Delivering nanomedicine to solid tumors

Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom Street, Boston, MA 02114, USA.
Nature Reviews Clinical Oncology (Impact Factor: 14.18). 11/2010; 7(11):653-64. DOI: 10.1038/nrclinonc.2010.139
Source: PubMed

ABSTRACT Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors.

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Available from: Triantafyllos Stylianopoulos, Jun 02, 2015
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    • "One of the ideas with a great potential in this area is the targeted delivery of drugs and imaging agents through micro-and nano-particles [2]. A very challenging task is to design suitable carriers which would meet several demands including good adhesion properties to targeted sites in blood flow, efficient transport through the biological barriers (e.g., vessel walls, interstitial space, and cell membranes), and low clearance by various defense mechanisms of the body [3] [4] [5] [6] [7]. Proposed solutions are polymer conjugates, which are already in clinical use [8] [9], fabricated nano-particles [9] [10], and self-assembled structures from lipids or block copolymers forming liposomes, polymersomes, or worm-like micelles [9]. "
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    ABSTRACT: Targeted delivery of drugs and imaging agents is very promising to develop new strategies for the treatment of various diseases such as cancer. For an efficient targeted adhesion, the particles have to migrate toward the walls in blood flow - a process referred to as margination. Due to a huge diversity of available carriers, a good understanding of their margination properties in blood flow depending on various flow conditions and particle properties is required. We employ a particle-based mesoscopic hydrodynamic simulation approach to investigate the margination of different carriers for a wide range of hematocrits (volume fraction of red blood cells) and flow rates. Our results show that margination strongly depends on the thickness of the available free space close to the wall, the so-called red blood cell-free layer (RBC-FL), in comparison to the carrier size. The carriers with a few micrometers in size are comparable with the RBC-FL thickness and marginate better than their sub-micrometer counterparts. Deformable carriers, in general, show worse margination properties than rigid particles. Particle margination is also found to be most pronounced in small channels with a characteristic size comparable to blood capillaries. Finally, different margination mechanisms are discussed.
    Medical Engineering & Physics 09/2015; DOI:10.1016/j.medengphy.2015.08.009 · 1.83 Impact Factor
    • "Overall, the reduction in functional vasculature and the increased IFP impedes transport of drugs out of the remaining perfused capillaries (reviewed in [1] [9] [10]). Additionally, the elevated IFP results in directional flow of fluid out of the tumor thereby reducing retention of drugs which are delivered [11] [12]. It has been shown that the use of some cytotoxic therapies can, by inducing apoptosis of tumor cells, lead to decompression of blood vessels (e.g. "
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    ABSTRACT: Interstitial fluid pressure (IFP) is elevated in tumors and high IFP, a negative cancer prognosticator, is known to limit the uptake and efficacy of anti-tumor therapeutics. Approaches that alter the tumor microenvironment and enhance uptake of therapeutics are collectively referred to as tumor "priming". Here we show that the cytotoxic biological therapy Apo2L/TRAIL can prime the tumor microenvironment and significantly lower IFP in three different human tumor xenograft models (Colo205, MiaPaca-2 and a patient gastrointestinal adenocarcinoma tumor xenograft). We found that a single dose of Apo2L/TRAIL resulted in a wave of apoptosis which reached a maximum at 8hrs post-treatment. Apoptotic debris subsequently disappeared concurrent with an increase in macrophage infiltration. By 24hrs post-treatment, treated tumors appeared less condensed with widening of the stromal areas which increased at 48 and 72hrs. Analysis of tumor vasculature demonstrated a significant increase in overall vessel size at 48 and 72hrs although the number of vessels did not change. Notably, IFP was significantly reduced in these tumors by 48hrs after Apo2L/TRAIL treatment. Administration of gemcitabine at this time resulted in increased tumor uptake of both gemcitabine and liposomal gemcitabine and significantly improved anti-tumor efficacy of liposomal gemcitabine. These results suggest that Apo2L/TRAIL has potential as a tumor priming agent and provides a rationale for developing a sequencing schema for combination therapy such that an initial dose of Apo2L/TRAIL would precede administration of gemcitabine or other therapies.
    Journal of Controlled Release 09/2015; DOI:10.1016/j.jconrel.2015.08.047 · 7.71 Impact Factor
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    • "The performance of systemic chemotherapy, accomplished with both traditional and innovative drugs, is restricted by a series of biological barriers hindering an effective drug delivery after intravenous administration. Actually, solid tumors have inherently aberrant features, such as a highly fibrous matrix and an abnormal blood flow in their inner regions and frontier, which limit the delivery of drugs to the target tissue because of arterial-venous shunting and a strong interstitial pressure gradient [1] [2] [3]. Furthermore, only a tiny fraction of chemotherapeutic agent(s) can reach the tumor site because of their non-specific distribution and uptake by the reticuloendothelial system (RES) [4]. "
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    ABSTRACT: The balance between dose-dependent tolerability, effectiveness and toxicity of systemically administered antitumor drugs is extremely delicate. This issue highlights the striking need for targeted release of chemotherapeutic drugs within tumors. In this work, a smart strategy of drug targeting to tumors relying upon biodegradable/biocompatible nanoparticles releasing cytotoxic drugs after sensing physiological variations intrinsic to the very nature of tumor tissues is exploited. Here, the well-known over-expression of matrix metallo-proteinase 2 (MMP2) enzyme in tumors has been chosen as a trigger for the release of a cytotoxic drug. Nanoparticles made up of a biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) - block - polyethylene glycol (PEG) copolymer (namely PELGA), blended with a tumor-activated prodrug (TAP) composed of a MMP2-sensitive peptide bound to doxorubicin (Dox) and to PLGA chain have been produced. The obtained devices are able to release Dox specifically upon MMP2 cleavage of the TAP. More interestingly, they can sense the differences in the expression levels of endogenous MMP2 protein, thus modulating drug penetration within a three-dimensional (3D) tumor spheroid matrix, accordingly. Therefore, the proposed nanoparticles hold promise as a useful tool for in vivo investigations aimed at an improved therapeutic efficacy of the conjugated drug payload. Copyright © 2015 Elsevier B.V. All rights reserved.
    Colloids and surfaces B: Biointerfaces 08/2015; 135:707-716. DOI:10.1016/j.colsurfb.2015.08.016 · 4.15 Impact Factor
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