in both cell lines (~20 % of decrease in metabolic activity). The high efficiency and rate of internalization of CMCht/PAMAM we show here suggest that these nanoparticles may be an attractive DDS for brain tumor treatment in the future.Journal of Nanoparticle Research 04/2013; DOI:10.1007/s11051-013-1621-6
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ABSTRACT: Nanocarrier systems are frequently characterized by their size distribution, while drug encapsulation in nanocarriers is generally characterized in terms of an entire population, assuming that drug distribution is uniform. Careful characterization of nanocarriers and assessment of their behavior in biological environments are essential for adequate prediction of the fate of the nanoparticles in vivo. Solid lipid nanoparticles containing [(3)H]-dexamethasone palmitate (an ester prodrug) and [(14)C]-stearyl alcohol (a component of the nanoparticle matrix) were prepared using the nanotemplate engineering method for bioresponsive tumor delivery to overcome interstitial fluid pressure gradients, a physiological barrier to tumor uptake of chemotherapeutic agents. While particle size analysis indicated a uniform size distribution of 93.2 ± 0.5 nm, gel filtration chromatography (GFC) revealed two nanoparticle populations. Drug encapsulation efficiency was 97%, but it distributed differently in the two populations, with average drug/lipid ratios of 0.04 and 0.25, respectively. The difference in surface properties resulted in distinguishing protein adsorption features of the two populations. GFC and HPLC profiles of the mixture of nanoparticles and human serum albumin (HSA) showed that no HSA was adsorbed to the first population of nanoparticles, but minor amounts were adsorbed to the second population. After 24 h incubation in 50% human plasma, ≥80% of the [(3)H]-dexamethasone palmitate was associated with nanoparticles. Thus, characterization of solid lipid nanoparticles produced by this method may be challenging from a regulatory perspective, but the strong association of the drug with the nanoparticles in plasma indicates that this nanocarrier system has the potential for in vivo application.ACS Nano 01/2011; 5(1):209-16. DOI:10.1021/nn102357y
Article: Nanomedicine(s) under the Microscope[Show abstract] [Hide abstract]
ABSTRACT: Depending on the context, nanotechnologies developed as nanomedicines (nanosized therapeutics and imaging agents) are presented as either a remarkable technological revolution already capable of delivering new diagnostics, treatments for unmanageable diseases, and opportunities for tissue repair or highly dangerous nanoparticles, nanorobots, or nanoelectronic devices that will wreak havoc in the body. The truth lies firmly between these two extremes. Rational design of "nanomedicines" began almost half a century ago, and >40 products have completed the complex journey from lab to routine clinical use. Here we critically review both nanomedicines in clinical use and emerging nanosized drugs, drug delivery systems, imaging agents, and theranostics with unique properties that promise much for the future. Key factors relevant to the design of practical nanomedicines and the regulatory mechanisms designed to ensure safe and timely realization of healthcare benefits are discussed.Molecular Pharmaceutics 12/2011; 8(6):2101-41. DOI:10.1021/mp200394t