SUMMARY PARAGRAPH MicroRNAs (miRNAs) are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, miRNAs are critical cogs in numerous biological processes1,2, and dysregulated miRNA expression is correlated with many human diseases. Certain miRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumors that depend on these miRNAs are said to display oncomiR addiction3–5. Some of the most effective anticancer therapies target oncogenes like EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (i.e. antimiRs) is an evolving therapeutic strategy6,7. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells8. Here we introduce a novel antimiR delivery platform that targets the acidic tumor microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We found that the attachment of peptide nucleic acid (PNA) antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produced a novel construct that could target the tumor microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumors (pH ~6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new paradigm in the use of antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.

is an oncogenic microRNA that regulates several pathways involved in cell division and immunoregulation. It is overexpressed in numerous cancers, is often correlated with poor prognosis, and is thus a key target for future therapies. In this work we show that overexpression of miR-155 in lymphoid tissues results in disseminated lymphoma characterized by a clonal, transplantable pre-B-cell population of neoplastic lymphocytes. Withdrawal of miR-155 in mice with established disease results in rapid regression of lymphadenopathy, in part because of apoptosis of the malignant lymphocytes, demonstrating that these tumors are dependent on miR-155 expression. We show that systemic delivery of antisense peptide nucleic acids encapsulated in unique polymer nanoparticles inhibits miR-155 and slows the growth of these "addicted" pre-B-cell tumors in vivo, suggesting a promising therapeutic option for lymphoma/leukemia. oncogene | oncomiR addiction | nanotechnology M icroRNAs (miRNAs) govern nearly every biological process investigated (1-8). in particular is one of the most salient miRNAs, and although its role in immune function has been the subject of much attention (9-14), manifold studies also implicate it in cancer pathways, particularly those of hematopoietic origin (11,(15)(16)(17)(18)(19)(20)(21). miR-155 is induced in several lymphomas, such as diffuse large B-cell lymphomas, Hodgkin lymphomas, and subsets of Burkitt lymphomas (16,18,22), and ectopic expression of miR-155 in a transgenic mouse model leads to B-cell malignancy (15, 23). Furthermore, miR-155 induction in hematopoietic cells of myeloid origin results in a myeloproliferative pathology characterized by granulocyte/ monocyte expansion in lymphoid tissues (24,25). At the molecular level, miR-155 directly targets SH2-containing inositol phosphatase (SHIP1), a negative regulator of myeloid cell proliferation and survival. Furthermore, in diffuse large B-cell lymphomas, miR-155 induction and subsequent SHIP1 repression are TNF-α-dependent (23,24,26). Although these studies provide compelling evidence for miR-155 involvement in lymphoproliferative disease, the degree to which the survival of these cancers depend on maintained miR-155 expression has not been established, a crucial point to ascertain in determining whether or not inhibition of miR-155 has therapeutic promise.It is known that several protein-coding oncogenes such as Egfr, Myc, Ras, and Her2 (among others) exhibit oncogene addiction and that tumors can become dependent on maintained expression of these genes in mouse models (27)(28)(29). Recently, we described a miR-21-induced mouse model of lymphoma in which tumors were dependent on maintained expression of miR-21, demonstrating that miRNAs are a unique class of genes that mediate oncogene addiction (30).Toward cancer therapy, anti-miR molecules could potentially be used to attenuate oncogenic miRNAs, ultimately exploiting the miRNA dependence exhibited by certain tumors. In recent years, anti-miRs have emerged as useful tools for inhibiting ...

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Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro, but their usually excessive charge density makes them toxic for in vivo applications. Here we describe the synthesis of a series of high molecular weight terpolymers with low charge density, and show that they exhibit efficient gene delivery, some surpassing the efficiency of the commercial transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymerization of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumour xenografts by one of the terpolymers results in significant inhibition of tumour growth, with minimal toxicity both in vitro and in vivo. Our findings suggest that the gene delivery ability of the terpolymers stems from their high molecular weight and increased hydrophobicity, which compensates for their low charge density.

PREFACE The primary goal of nanomedicine is to improve clinical outcomes. Toward this end, targeted nanoparticles are engineered to reduce non-productive distribution while improving diagnostic and therapeutic efficacy. Paradoxically, as this field has matured, the notion of ‘targeting’ has been minimized to the concept of increasing affinity of a nanoparticle for its target. This review outlines a holistic view of nanoparticle targeting, in which nanoparticle route of administration, molecular characteristics, and temporal control are potential design variables that must be considered simultaneously. This comprehensive vision for nanoparticle targeting will hasten the integration of nanomedicines into clinical practice.