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Neha N Parayath,1 Hayley Nehoff,1 Samuel E Norton,2 Andrew J Highton,2 Sebastien Taurin,1,3 Roslyn A Kemp,2 Khaled Greish1,4 1Department of Pharmacology and Toxicology, 2Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand; 3Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, UT, USA; 4Princess Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Oral administration of paclitaxel (PTX), a broad spectrum anticancer agent, is challenged by its low uptake due to its poor bioavailability, efflux through P-glycoprotein, and gastrointestinal toxicity. We synthesized PTX nanomicelles using poly(styrene-co-maleic acid) (SMA). Oral administration of SMA-PTX micelles doubled the maximum tolerated dose (60 mg/kg vs 30 mg/kg) compared to the commercially available PTX formulation (PTX [Ebewe]). In a murine orthotopic colon cancer model, oral administration of SMA-PTX micelles at doses 30 mg/kg and 60 mg/kg reduced tumor weight by 54% and 69%, respectively, as compared to the control group, while no significant reduction in tumor weight was observed with 30 mg/kg of PTX (Ebewe). In addition, toxicity of PTX was largely reduced by its encapsulation into SMA. Furthermore, examination of the tumors demonstrated a decrease in the number of blood vessels. Thus, oral delivery of SMA-PTX micelles may provide a safe and effective strategy for the treatment of colon cancer. Keywords: oral delivery, anticancer nanomedicine, CT-26, enhanced permeability and retention (EPR) effect, HUVEC, antiangiogenic

Neha N Parayath,1 Hayley Nehoff,1 Philipp Müller,1 Sebastien Taurin,1 Khaled Greish1,21Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Department of Oncology, Faculty of Medicine, Suez Canal University, Ismaileya, EgyptAbstract: Drug delivery systems could potentially overcome low bioavailability and gastrointestinal toxicity, which are the major challenges for the development of oral anticancer drugs. Herein, we demonstrate the ability of styrene maleic acid (SMA) nanomicelles encapsulating epirubicin to traverse in vitro and ex vivo models of the intestinal epithelium without affecting the tissue integrity. Further, SMA micelles encapsulating a fluorescent dye dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) showed twofold higher accumulation in the liver and spleen, 15-fold higher accumulation in the tumor, and sixfold higher accumulation in the lung as compared with the free DiI, following oral administration in a mice xenograft breast cancer model. Additionally, SMA micelles showed colocalization with microfold (M)-cells and accumulation in Peyer’s patches, which together confirms the M-cell mediated uptake and transport of SMA micelles. Our results indicate that SMA micelles, showing dual uptake by enterocytes and M-cells, are a potential tool for safe oral anticancer drug delivery.Keywords: oral delivery, anticancer nanomedicine, enhanced permeability and retention effect, EPR

Hayley Nehoff,1 Neha N Parayath,1 Laura Domanovitch,1 Sebastien Taurin,1 Khaled Greish1,2 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Department of Oncology, Faculty of Medicine, Suez Canal University, Egypt Abstract: The growing research interest in nanomedicine for the treatment of cancer and inflammatory-related pathologies is yielding encouraging results. Unfortunately, enthusiasm is tempered by the limited specificity of the enhanced permeability and retention effect. Factors such as lack of cellular specificity, low vascular density, and early release of active agents prior to reaching their target contribute to the limitations of the enhanced permeability and retention effect. However, improved nanomedicine designs are creating opportunities to overcome these problems. In this review, we present examples of the advances made in this field and endeavor to highlight the potential of these emerging technologies to improve targeting of nanomedicine to specific pathological cells and tissues. Keywords: nanomedicine, permeability and retention effect, tissue targeting, cancer treatment, inflammation

Nucleic acid therapeutics have emerged as one of the very advanced and efficacious treatment approaches for debilitating health conditions, including those diseases affecting the central nervous system (CNS). Precise targeting with an optimal control over gene regulation confers long-lasting benefits through the administration of nucleic acid payloads via viral, non-viral, and engineered vectors. The current review majorly focuses on the development and clinical translational potential of non-viral vectors for treating CNS diseases with a focus on their specific design and targeting approaches. These carriers must be able to surmount the various intracellular and extracellular barriers, to ensure successful neuronal transfection and ultimately attain higher therapeutic efficacies. Additionally, the specific challenges associated with CNS administration also include the presence of blood-brain barrier (BBB), the complex pathophysiological and biochemical changes associated with different disease conditions and the existence of non-dividing cells. The advantages offered by lipid-based or polymeric systems, engineered proteins, particle-based systems coupled with various approaches of neuronal targeting have been discussed in the context of a variety of CNS diseases. The possibilities of rapid yet highly efficient gene modifications rendered by the breakthrough methodologies for gene editing and gene manipulation have also opened vast avenues of research in neuroscience and CNS disease therapy. The current review also underscores the extensive scientific efforts to optimize specialized, efficacious yet non-invasive and safer administration approaches to overcome the therapeutic delivery challenges specifically posed by the CNS transport barriers and the overall obstacles to clinical translation., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts., (Copyright © 2022 Elsevier B.V. All rights reserved.)

miRNA are critical messengers in the tumor microenvironment (TME) that influence various processes leading to immune suppression, tumor progression, metastasis and resistance. Strategies to modulate miRNAs in the TME have important implications in overcoming these challenges. However, miR delivery to specific cells in the TME has been challenging. This review discusses nanomedicine strategies to achieve cell-specific delivery of miRNAs. The key goal of delivery is to activate the tumor immune landscape as well as to prevent chemotherapy resistance. Specifically, the use of hyaluronic acid-based nanoparticle miRNA delivery to the TME is discussed. The discussion is focused on miRNA-125b for reprogramming tumor-associated macrophages to overcome immunosuppression and miRNA-let-7b to overcome resistance to anticancer chemotherapeutics because both these miRNAs have been extensively evaluated for delivery with hyaluronic acid-based delivery systems.

The ability of myeloid regulatory cells (MRCs) to control immune responses and to promote tolerance has prompted enormous interest in exploiting them therapeutically to treat inflammation, autoimmunity, or to improve outcomes in transplantation. While immunomodulatory small-molecule compounds and antibodies have provided relief for some patients, the dosing entails high systemic drug exposures and thus increased risk of off-target adverse effects. More recently, MRC-based cell-therapy products have entered clinical testing for tolerance induction. However, the elaborate and expensive protocols currently required to manufacture engineered MRCs ex vivo put this approach beyond the reach of many patients who might benefit. A solution could be to directly program MRCs in vivo. Here we describe a targeted nanocarrier that delivers in vitro-transcribed mRNA encoding a key anti-inflammatory mediator. We demonstrate in models of systemic lupus erythematosus that infusions of nanoparticles formulated with mRNA encoding glucocorticoid-induced leucine zipper (GILZ) effectively control the disease. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this new therapy could enable physicians to treat autoimmune disease while avoiding systemic treatments that disrupt immune homeostasis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To investigate a novel strategy to target tumor-associated macrophages and reprogram them to an antitumor phenotype in pancreatic adenocarcinoma (PDAC). Methods: M2 peptides were conjugated to HA-PEG/HA-PEI polymer to form self-assembled nanoparticles with miR-125b. The efficacy of HA-PEI/PEG-M2peptide nanoparticles in pancreatic tumors from LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre genetically engineered mice was evaluated. Results: In vitro M2 macrophage-specific delivery of targeted nanoformulations was demonstrated. Intraperitoneal administration of M2-targeted nanoparticles showed preferential accumulation in the pancreas of KPC-PDAC mice and an above fourfold increase in the M1-to-M2 macrophage ratio compared with transfection with scrambled miR. Conclusion: M2-targeted HA-PEI/PEG nanoparticles with miR-125b can transfect tumor-associated macrophages in pancreatic tissues and may have implications for PDAC immunotherapy.

Gene therapy makes it possible to engineer chimeric antigen receptors (CARs) to create T cells that target specific diseases. However, current approaches require elaborate and expensive protocols to manufacture engineered T cells ex vivo, putting this therapy beyond the reach of many patients who might benefit. A solution could be to program T cells in vivo. Here, we evaluate the clinical need for in situ CAR T cell programming, compare competing technologies, review current progress, and provide a perspective on the long-term impact of this emerging and rapidly flourishing biotechnology field.

The most significant obstacle in the treatment of neurological disorders is the blood-brain barrier (BBB), which prevents 98% of all potential neuropharmaceuticals from reaching the central nervous system (CNS). Brain derived neurotrophic factor (BDNF) is one of the most intensely studied targets in Parkinson's disease (PD) as it can reverse disease progression. BDNF AntagoNAT's (ATs) are synthetic oligonucleotide-like compounds capable of upregulating endogenous BDNF expression. Despite the significant promise of BDNF AT therapies for PD, they cannot cross the blood-brain barrier (BBB). Our group has developed an innovative endonasal heterotopic mucosal grafting technique to provide a permanent method of permeabilizing the BBB. This method is based on established endoscopic surgical procedures currently used in routine clinical practice. Our overall goal for the study was to investigate the distribution and efficacy of BDNF AT's using an extra-cranial graft model in naïve rats using the innovative heterotopic mucosal engrafting technique. BDNF AT cationic liposomes (ideal size range 200-250 nm) were developed and characterized to enhance the delivery to rat brain. Uptake, distribution and transfection efficiency of BDNF AntagoNAT's in saline and liposomes were evaluated qualitatively (microscopy) and quantitatively (ELISA and AT hybridization assays) in RT4-D6P2T rat schwannoma cells and in naïve rats. In vivo therapeutic efficacy of BDNF AT's encapsulated in liposomes was evaluated in a 6-OHDA toxin model of PD using western blot and tyrosine hydroxylase immunohistochemistry. Using complimentary in vitro and in vivo techniques, our results demonstrate that grafts are capable of delivering therapeutic levels of BDNF ATs in liposomes and saline formulation throughout the brain resulting in significant BDNF upregulation in key end target regions relevant to PD. BDNF AT liposomes resulted in a better distribution in rat brain as compared to saline control. The delivered BDNF AT's encapsulated in liposomes also conferred a neuroprotective effect in a rat 6-OHDA model of PD. As a platform technique, these results further suggest that this approach may be utilized to deliver other BBB impermeant oligonucleotide-based therapeutics thereby opening the door to additional treatment options for CNS disease., Competing Interests: CC, OK and JH were employed by OPKO Health Inc. BB holds a patent assigned to Massachusetts Eye and Ear covering transmucosal delivery methods to the central nervous system. BB has consultant relationships with Inquis Medical, Olympus, Medtronic, Karl Storz, Sinopsys, Baxter, and 3D Matrix and receives royalties from Theime. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pawar, Parayath, Sharma, Coito, Khorkova, Hsiao, Curry, Amiji and Bleier.)

Engineering chimeric antigen receptors (CAR) or T cell receptors (TCR) helps create disease-specific T cells for targeted therapy, but the cost and rigor associated with manufacturing engineered T cells ex vivo can be prohibitive, so programing T cells in vivo may be a viable alternative. Here we report an injectable nanocarrier that delivers in vitro-transcribed (IVT) CAR or TCR mRNA for transiently reprograming of circulating T cells to recognize disease-relevant antigens. In mouse models of human leukemia, prostate cancer and hepatitis B-induced hepatocellular carcinoma, repeated infusions of these polymer nanocarriers induce sufficient host T cells expressing tumor-specific CARs or virus-specific TCRs to cause disease regression at levels similar to bolus infusions of ex vivo engineered lymphocytes. Given their ease of manufacturing, distribution and administration, these nanocarriers, and the associated platforms, could become a therapeutic for a wide range of diseases.

Extracellular vesicles (EVs) have garnered much attention as key mediators of intercellular communication within the tumor microenvironment (TME) as well as at distinct metastatic sites. Nucleic acid molecules are the important components of the EV cargo. Characterizing EVs and strategies for modulating the nucleic acid content to promote anti-tumoral functions has led to the emerging role of EVs as potential novel targets for cancer therapy. Recent approaches of engineering the EVs to reach targeted sites have bought this to the forefront for nucleic acid delivery. In this article, we discuss EV biology with recent methods to analyze their nucleic acid contents. We emphasize the role of EV-mediated nucleic acid transfer in the TME assisting in tumor progression and metastasis and further review the strategies for modulating the nucleic acid content in EV for suppressing tumor growth and immune activation. The article further discusses the recent developments in generating EV mimics as nucleic acid delivery systems., Competing Interests: Declaration of competing interest The authors declare no conflicts., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Skewing the macrophage polarity to achieve a favorable phenotype is a recently investigated therapeutic strategy in multiple disease/dysfunctional conditions such as inflammation, tumors, autoimmune disorders, and tissue repairs. However, delivering the therapeutic agent specifically to the macrophages has been a challenge in this field. Here, we describe the synthesis of hyaluronic acid (HA)-based nanoparticles for targeting CD44 receptors on the macrophages. The HA backbone is modified with cationic polyethyleneimine (PEI) for efficient encapsulation of microRNA into the self-assembling nanoparticles for targeted delivery to macrophages.

In epithelial ovarian cancers, the presence of tumor-associated macrophages (TAMs) is well correlated with the poor disease outcomes. TAMs are know to suppress the immune system, induce pro-tumoral functions and inhibit anti-tumor responses associated with chemotherapy. In this study, we have evaluated the synergistic efficacy of TAM repolarization and intraperitoneal paclitaxel in epithelial ovarian cancers. We demonstrate that hyaluronic acid-based nanoparticles encapsulating miR-125b (HA-PEI-miR-125b) can specifically target TAMs in the peritoneal cavity of a syngeneic ID8-VEGF ovarian cancer mouse model and can repolarize macrophages to an immune-activating phenotype. These HA-PEI-miR-125b nanoparticles in combination with intraperitoneal paclitaxel can enhance the anti-tumor efficacy of paclitaxel during the later stages of disease progression as seen by the significant reduction in the ascitic fluid and peritoneal VEGF levels. Furthermore, these HA-PEI-miR-125b nanoparticles do not induce systemic toxicity and thus warrant a further evaluation in the clinical setting., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Tumor-associated macrophages (TAMs) usually express an M2 phenotype, which enables them to perform immunosuppressive and tumor-promoting functions. Reprogramming these TAMs toward an M1 phenotype could thwart their pro-cancer activities and unleash anti-tumor immunity, but efforts to accomplish this are nonspecific and elicit systemic inflammation. Here we describe a targeted nanocarrier that can deliver in vitro-transcribed mRNA encoding M1-polarizing transcription factors to reprogram TAMs without causing systemic toxicity. We demonstrate in models of ovarian cancer, melanoma, and glioblastoma that infusions of nanoparticles formulated with mRNAs encoding interferon regulatory factor 5 in combination with its activating kinase IKKβ reverse the immunosuppressive, tumor-supporting state of TAMs and reprogram them to a phenotype that induces anti-tumor immunity and promotes tumor regression. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this immunotherapy could enable physicians to obviate suppressive tumors while avoiding systemic treatments that disrupt immune homeostasis.

The objective of this study was to evaluate intraperitoneal (IP) metronomic chemotherapy using sustained release paclitaxel (PTX) delivery from electrospun biodegradable polymeric yarns woven into suturable nanotextiles. Following confirmation of in vitro PTX efficacy in ID8-VEGF epithelial ovarian cancer cells, in vivo studies were performed upon surgical peritoneal implantation of nanotextile implants in orthotopic, syngeneic ID8-VEGF tumor-bearing C57BL/6 mice. In comparison to the clinical PTX-solution, there was a significant enhancement of anti-tumor efficacy and safety with PTX-nanotextiles. After 35-days, the peritoneum of tumor-bearing mice with PTX-nanotextiles was completely devoid of tumor nodules and ascitic fluid. Additionally, VEGF levels measured in peritoneal lavage fluid were 300-fold lower compared to PTX-solution and 600-fold lower as compared to untreated tumor-bearing animals. PTX-solution treated group also developed severe metastatic lesions and progressive ascitic fluid buildup. More importantly, no signs of systemic/ organ toxicity were observed in PTX-nanotextile implanted mice, unlike the systemic toxic effects induced by PTX-solution. Collectively, our results show the therapeutic and safety advantages offered by combining clinically translatable metronomic low-dose chemotherapy and IP pharmacokinetics using biodegradable nanotextile implants in addressing the challenges of late-stage ovarian cancer., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Delivering therapeutics across the blood-brain barrier (BBB) for treating central nervous system (CNS) diseases is one of the biggest challenges today as the BBB limits the uptake of molecules greater than 500 Da into the CNS. Here we describe a novel trans-nasal mucosal drug delivery as an alternative to the intranasal drug delivery to overcome its limitations and deliver high molecular weight (HMW) therapeutics efficiently to the brain. This approach is based on human endoscopic skull base surgical techniques in which a surgical defect is repaired by engrafting semipermeable nasal mucosa over a skull base defect. Based on endoscopic skull based surgeries, our groups has developed a trans-nasal mucosal rodent model where we have evaluated the permeability of ovalbumin (45 kDa) as a model protein through the implanted mucosal graft for delivering HMW therapeutics to the brain. A thermo sensitive liposome-in-gel (LiG) system was developed for creating a drug depot allowing for a sustained release from the site of delivery to the brain through the implanted nasal graft. We would like to report this as an exploratory pilot study where we are using this novel surgical model to show that the implanted nasal mucosal graft and the LiG delivery system result in an efficient and a sustained brain delivery of HMW proteins. Hence, this study demonstrates that the trans-nasal mucosal engrafting technique could overcome the limitations for intranasal drug delivery and enable the uptake of HMW protein therapeutics into the CNS for the treatment of a wide range of neurodegenerative diseases., Competing Interests: The authors have declared that no competing interests exist.

Tumor-associated macrophages (TAMs) acquire a pro-tumor (M2) phenotype, which promotes tumor growth, angiogenesis, and metastasis. Certain microRNAs (miRs), such as miR-125b, can reprogram TAMs into an antitumor/pro-inflammatory (M1) phenotype. Using CD44 targeting hyaluronic acid-poly(ethylenimine) (HA-PEI)-based nanoparticles encapsulating miR-125b, we have herein shown macrophage-specific delivery and transfection upon intraperitoneal (i.p.) administration. We have exploited the inherent ability of peritoneal macrophages to migrate toward the inflammation/injury and demonstrated that following intraperitoneal administration of HA-PEI nanoparticles, there is an accumulation of HA-PEI nanoparticles in the macrophage-ablated lung tissues of both naïve and KRAS/p53 double mutant genetically engineered (KP-GEM) nonsmall cell lung cancer (NSCLC) mouse model. Additionally, upon transfection with miR-125b, we observed a >6-fold increase in the M1 to M2 macrophage ratio and 300-fold increase in the iNOS (M1 marker)/Arg-1 (M2 marker) ratio in TAMs as compared to the untreated control group. The results of these studies show that i.p. administered macrophage-specific HA-PEI nanoparticles can successfully transfect TAMs in lung tissues of both naïve mice and a KP-GEM NSCLC mouse model. Successful TAM repolarization toward the M1 phenotype has significant implication in anticancer immunotherapy.

Targeted drug delivery has become extremely important in enhancing efficacy and reducing the toxicity of therapeutics in the treatment of various disease conditions. Current approaches include passive targeting, which relies on naturally occurring differences between healthy and diseased tissues, and active targeting, which utilizes various ligands that can recognize targets expressed preferentially at the diseased site. Clinical translation of these mechanisms faces many challenges including the immunogenic and toxic effects of these non-natural systems. Thus, use of endogenous targeting systems is increasingly gaining momentum. This review is focused on strategies for employing endogenous moieties, which could serve as safe and efficient carriers for targeted drug delivery. The first part of the review involves cells and cellular components as endogenous carriers for therapeutics in multiple disease states, while the second part discusses the use of endogenous plasma components as endogenous carriers. Further understanding of the biological tropism with cells and proteins and the newer generation of delivery strategies that exploits these endogenous approaches promises to provide better solutions for site-specific delivery and could further facilitate clinical translations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The oral route is the preferred mode of administration, however the poor intestinal absorption of many bioactive compounds limit their efficacy. Several strategies have been developed to overcome the low oral bioavailability of bioactive compounds. Nanocarriers present a unique opportunity to overcome this limitation due to their diverse bioactive carriage potential, surface functionality and design flexibility. Despite these favorable characteristics, the oral delivery of nanocarriers faces several challenges which are discussed in this review. The review addresses the different mechanisms of transport across the intestinal epithelium. In addition, we will comment on the various methods and models for evaluating the intestinal permeability, with a critical discussion of the uniformity of these models in investigating the oral bioavailability of nanocarrier systems. Finally, we will discuss some of the recently developed nanocarriers for oral delivery of bioactives that show promising results.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Despite the advances in surgery, radiotherapy and chemotherapy, patient survival averages only 14.6 months. In most GBM tumors, tyrosine kinases show increased activity and/or expression and actively contribute to the development, recurrence and onset of treatment resistance; making their inhibition an appealing therapeutic strategy. We compared the cytotoxicity of 12 tyrosine kinase inhibitors in vitro. A combination of crizotinib and dasatinib emerged as the most cytotoxic across established and primary human GBM cell lines. The combination treatment induced apoptotic cell death and polyploidy. Furthermore, the combination treatment led to the altered expression and localization of several tyrosine kinase receptors such as Met and EGFR and downstream effectors as such as SRC. Furthermore, the combination treatment reduced the migration and invasion of GBM cells and prevented endothelial cell tube formation in vitro. Overall, our study demonstrated the broad specificity of a combination of crizotinib and dasatinib across multiple GBM cell lines. These findings provide insight into the development of alternative therapy for the treatment of GBM.

Unlabelled: Synthetic cannabinoid WIN55,212-2 (WIN) has shown a promise as an anticancer agent but causes psychoactive side-effects. In the present study, nano-micelles of styrene maleic acid (SMA)-conjugated WIN were synthesized to reduce side-effects and increase drug efficacy. SMA-WIN micelles were characterised and their in vitro cytotoxic effect was compared to that of free WIN against triple-negative breast cancer (MDA-MB-231), hormone receptor-positive breast cancer (MCF-7) and castration-resistant prostate cancer (PC3) cell lines. SMA-WIN micelles were synthesised with a ~15% loading, 132.7 nm average diameter, -0.0388 mV charge, and pH-dependent release rate. A dose-dependent inhibition of cell growth was observed in all three cell lines treated with both free and micellar WIN, with both formulations demonstrating equal cytotoxicity., Conclusion: SMA-WIN demonstrated characteristics theorized to improve in vivo drug biodistribution. Potent cytotoxicity was found against breast and prostate cancer cells in vitro, showing promise as a novel treatment against breast and prostate cancer., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Heme oxygenase (HO) is a cytoprotective enzyme that can be overexpressed in some pathological conditions, including certain cancers. In this work, novel imidazole derivatives were designed and synthesized as inhibitors of heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2). In these compounds the imidazole ring, crucial for the activity, is connected to a hydrophobic group, represented by aryloxy, benzothiazole, or benzoxazole moieties, by means of alkyl or thioalkyl chains of different length. Many of the tested compounds were potent and/or selective against one of the two isoforms of HO. Furthermore, most of the pentyl derivatives showed to be better inhibitors of HO-2 with respect to HO-1, revealing a critical role of the alkyl chain in discriminating between the two isoenzymes. Compounds which showed the better profile of HO inhibition were selected and tested to evaluate their cytotoxic properties in prostate and breast cancer cell lines (DU-145, PC3, LnCap, MDA-MB-231, and MCF-7). In these assays, aryloxyalkyl derivatives resulted more cytotoxic than benzothiazolethioalkyl ones; in particular compound 31 was active against all the cell lines tested, confirming the anti-proliferative properties of HO inhibitors and their potential use in the treatment of specific cancers., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Polymeric micelles are among the most promising delivery systems in nanomedicine. The growing interest in polymeric micelles as drug delivery vehicle is promoted by the advantages they offer for hydrophobic anticancer agents. The size of most polymeric micelles lies within the range 10-100 nm ensuring that they can selectively leave the circulation at tumor site via the enhanced permeability and retention effect. Their unique structure allows them to solubilize hydrophobic drugs, prolongs their circulatory half-life and eventually leads to enhanced therapeutic efficacy. In addition, they can undergo several structural modifications to further augment tumor cell uptake. In this review, we will discuss various micellar systems that have been studied in preclinical and clinical settings.