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Design considerations for nanotherapeutics in oncology.

ABSTRACT: Nanotherapeutics have improved the quality of life of cancer patients, primarily by reducing the adverse effects of chemotherapeutic agents, but improvements in overall survival are modest. This is in large part due to the fact that the enhanced permeability and retention effect, which is the basis for the use of nanoparticles in cancer, can be also a barrier to the delivery of nanomedicines. A careful design of nanoparticle formulations can overcome barriers posed by the tumor microenvironment and result in better treatments. In this review, we first discuss strengths and limitations of clinically-approved nanoparticles. Then, we evaluate design parameters that can be modulated to optimize delivery. The benefits of active tumor targeting and drug release rate on intratumoral delivery and treatment efficacy are also discussed. Finally, we suggest specific design strategies that should optimize delivery to most solid tumors and discuss under what conditions active targeting would be beneficial.Advances in nanotechnology have seen the introduction of new treatment modalities for cancer. The principle of action using nanocarriers for drug delivery is based mostly on the Enhanced Permeability and Retention effect. This phenomenon however, can also be a hindrance. In this article, the authors performed an in-depth review on various nanoparticle platforms in cancer therapeutics. They also suggested options to improve drug delivery, in terms of carrier design.

SUBMITTER: Stylianopoulos T

PROVIDER: S-EPMC4628869 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Design considerations for nanotherapeutics in oncology.

Stylianopoulos Triantafyllos T Jain Rakesh K RK

Nanomedicine : nanotechnology, biology, and medicine 20150815 8

Nanotherapeutics have improved the quality of life of cancer patients, primarily by reducing the adverse effects of chemotherapeutic agents, but improvements in overall survival are modest. This is in large part due to the fact that the enhanced permeability and retention effect, which is the basis for the use of nanoparticles in cancer, can be also a barrier to the delivery of nanomedicines. A careful design of nanoparticle formulations can overcome barriers posed by the tumor microenvironment ...[more]

PMID: 26282377

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Project description:Chronic transfusion of red blood cells (RBCs) to patients with β-thalassemia, sickle cell disease, and other acquired anemic disorders generates significant amounts of bioactive iron deposits in the body. The inactivation and excretion of redox active iron(III) from the blood pool and organs are critical to prevent organ damage, and are the focus of iron chelation therapy (ICT) using low molecular weight Fe(III) specific chelators. However, the current ICT is suboptimal because of the short circulation time of chelators, toxicity, severe side effects, difficult regime of administration, and patient noncompliance. To address this issue, we have designed long circulating and biodegradable nanoconjugates with enhanced circulation time and well-defined biodegradability to improve iron excretion and avoid nonspecific organ accumulation. A series of iron chelating nanoconjugates were generated with deferoxamine (DFO) as the iron(III) specific chelator using polymer scaffolds containing structurally different acidic pH sensitive ketal groups. The type of degradation linkages used in the polymer scaffold significantly influenced the vascular residence time, biodistribution, and mode of excretion of chelators in mice. Remarkably, the conjugate, BGD-60 (140 kDa; R h, 10.6 nm; cyclic ketal), exhibited the long circulation half-life (t 1/2β, 64 h), a 768-fold increase compared to DFO, and showed minimal polymer accumulation in major organs. The nanoconjugates were found to be nontoxic and excreted iron significantly better than DFO in iron overloaded mice. BGD-60 showed greater iron mobilization from plasma (p = 0.0390), spleen (p < 0.0001), and pancreas (p < 0.0001) whereas BDD-200 (340 kDa; R h, 13.7 nm; linear ketal) mobilized iron significantly better from the spleen, liver, and pancreas (p < 0.0001, p < 0.0001, and p < 0.0001, respectively) compared to DFO at equivalent doses. The nanoconjugate's favorable long blood circulation time, biodegradability, and iron excretion profiles highlight their potential for future clinical translation.

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Design considerations for nanotherapeutics in oncology.

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Design considerations for nanotherapeutics in oncology.

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