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      Cancer Nanomedicine: From Targeted Delivery to Combination Therapy

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          Abstract

          The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of a variety of diseases, including cancer. The unique properties of nanoparticles, such as large surface-to volume ratio, small size, the ability to encapsulate a variety of drugs, and tunable surface chemistry, gives them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make nanoparticles a mode of treatment potentially superior to conventional cancer therapies. This article highlights the most recent developments in cancer treatment using nanoparticles as drug-delivery vehicles, including promising opportunities in targeted and combination therapy.

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          Most cited references50

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          A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs.

          We previously found that a polymer conjugated to the anticancer protein neocarzinostatin, named smancs, accumulated more in tumor tissues than did neocarzinostatin. To determine the general mechanism of this tumoritropic accumulation of smancs and other proteins, we used radioactive (51Cr-labeled) proteins of various molecular sizes (Mr 12,000 to 160,000) and other properties. In addition, we used dye-complexed serum albumin to visualize the accumulation in tumors of tumor-bearing mice. Many proteins progressively accumulated in the tumor tissues of these mice, and a ratio of the protein concentration in the tumor to that in the blood of 5 was obtained within 19 to 72 h. A large protein like immunoglobulin G required a longer time to reach this value of 5. The protein concentration ratio in the tumor to that in the blood of neither 1 nor 5 was achieved with neocarzinostatin, a representative of a small protein (Mr 12,000) in all time. We speculate that the tumoritropic accumulation of these proteins resulted because of the hypervasculature, an enhanced permeability to even macromolecules, and little recovery through either blood vessels or lymphatic vessels. This accumulation of macromolecules in the tumor was also found after i.v. injection of an albumin-dye complex (Mr 69,000), as well as after injection into normal and tumor tissues. The complex was retained only by tumor tissue for prolonged periods. There was little lymphatic recovery of macromolecules from tumor tissue. The present finding is of potential value in macromolecular tumor therapeutics and diagnosis.
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            Knocking down barriers: advances in siRNA delivery

            Key Points RNA interference (RNAi) is a fundamental pathway in eukaryotic cells by which sequence-specific small interfering RNA (siRNA) is able to silence genes through the destruction of complementary mRNA. RNAi is an important therapeutic tool that can be used to silence aberrant endogenous genes or to knockdown genes essential to the proliferation of infectious organisms. Delivery remains the central challenge to the therapeutic application of RNAi technology. Before siRNA can take effect in the cytoplasm of a target cell, it must be transported through the body to the target site without undergoing clearance or degradation. Currently, the most effective synthetic, non-viral delivery agents of siRNA are lipids, lipid-like materials and polymers. Various cationic agents including stable nucleic acid–lipid particles, lipidoids, cyclodextrin polymers and polyethyleneimine polymers have been used to achieve the successful systemic delivery of siRNA in mammals without inducing significant toxicity. Direct conjugation of delivery agents to siRNA can facilitate delivery. For example, cholesterol-modified siRNA enables targeting to the liver. RNAi therapeutics have progressed to the clinic, where studies are being conducted to determine siRNA efficacy in treating several diseases, including age-related macular degeneration and respiratory syncytial virus. Moving forward, it will be important to pay close attention to the potential nonspecific immunostimulatory effects of siRNA. Modifications to siRNA can be used to minimize stimulation of the immune system, and an increased emphasis must be placed on performing proper controls to ensure that therapeutic effects are sequence-specific.
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              Tumor delivery of macromolecular drugs based on the EPR effect.

              Enhanced permeability and retention (EPR) effect is the physiology-based principal mechanism of tumor accumulation of large molecules and small particles. This specific issue of Advanced Drug Delivery Reviews is summing up multiple data on the EPR effect-based drug design and clinical outcome. In this commentary, the role of the EPR effect in the intratumoral delivery of protein and peptide drugs, macromolecular drugs and drug-loaded long-circulating pharmaceutical nanocarriers is briefly discussed together with some additional opportunities for drug delivery arising from the initial EPR effect-mediated accumulation of drug-containing macromolecular systems in tumors. Copyright © 2010 Elsevier B.V. All rights reserved.
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                Author and article information

                Journal
                100966035
                22040
                Trends Mol Med
                Trends Mol Med
                Trends in molecular medicine
                1471-4914
                1471-499X
                10 February 2015
                2 February 2015
                April 2015
                01 April 2016
                : 21
                : 4
                : 223-232
                Affiliations
                [a ]Laboratory of Nanomedicine and Biomaterials, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
                [b ]The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
                [c ]Department of Chemical, Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA
                Author notes
                Corresponding authors: Xu, X. ( xiaoyang@ 123456njit.edu ) and Farokhzad, O. ( ofarokhzad@ 123456zeus.bwh.harvard.edu )
                Article
                NIHMS661157
                10.1016/j.molmed.2015.01.001
                4385479
                25656384
                ad599f07-4141-4fba-b47a-3c40bd8217e4
                © 2015 Published by Elsevier Ltd.

                This manuscript version is made available under the CC BY-NC-ND 4.0 license.

                Categories
                Article

                Molecular medicine
                nanomedicine,targeted delivery,combination therapy,cancer
                Molecular medicine
                nanomedicine, targeted delivery, combination therapy, cancer

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