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Π electron-stabilized polymeric micelles potentiate docetaxel therapy in advanced-stage gastrointestinal cancer

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Abstract

Gastrointestinal (GI) cancers are among the most lethal malignancies. The treatment of advanced-stage GI cancer involves standard chemotherapeutic drugs, such as docetaxel, as well as targeted therapeutics and immuno-modulatory agents, all of which are only moderately effective. We here show that Π electron-stabilized polymeric micelles based on PEG-b-p(HPMAm-Bz) can be loaded highly efficiently with docetaxel (loading capacity up to 23 wt%) and potentiate chemotherapy responses in multiple advanced-stage GI cancer mouse models. Complete cures and full tumor regression were achieved upon intravenously administering micellar docetaxel in subcu-taneous gastric cancer cell line-derived xenografts (CDX), as well as in CDX models with intraperitoneal and lung metastases. Nanoformulated docetaxel also outperformed conventional docetaxel in a patient-derived xenograft (PDX) model, doubling the extent of tumor growth inhibition. Furthermore, micellar docetaxel modulated the tumor immune microenvironment in CDX and PDX tumors, increasing the ratio between M1-and M2-like macrophages, and toxicologically, it was found to be very well-tolerated. These findings demonstrate that Π electron-stabilized polymeric micelles loaded with docetaxel hold significant potential for the treatment of advanced-stage GI cancers.

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... Polymeric nanoparticles were usually applied for the delivery of a single chemotherapy agent. 20,21 Current cancer therapy has gradually changed from single therapy into combinational therapy, such as photothermal therapy (PTT), photodynamic therapy, immunotherapy and gene therapy. [22][23][24] It integrated the merits of various treatments. ...
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Background: Multifunctional stimuli-responsive nanoparticles with photothermal-chemotherapy provided a powerful tool for improving the accuracy and efficiency in the treatment of malignant tumors. Methods: Herein, photosensitizer indocyanine green (ICG)-loaded amorphous calcium-carbonate (ICG@) nanoparticle was prepared by a gas diffusion reaction. Doxorubicin (DOX) and ICG@ were simultaneously encapsulated into poly(lactic-co-glycolic acid)-ss-chondroitin sulfate A (PSC) nanoparticles by a film hydration method. The obtained PSC/ICG@+DOX hybrid nanoparticles were characterized and evaluated by Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), transmission electron microscopy (TEM), and differential scanning calorimetry (DSC). The cellular uptake and cytotoxicity of PSC/ICG@+DOX nanoparticles were analyzed by confocal laser scanning microscopy (CLSM) and MTT assay in 4T1 cells. In vivo antitumor activity of the nanoparticles was evaluated in 4T1-bearing Balb/c mice. Results: PSC/ICG@+DOX nanoparticles were nearly spherical in shape by TEM observation, and the diameter was 407 nm determined by DLS. Owing to calcium carbonate and disulfide bond linked copolymer, PSC/ICG@+DOX nanoparticles exhibited pH and reduction-sensitive drug release. Further, PSC/ICG@+DOX nanoparticles showed an effective photothermal effect under near-infrared (NIR) laser irradiation, and improved cellular uptake and cytotoxicity in breast cancer 4T1 cells. Importantly, PSC/ICG@+DOX nanoparticles demonstrated the most effective suppression of tumor growth in orthotopic 4T1-bearing mice among the treatment groups. In contrast with single chemotherapy or photothermal therapy, chemo-photothermal treatment by PSC/ICG@+DOX nanoparticles synergistically inhibited the growth of 4T1 cells. Conclusion: This study demonstrated that PSC/ICG@+DOX nanoparticles with active targeting and stimuli-sensitivity would be a promising strategy to enhance chemo-photothermal cancer therapy.
... Evaluation of Drug Release Using an Ultraviolet-Visible Spectrophotometer 1 mg of SPI/SU nanomicelles suspended, respectively, 1 mL of PBS were sealed in dialysis bag (MWCO 3.5 kDa) and then immersed in 30 mL PBS with pH at 7.4, 6.8 and 5.5 containing 0.5% Tween-80 to evaluate the sunitinib release. 42 At the designed time interval (0.5, 1, 2, 4, 8, 12, 24 and 48 h), 3 mL of the release solution including 5 units of esterase was taken out and the corresponding volume of new PBS was added. All the above drug release behaviors were carried out at 100 rpm on a shaker at 37°C, which was shielded from light. ...
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Introduction: Sunitinib, a first-line therapy with a certain effect, was utilized in the early stages of renal cell carcinoma treatment. However, its clinical toxicity, side effects, and its limited bioavailability, resulted in inadequate clinical therapeutic efficacy. Building neoteric, simple, and safe drug delivery systems with existing drugs offers new options. Therefore, we aimed to construct a micelle to improve the clinical efficacy of sunitinib by reusing ibuprofen. Methods: We synthesized the sialic acid-poly (ethylene glycol)-ibuprofen (SA-PEG-IBU) amphipathic conjugate in two-step reaction. The SA-PEG-IBU amphiphilic conjugates can form into stable SPI nanomicelles in aqueous solution, which can be further loaded sunitinib (SU) to obtain the SPI/SU system. Following nanomicelle creation, sialic acid exposed to the nanomicelle surface can recognize the overexpressed E-selectin receptor on the membrane of cancer cells to enhance cellular uptake. The properties of morphology, stability, and drug release about the SPI/SU nanomicelles were investigated. Confocal microscopy and flow cytometry were used to assess the cellular uptake efficiency of nanomicelles in vitro. Finally, a xenograft tumor model in nude mice was constructed to investigate the body distribution and tumor suppression of SPI/SU in vivo. Results: The result showed that SPI nanomicelles exhibited excellent tumor targeting performance and inhibited the migration and invasion of tumor cell in vitro. The SPI nanomicelles can improve the accumulation of drugs in the tumor site that showed effective tumor inhibition in vivo. In addition, H&E staining and immunohistochemical analysis demonstrated that the SPI/SU nanomicelles had a superior therapeutic effect and lower biotoxicity. Conclusion: The SPI/SU nanomicelles displayed excellent anti-tumor ability, and can suppress the metastasis of tumor cell by decreasing the expression of Cyclooxygenase-2 due to the ibuprofen, providing an optimistic clinical application potential by developing a simple but safe drug delivery system.
... Nanoparticle carriers may also be used to modify some properties of the drug, including its solubility, stability, and immunogenicity [19,20]. However, those artificial nanoparticles encounter several tricky issues for their clinical applications, including (1) the potential in vivo toxicities, (2) the high cost for mass production, and (3) potential adverse environmental impacts [21][22][23][24]. In contrast, plant-derived edible nanoparticles with unique properties have good application prospects for colitis-targeted therapy [25][26][27][28]. ...
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Background Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by diffuse inflammation of the colonic mucosa and a relapsing and remitting course. The current therapeutics are only modestly effective and carry risks for unacceptable adverse events, and thus more effective approaches to treat UC is clinically needed. Results For this purpose, turmeric-derived nanoparticles with a specific population (TDNPs 2) were characterized, and their targeting ability and therapeutic effects against colitis were investigated systematically. The hydrodynamic size of TDNPs 2 was around 178 nm, and the zeta potential was negative (− 21.7 mV). Mass spectrometry identified TDNPs 2 containing high levels of lipids and proteins. Notably, curcumin, the bioactive constituent of turmeric, was evidenced in TDNPs 2. In lipopolysaccharide (LPS)-induced acute inflammation, TDNPs 2 showed excellent anti-inflammatory and antioxidant properties. In mice colitis models, we demonstrated that orally administrated of TDNPs 2 could ameliorate mice colitis and accelerate colitis resolution via regulating the expression of the pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and antioxidant gene, HO-1. Results obtained from transgenic mice with NF-κB-RE-Luc indicated that TDNPs 2-mediated inactivation of the NF-κB pathway might partially contribute to the protective effect of these particles against colitis. Conclusion Our results suggest that TDNPs 2 from edible turmeric represent a novel, natural colon-targeting therapeutics that may prevent colitis and promote wound repair in colitis while outperforming artificial nanoparticles in terms of low toxicity and ease of large-scale production.
... It is known that DTX is a specific drug acting on the M-phase in the cell cycle, which promotes the aggregation of tubules into stable microtubules and inhibits their aggregation, resulting in the formation of stable non-functional microtubule bundles, thus destroying the mitosis of tumor cells (Liang et al., 2021). Consequently, we performed an analysis of the cell cycle of the two drugs. ...
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Ovarian cancer is the second most common cause of gynecological cancer death in women. It is usually diagnosed late and accompanied by peritoneal metastasis. For ovarian cancer with peritoneal metastasis, intraperitoneal (IP) chemotherapy can maintain a high drug concentration in the abdominal cavity and reduce local and systemic toxicity. Recently, docetaxel (DTX) has shown broad-spectrum antitumor activity against various malignant tumors, including ovarian cancer with peritoneal metastasis. However, DTX has limited clinical applications due to its poor water solubility, predisposition to hypersensitivity, fluid retention, and varying degrees of neurotoxicity. In this study, we prepared methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) micelles loaded with DTX and developed an alternative, less toxic, more effective DTX formulation, without Tween 80, and evaluated its pharmacokinetics in the abdominal cavity and its efficacy in ovarian cancer with peritoneal metastasis. The mean diameter of DTX-mPEG-PDLLA was about 25 nm, and the pharmacokinetics of BALB/c mice via IP showed that the plasma exposure of DTX-mPEG-PDLLA was about four times lower than that of DTX. Importantly, DTX-mPEG-PDLLA was significantly more effective than DTX and prolonged the survival period in a SKOV-3 ovarian cancer peritoneal metastasis model. Moreover, the apoptosis rate was significantly increased in vitro. Based on these findings, it is expected that DTX-mPEG-PDLLA can enhance efficacy against ovarian cancer peritoneal metastasis, while reducing toxic side effects, and has the potential to be used in the clinical treatment of peritoneal metastatic cancer.
... A variety of natural or synthetic nanomaterials have been developed for biomedical application including DNA nanostructures [7], polymeric micelles [8], silica nanoparticles [9], gold nanoparticles or carbon nanotubes [10,11]. They are commonly used to develop favorable formulations for different therapeutic agents, particularly insoluble compounds or biotherapeutics [12,13]. ...
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A wide variety of nanomaterials have emerged in recent years with advantageous properties for a plethora of therapeutic and diagnostic applications. Such applications include drug delivery, imaging, anti-cancer therapy and radiotherapy. There is a critical need for further components which can facilitate therapeutic targeting, augment their physicochemical properties, or broaden their theranostic applications. Aptamers are single-stranded nucleic acids which have been selected or evolved to bind specifically to molecules, surfaces, or cells. Aptamers can also act as direct biologic therapeutics, or in imaging and diagnostics. There is a rich field of discovery at the interdisciplinary interface between nanomaterials and aptamer science that has significant potential across biomedicine. Herein, we review recent progress in aptamer-enabled materials and discuss pending challenges for their future biomedical application.
... loading of poorly soluble drugs e.g., paclitaxel Docetaxel [45] Doxorubicin [46,47] 5-Fluorouracil [48] Camptothecin [49] Cisplatin [50] Oxaliplatin [51] Ophthalmic Acyclovir [52] Myricetin [53] Local Anesthetic Tetracaine [54] Neuroprotective Honokiol [55] Anti-Malarial Artemisinin [56] Anti-fungal Griseofulvin [57] and nanocylinders bearing amino groups (ANCs) from poly (tert-butyl acrylate)-block-poly (2-A solution of ANC was added to the CNF, and when the mass ratio of ANC: CNF reached 5:1, wrapping of ANC took place around the CNF. This process is induced by opposite charges of carboxyl and amino groups. ...
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Nano delivery systems, polymeric micelles represent one of the most promising delivery platforms for therapeutic compounds. It has shown that a poorly soluble molecule which has high potency and remarkable toxicity can be encapsulated with the polymeric micelle. There are various poorly soluble drugs used in micellar preparations, mostly for their anti-cancer activity. Drugs in the inner core protect the drug from degradation and allow drug accumulation in the tumour site in the case of cancer treatment. Block copolymers are chosen based on the physicochemical characteristics of medicinal drugs. The amphiphilic block copolymer structure has both lipophilic and hydrophilic blocks, which enclose tiny hydrophobic molecules. It is a targeted drug delivery method because of its high effectiveness for drug retention in tissue, prevention of enzymes from degradation, and improvement of the cellular absorption mechanism. In an experimental environment, variations in temperature and solvent polarity stimulate copolymer micelle self-assembly. This is a thermodynamically guided procedure in which self-assembly happens by converting polymeric micelles. These aggregates go from a non-equilibrium to a thermodynamically equilibrium state, and they stay stable for a long time. The balance of thermodynamic and kinetic forces is critical in micelles self-assembly because the kinetic process predicts assembly behaviour and hierarchical structure. The purpose of this special issue is to provide an updated overview of micelles, a number of polymers and drugs commonly used in micellar preparation and their application.
... The larger size of micelles (10-200 nm), relative to free drug molecules, prevents their extravasation into healthy tissue while taking advantage of the leaky vasculature of solid tumors through the enhanced permeability and retention (EPR) effect [11,12]. Recent nano-sized formulations of DTX have shown promise in preclinical cancer models [13][14][15][16][17][18][19][20], and a phase I clinical trial of a core cross-linked micellar DTX formulation was recently completed [21]. ...
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Docetaxel (DTX) is among the most frequently prescribed chemotherapy drugs and has recently been shown to extend survival in advanced prostate cancer patients. However, the poor water solubility of DTX prevents full exploitation of this potent anticancer drug. The current marketed formulation, Taxotere®, contains a toxic co-solvent that induces adverse reactions following intravenous injection. Nano-sized polymeric micelles have been proposed to create safer, water-soluble carriers for DTX, but many have failed to reach the clinic due to poor carrier stability in vivo. In this study, we aimed to improve micelle stability by synthesizing an ester prodrug of DTX, oligo(lactic acid)8-docetaxel (o(LA)8-DTX), for augmented compatibility with the core of poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) micelles. Due to the enhancement of drug-carrier compatibility, we were able to load 50% (w/w) prodrug within the micelle, solubilize 20 mg/mL o(LA)8-DTX (~12 mg/mL DTX-equivalent) in aqueous media, and delay payload release. While the micelle core prohibited premature degradation, o(LA)8-DTX was rapidly converted to parent drug DTX through intramolecular backbiting (t1/2 = 6.3 h) or esterase-mediated degradation (t1/2 = 2.5 h) following release. Most importantly, o(LA)8-DTX micelles proved to be as efficacious but less toxic than Taxotere® in a preclinical mouse model of prostate cancer.
... Molecular weight of the hydrophobic blocks were comparable, with 19720 to 38512 Da for n = 170 and 332 for P(PTMC) n and 4728 to 31914 Da for n = 8 and 54 for P(TPE-TMC) n . Note the p-p interaction could drive the assembly of polymer micelles [53]. The trilayer arrangement was further confirmed by contact angle measurements, see S23. ...
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Polymersomes and related self-assembled nanostructures displaying Aggregation-Induced Emission (AIE) are highly relevant for plenty of applications in imaging, biology and functional devices. Experimentally simple, scalable and universal strategies for on-demand self-assembly of polymers rendering well-defined nanostructures are highly desirable. A purposefully designed combination of amphiphilic block copolymers including tunable lengths of hydrophilic polyethylene glycol (PEGm) and hydrophobic AIE polymer poly(tetraphenylethylene-trimethylenecarbonate) (P(TPE-TMC)n) has been studied at the air/liquid interface. The unique 2D assembly properties have been analyzed by thermodynamic measurements, UV-vis reflection spectroscopy and photoluminescence in combination with molecular dynamics simulations. The (PEG)m-b-P(TPE-TMC)n monolayers formed tunable 2D nanostructures self-assembled on demand by adjusting the available surface area. Tuning of the PEG length allows to modification of the area per polymer molecule at the air/liquid interface. Molecular detail on the arrangement of the polymer molecules and relevant molecular interactions has been convincingly described. AIE fluorescence at the air/liquid interface has been successfully achieved by the (PEG)m-b-P(TPE-TMC)n nanostructures. An experimentally simple 2D to 3D transition allowed to obtain 3D polymersomes in solution. This work suggests that engineered amphiphilic polymers for AIE may be suitable for selective 2D and 3D self-assembly for imaging and technological applications
... Even with the help of solubilizers, Taxotere ® has poor stability and tend to precipitate after dilution. All these drawbacks restrict the clinical application of DTX [9]. Rational design of advanced drug delivery systems (DDS) for efficient cancer therapy is still a challenge. ...
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Homodimeric prodrug-based self-assembled nanoparticles, with carrier-free structure and ultrahigh drug loading, is drawing more and more attentions. Homodimeric prodrugs are composed of two drug molecules and a pivotal linkage. The influence of the linkages on the self-assembly, in vivo fate and antitumor activity of homodimeric prodrugs is the focus of research. Herein, three docetaxel (DTX) homodimeric prodrugs are developed using different lengths of diselenide bond-containing linkages. Interestingly, compared with the other two linkages, the longest diselenide bond-containing linkage could facilitate the self-delivery of DTX prodrugs, thus improving the stability, circulation time and tumor targeting of prodrug nanoassemblies. Besides, the extension of linkages reduces the redox-triggered drug release and cytotoxicity of prodrug nanoassemblies in tumor cells. Although the longest diselenide bond-containing prodrug nanoassemblies possessed the lowest cytotoxicity to 4T1 cells, their stable nanostructure maintained intact during circulation and achieve the maximum accumulation of DTX in tumor cells, which finally “turned the table”. Our study illustrates the crucial role of linkages in homodimeric prodrugs, and gives valuable proposal for the development of advanced nano-DDS for cancer treatment.
... [76] More recently, a PEGylated micellar formulation containing docetaxel was shown to achieve an impressive in vivo tumor regression, in multiple gastrointestinal cancer models. [77] Polymer-based NPs have also been extensively explored as carriers of cytotoxic drugs. Couvreur et al. pioneered the development of polycyanoacrylate NPs loaded with cytotoxic drugs. ...
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... Polymeric micelles have core-shell structure, which can encapsulate hydrophobic drugs, provide modification points and reduce drug toxicity [71]. Micellar docetaxel regulates tumor immune microenvironment and increases the proportion between M1 and M2-like macrophages, which can be used in combination chemotherapy and immunotherapy [72]. It should not be ignored that photodynamic therapy combined with chemotherapy is toxic, and a polymeric micelle can control drug release and reduce off-target toxicity [42]. ...
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The use of nanotechnology in medicine has the potential to have a major impact on human health for the prevention, diagnosis, and treatment of diseases. One particular aspect of the nanomedicine field which has received a great deal of attention is the design and development of nanoparticulate nanomedicines (NNMs) for drug delivery (i.e., drug-containing nanoparticles). NNMs are intended to deliver drugs via various mechanisms: solubilization, passive targeting, active targeting, and triggered release. The NNM approach aims to increase therapeutic efficacy, decrease the therapeutically effective dose, and/or reduce the risk of systemic side effects. In order to move a NNM from the bench to the bedside, several experimental challenges need to be addressed. This review will discuss the current trends and challenges in the clinical translation of NNMs as well as the potential pathways for translational development and commercialization. Key issues related to the clinical development of NNMs will be covered, including biological challenges, large-scale manufacturing, biocompatibility and safety, intellectual property (IP), government regulations, and overall cost-effectiveness in comparison to current therapies. These factors can impose significant hurdles limiting the appearance of NNMs on the market, irrelevant of whether they are therapeutically beneficial or not.
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Significance Cancer immunotherapy is a promising therapeutic intervention. However, complete and durable responses are seen in only a fraction of cancer patients. A key factor that limits therapeutic success is the lack of T cells in tumor cell regions, a profile termed “immune-excluded.” Here, we provide evidence that tumor-associated macrophages (TAMs) are an important determinant of the establishment of a T cell-excluded tumor phenotype. In human and murine tumors, we found that CD8 T cells poorly migrate and invade tumor nests due to long-lasting interactions with TAMs. The depletion of TAMs restores T cell migration and infiltration into tumor islets and improves the efficacy of anti–PD-1 immunotherapy. This study highlights the rationale of combining approaches targeting TAM and immune checkpoint proteins.
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Introduction: Regulatory agency comparisons can be of more value and facilitate improvements if conducted among countries with common challenges and similar health agency characteristics. A study was conducted to compare the registration review model used by the Turkish Medicines and Medical Devices Agency (Türkiye Ilaç ve Tibbi Cihaz Kurumu; TITCK) with those of four similar-sized regulatory agencies to identify areas of strength and those requiring further improvement within the TITCK in relation to the review process as well as to assess the level of adherence to good review practices (GRevP) in order to facilitate the TITCK progress toward agency goals. Methods: A questionnaire was completed and validated by the TITCK to collect data related to agency organizational structure, regulatory review process and decision-making practices. Similar questionnaires were completed and validated by Australia's Therapeutic Goods Administration (TGA), Health Canada, Singapore's Health Science Authority (HSA), and the Saudi Arabia Food and Drug Administration (SFDA). Results: The TITCK performs a full review for all new active substance (NAS) applications. Submission of a Certificate of Pharmaceutical product (CPP) with an application is not required; however, evidence of approval in another country is required for final authorization by the TITCK. Pricing data are not required by the TITCK at the time of submission; however, pricing must be completed to enable products to be commercially available. Mean approval times at the TITCK exceeded the agency's overall target time suggesting room for improved performance, consistency, and process predictability. Measures of GRevP are in place, but the implementation by the TITCK is not currently formalized. Discussion: Comparisons made through this study enabled recommendations to the TITCK that include streamlining the good manufacturing practice (GMP) process by sharing GMP inspection outcomes and certificates issued by other authorities, thus avoiding the delays by the current process; removing the requirement for prior approval or CPP; introducing shared or joint reviews with other similar regulatory authorities; formally implementing and monitoring GRevP; defining target timing for each review milestone; redefining the pricing process; and improving transparency by developing publicly available summaries for the basis of approval.
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Peritoneal carcinomatosis (PC) is typically identified in advanced stage gastric cancer and is frequently considered to be an incurable disease. Along with macroscopic PC, microscopic PC may be diagnosed through pathological examination of tissue specimens and is not detectable during surgical intervention. The present study aimed to analyse the prevalence, prognostic value and predictive factors for microscopic PC. In the present retrospective study, data from patients with epithelial gastric cancer that were treated with curative intent surgery were examined. Patients with macroscopic PC were excluded. Additionally, the study population was divided into two groups based on the presence or absence of microscopic PC. The prevalence of microscopic PC was 5.5%. Microscopic PC exhibited a significant negative effect on overall survival. In addition, multivariate analyses revealed that the significant predictive factors for the presence of microscopic PC were adenocarcinoma of a diffuse type, lymphatic and vascular invasion, cancer location at the site of previous gastric surgery and a tumour extent >T2. In particular, the presence of lymphatic and vascular invasion was the most significant predictive factor. These results indicate that ≥5.5% of patients with gastric cancer who undergo surgery with a curative intent may benefit from more aggressive loco-regional treatment against microscopic PC at the time of surgery.
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Chemotherapeutic drugs have multiple drawbacks, including severe side effects and suboptimal therapeutic efficacy. Nanomedicines assist in improving the biodistribution and the target accumulation of chemotherapeutic drugs, and are therefore able to enhance the balance between efficacy and toxicity. Multiple different types of nanomedicines have been evaluated over the years, including liposomes, polymer-drug conjugates and polymeric micelles, which rely on strategies such as passive targeting, active targeting and triggered release for improved tumor-directed drug delivery. Based on the notion that tumors and metastases are highly heterogeneous, it is important to integrate imaging properties in nanomedicine formulations in order to enable non-invasive and quantitative assessment of targeting efficiency. By allowing for patient pre-selection, such next generation nanotheranostics are useful for facilitating clinical translation and personalizing nanomedicine treatments.
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Successfully translating anti-cancer nanomedicines from pre-clinical proof of concept to demonstration of therapeutic value in the clinic is challenging. Having made significant advances with drug delivery technologies, we must learn from other areas of oncology drug development, where patient stratification and target-driven design have improved patient outcomes. We should evolve our nanomedicine development strategies to build the patient and disease into the line of sight from the outset. The success of small molecule targeted therapies has been significantly improved by employing a specific decision-making framework, such as AstraZeneca's 5R principle: right target/efficacy, right tissue/exposure, right safety, right patient, and right commercial potential. With appropriate investment and collaboration to generate a platform of evidence supporting the end clinical application, a similar framework can be established for enhancing nanomedicine translation and performance. Building informative data packages to answer these questions requires the following: (I) an improved understanding of the heterogeneity of clinical cancers and of the biological factors influencing the behaviour of nanomedicines in patient tumours; (II) a transition from formulation-driven research to disease-driven development; (III) the implementation of more relevant animal models and testing protocols; and (IV) the pre-selection of the patients most likely to respond to nanomedicine therapies. These challenges must be overcome to improve (the cost-effectiveness of) nanomedicine development and translation, and they are key to establishing superior therapies for patients.
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Targeting nanoparticles to malignant tissues for improved diagnosis and therapy is a popular concept. However, after surveying the literature from the past 10 years, only 0.7% (median) of the administered nanoparticle dose is found to be delivered to a solid tumour. This has negative consequences on the translation of nanotechnology for human use with respect to manufacturing, cost, toxicity, and imaging and therapeutic efficacy. In this article, we conduct a multivariate analysis on the compiled data to reveal the contributions of nanoparticle physicochemical parameters, tumour models and cancer types on the low delivery efficiency. We explore the potential causes of the poor delivery efficiency from the perspectives of tumour biology (intercellular versus transcellular transport, enhanced permeability and retention effect, and physicochemical-dependent nanoparticle transport through the tumour stroma) as well as competing organs (mononuclear phagocytic and renal systems) and present a 30-year research strategy to overcome this fundamental limitation. Solving the nanoparticle delivery problem will accelerate the clinical translation of nanomedicine.
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Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials.
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Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.
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Unlabelled: Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biologic studies, and personalized medicine strategies. This article summarizes the current state of the art in this field, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and introduces a European consortium of PDX models. Significance: PDX models are increasingly used in translational cancer research. These models are useful for drug screening, biomarker development, and the preclinical evaluation of personalized medicine strategies. This review provides a timely overview of the key characteristics of PDX models and a detailed discussion of future directions in the field.
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Gastric cancer often presents in a metastasized stage. We conducted a population-based study to evaluate trends in systemic treatment and survival of metastatic noncardia gastric cancer. All patients with noncardia adenocarcinoma of the stomach, diagnosed between 1990 and 2011 in the Eindhoven Cancer Registry area in the Netherlands were included (N = 4797). We conducted multivariable logistic regression analysis to evaluate trends in administration of palliative chemotherapy and multivariable proportional hazards regression analyses to evaluate trends in crude overall survival. The proportion of patients presenting with metastatic gastric cancer increased from 24% in 1990 to 44% in 2011 (P < 0.0001). The use of palliative chemotherapy increased, from 5% in 1990 to 36% in 2011, with a strong increase in particular after 2006 (P < 0.0001). Younger patients [<50 years: adjusted odds ratio (ORadj) 3.9, P < 0.001; 50-59 years: ORadj 1.7, P = 0.01] and patients with a high socioeconomic status (ORadj 1.7, P = 0.01) more often received chemotherapy. In contrast, older patients (70-79 years: ORadj 0.3, P < 0.001; 80+ years: ORadj 0.02, P < 0.001), patients with comorbidity (ORadj 0.6, P = 0.03), linitis plastica (ORadj 0.5, P = 0.03) and multiple distant metastases (ORadj 0.5, P = 0.01) were less often treated with chemotherapy. A large hospital variation was observed in the administration of palliative chemotherapy (9%-27%). Median overall survival remained constant between 15 [95% confidence interval (CI) 11.9-17.7] and 17 (95% CI 15.0-20.0) weeks (P = 0.10). The increased administration of chemotherapy in patients with metastatic gastric cancer did not lead to an increase in population-based overall survival. Identification of the subgroup of patients which benefits from palliative chemotherapy is of utmost importance to avoid unnecessary treatment.
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The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described. Participants of the GeparTrio study with primary breast cancer randomly received neoadjuvant response-guided (8 cycles TAC (docetaxel/doxorubicin/cyclophosphamide) in responding and TAC-NX (vinorelbine/capecitabine) in non-responding patients) or conventional (6 cycles TAC) chemotherapy according to interim response assessment. Ki67 levels were centrally measured immunohistochemically post-neoadjuvant treatment if tumor tissue was available. We here analyze 1151 patients having a pCR (N=484), or residual disease with low (0-15%), intermediate (15.1-35%), or high (35.1-100%) post-treatment Ki67 levels in 488, 77, and 102 patients, respectively. Patients with high post-treatment Ki67 levels showed higher risk for disease relapse (p<.0001) and death (p<.0001) compared to patients with low or intermediate Ki67 levels. Patients with low Ki67 levels showed a comparable outcome to patients with a pCR (p=0.211 for disease-free and p=0.779 for overall survival). Post-treatment Ki67 levels provided more prognostic information than pre-treatment Ki67 levels or changes of Ki67 from pre- to post-treatment. Information on pCR plus post-treatment Ki67 levels surmounts the prognostic information of pCR alone in hormone-receptor-positive disease (hazard ratios between 1.82 to 5.88) but not in hormone-receptor-negative disease (hazard ratios between 0.61 and 1.73). Patients with conventional and response-guided treatment did not show a different distribution of Ki67 (p=0.965). Post-treatment Ki67 levels provide prognostic information for patients with hormone-receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy. Levels were not prognostic for outcome after response-guided chemotherapy. High post-treatment Ki67 indicates the need for innovative post-neoadjuvant treatments.
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Personalized medicine aims to individualize chemotherapeutic interventions on the basis of ex vivo and in vivo information on patient- and disease-specific characteristics. By noninvasively visualizing how well image-guided nanomedicines-that is, submicrometer-sized drug delivery systems containing both drugs and imaging agents within a single formulation, and designed to more specifically deliver drug molecules to pathologic sites-accumulate at the target site, patients likely to respond to nanomedicine-based therapeutic interventions may be preselected. In addition, by longitudinally monitoring how well patients respond to nanomedicine-based therapeutic interventions, drug doses and treatment protocols can be individualized and optimized during follow-up. Furthermore, noninvasive imaging information on the accumulation of nanomedicine formulations in potentially endangered healthy tissues may be used to exclude patients from further treatment. Consequently, combining noninvasive imaging with tumor-targeted drug delivery seems to hold significant potential for personalizing nanomedicine-based chemotherapeutic interventions, to achieve delivery of the right drug to the right location in the right patient at the right time. Clin Cancer Res; 18(18); 4889-94. ©2012 AACR.
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Polymeric micelles (PM) based on poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) loaded with paclitaxel (PTX-PM) have shown promising results in overcoming the suboptimal efficacy/toxicity profile of paclitaxel. To get insight into the stability of PTX-PM formulations upon storage and to optimize their in vivo tumor-targeted drug delivery properties, we set out to identify a lead PTX-PM formulation with the optimal polymer composition. To this end, PM based on four different mPEG5k-b-p(HPMA-Bz) block copolymers with varying molecular weight of the hydrophobic block (17 to 3 kDa) were loaded with different amounts of PTX. The hydrodynamic diameter was 52±1 nm for PM prepared using polymers with longer hydrophobic blocks (mPEG5k-b-p(HPMA-Bz)17k and mPEG5k-b-p(HPMA-Bz)10k) and 39±1 nm for PM composed of polymers with shorter hydrophobic blocks (mPEG5k-b-p(HPMA-Bz)5k and mPEG5k-b-p(HPMA-Bz)3k). The best storage stability and the slowest PTX release was observed for PM with larger hydrophobic blocks. On the other hand, smaller sized PM of shorter mPEG5k-b-p(HPMA-Bz)5k showed a better tumor penetration in 3D spheroids. Considering better drug retention capacity of the mPEG5k-b-p(HPMA-Bz)17k and smaller size of the mPEG5k-b-p(HPMA-Bz)5k as two desirable design features, we argue that PM based on these two polymers are the lead candidates for further in vivo studies.
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Nanomedicines are extensively employed in cancer therapy. We here propose four strategic directions to improve nanomedicine translation and exploitation. (1) Patient stratification has become common practice in oncology drug development. Accordingly, probes and protocols for patient stratification are urgently needed in cancer nanomedicine, to identify individuals suitable for inclusion in clinical trials. (2) Rational drug selection is crucial for clinical and commercial success. Opportunistic choices based on drug availability should be replaced by investments in modular (pro)drug and nanocarrier design. (3) Combination therapies are the mainstay of clinical cancer care. Nanomedicines synergize with pharmacological and physical co-treatments, and should be increasingly integrated in multimodal combination therapy regimens. (4) Immunotherapy is revolutionizing the treatment of cancer. Nanomedicines can modulate the behaviour of myeloid and lymphoid cells, thereby empowering anticancer immunity and immunotherapy efficacy. Alone and especially together, these four directions will fuel and foster the development of successful cancer nanomedicine therapies. The use of nanomedicine in cancer requires the adoption of specific strategies to optimize its potential. This perspective proposes four strategies including the identification of patients for clinical trials, investments in modular nanocarrier design, the integration in multimodal combination therapy regimes and the inclusion in immunotherapy studies
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Importance Peritoneal metastasis is the most frequent pattern of postoperative recurrence in patients with gastric cancer. Extensive intraoperative peritoneal lavage (EIPL) is a new prophylactic strategy for treatment of peritoneal metastasis of locally advanced gastric cancer; however, the safety and efficacy of EIPL is currently unknown. Objective To evaluate short-term outcomes of patients with advanced gastric cancer who received combined surgery and EIPL or surgery alone. Design, Setting, and Participants From March 2016 to November 2017, 662 patients with advanced gastric cancer receiving D2 gastrectomy were enrolled in a large, multicenter, randomized clinical trial from 11 centers across China. In total, 329 patients were randomly assigned to receive surgery alone, and 333 patients were randomly assigned to receive surgery plus EIPL. Clinical characteristics, operative findings, and postoperative short-term outcomes were compared between the 2 groups in the intent-to-treat population. Main Outcomes and Measures Short-term postoperative complications and mortality. Results The present analysis included data from 550 patients, 390 men and 160 women, with a mean (SD) age of 60.8 (10.7) years in the surgery alone group and 60.6 (10.8) in the surgery plus EIPL group. Patients assigned to the surgery plus EIPL group exhibited reduced mortality (0 of 279 patients) compared with those assigned to surgery alone (5 of 271 patients [1.9%]) (difference, 1.9%; 95% CI, 0.3%-3.4%; P = .02). A significant difference in the overall postoperative complication rate was observed between patients receiving surgery alone (46 patients [17.0%]) and those receiving surgery plus EIPL (31 patients [11.1%]) (difference, 5.9%; 95% CI, 0.1%-11.6%; P = .04). Postoperative pain occurred more often following surgery alone (48 patients [17.7%]) than following surgery plus EIPL (30 patients [10.8%]) (difference, 7.0%; 95% CI, 0.8%-13.1%; P = .02). Conclusions and Relevance Inclusion of EIPL can increase the safety of D2 gastrectomy and decrease postoperative short-term complications and wound pain. As a new, safe, and simple procedure, EIPL therapy is easily performed anywhere and does not require any special devices or techniques. Our study suggests that patients with advanced gastric cancer appear to be candidates for the EIPL approach. Trial Registration ClinicalTrials.gov identifier: NCT02745509
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Macrophages are critical mediators of tissue homeostasis, with tumours distorting this proclivity to stimulate proliferation, angiogenesis and metastasis. This had led to an interest in targeting macrophages in cancer, and preclinical studies have demonstrated efficacy across therapeutic modalities and tumour types. Much of the observed efficacy can be traced to the suppressive capacity of macrophages, driven by microenvironmental cues such as hypoxia and fibrosis. As a result, tumour macrophages display an ability to suppress T cell recruitment and function as well as to regulate other aspects of tumour immunity. With the increasing impact of cancer immunotherapy, macrophage targeting is now being evaluated in this context. Here, we discuss the results of clinical trials and the future of combinatorial immunotherapy. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
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The clinical translation of promising products, technologies and interventions from the disciplines of nanomedicine and cell therapy has been slow and inefficient. In part, translation has been hampered by suboptimal research practices that propagate biases and hinder reproducibility. These include the publication of small and underpowered preclinical studies, suboptimal study design (in particular, biased allocation of experimental groups, experimenter bias and lack of necessary controls), the use of uncharacterized or poorly characterized materials, poor understanding of the relevant biology and mechanisms, poor use of statistics, large between-model heterogeneity, absence of replication, lack of interdisciplinarity, poor scientific training in study design and methods, a culture that does not incentivize transparency and sharing, poor or selective reporting, misaligned incentives and rewards, high costs of materials and protocols, and complexity of the developed products, technologies and interventions. In this Perspective, we discuss special manifestations of these problems in nanomedicine and in cell therapy, and describe mitigating strategies. Progress on reducing bias and enhancing reproducibility early on ought to enhance the translational potential of biomedical findings and technologies.
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This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high‐quality cancer registry data, the basis for planning and implementing evidence‐based cancer control programs, are not available in most low‐ and middle‐income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1‐31. © 2018 American Cancer Society
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The tumor accumulation of nanomedicines relies on the enhanced permeability and retention (EPR) effect. In the last 5-10 years, it has been increasingly recognized that there is a large inter- and intra-individual heterogeneity in EPR-mediated tumor targeting, explaining the heterogeneous outcomes of clinical trials in which nanomedicine formulations have been evaluated. To address this heterogeneity, as in other areas of oncology drug development, we have to move away from a one-size-fits-all tumor targeting approach, towards methods that can be employed to individualize and improve nanomedicine treatments. To this end, efforts have to be invested in better understanding the nature, the complexity and the heterogeneity of the EPR effect, and in establishing systems and strategies to enhance, combine, bypass and image EPR-based tumor targeting. In the present manuscript, we summarize key studies in which these strategies are explored, and we discuss how these approaches can be employed to enhance patient responses.
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The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
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Pancreatic cancer is a devastating disease that is largely refractory to currently available treatment strategies. Therapeutic resistance is partially attributed to the dense stromal reaction of PDAC tumors that includes a pervasive infiltration of immunosuppressive (M2) macrophages. Nab-paclitaxel (trade name Abraxane) is a nanoparticle albumin-bound formulation of paclitaxel that, in combination with gemcitabine, is currently the first line treatment for pancreatic cancer. Here, we show that macrophages internalized nab-paclitaxel via macropinocytosis. The macropinocytic uptake of nab-paclitaxel induced macrophage immunostimulatory (M1) cytokine expression and synergized with IFNγ to promote inducible nitric oxide synthase (iNOS) expression in a TLR4-dependent manner. Nab-paclitaxel was internalized by tumor-associated macrophages in vivo, and therapeutic doses of nab-paclitaxel alone, and in combination with gemcitabine, increased the MHCII(+)CD80(+)CD86(+) M1 macrophage population. These data revealed an unanticipated role for nab-paclitaxel in macrophage activation and rationalize its potential use to target immune evasion in pancreatic cancer.
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Remarkable progress has recently been made in the synthesis and characterization of engineered nanoparticles for imaging and treatment of cancers, resulting in several promising candidates in clinical trials. Despite these advances, clinical applications of nanoparticle-based therapeutic/imaging agents remain limited by biological, immunological, and translational barriers. In order to overcome the existing status quo in drug delivery, there is a need for open and frank discussion in the nanomedicine community on what is needed to make qualitative leaps toward translation. In this Nano Focus, we present the main discussion topics and conclusions from a recent workshop: "Mechanisms and Barriers in Nanomedicine". The focus of this informal meeting was on biological, toxicological, immunological, and translational aspects of nanomedicine and approaches to move the field forward productively. We believe that these topics reflect the most important issues in cancer nanomedicine.
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Tumor targeting by nanomedicine-based therapeutics has emerged as a promising approach to overcome the lack of specificity of conventional chemotherapeutic agents and to provide clinicians the ability to overcome shortcomings of current cancer treatment. The major underlying mechanism of the design of nanomedicines was the Enhanced Permeability and Retention (EPR) effect, considered as the “royal gate” in the drug delivery field. However, after the publication of thousands of research papers, the verdict has been handed down: the EPR effect works in rodents but not in humans! Thus the basic rationale of the design and development of nanomedicines in cancer therapy is failing making it necessary to stop claiming efficacy gains via the EPR effect, while tumor targeting cannot be proved in the clinic. It is probably time to dethrone the EPR effect and to ask the question: what is the future of nanomedicines without the EPR effect? The aim of this review is to provide a general overview on (i) the current state of the EPR effect, (ii) the future of nanomedicine and (iii) the strategies of modulation of the tumor microenvironment to improve the delivery of nanomedicine.
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The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.
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Nanomedicine may have a delivery problem. Rigorous, realistic and holistic rethinking is needed to improve nanomedicine performance and increase patient benefit.
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Background: Expression of PD-L1 has been shown to be upregulated in some patients with gastric cancer. As part of the phase 1b KEYNOTE-012 study, we aimed to assess the safety and activity of the anti-PD-1 antibody pembrolizumab in patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Methods: This study was a multicentre, open-label, phase 1b trial done at 13 cancer research centres in the USA, Israel, Japan, South Korea, and Taiwan. We enrolled patients with PD-L1-positive recurrent or metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Patients received intravenous pembrolizumab at 10 mg/kg once every 2 weeks for 24 months or until progression or unacceptable toxic effects occurred. Response was assessed every 8 weeks in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. The primary objectives were safety in patients who received at least one dose of pembrolizumab and the proportion of patients achieving overall responses in patients who received at least one pembrolizumab dose and who either had a post-baseline scan or who discontinued therapy because of clinical disease progression or a treatment-related adverse event before the first post-baseline scan. The study is registered with ClinicalTrials.gov, number NCT01848834, and is ongoing but no longer enrolling patients. Findings: From Oct 23, 2013, to May 5, 2014, 39 patients were enrolled. 36 were evaluable for response by central assessment. Eight (22%, 95% CI 10-39) patients were judged to have had an overall response at central review; all responses were partial. All 39 patients were included in the safety analyses. Five (13%) patients had a total of six grade 3 or 4 treatment-related adverse events, consisting of two cases of grade 3 fatigue, one case each of grade 3 pemphigoid, grade 3 hypothyroidism, and grade 3 peripheral sensory neuropathy, and one case of grade 4 pneumonitis. No treatment-related deaths occurred. Interpretation: In this population of patients with recurrent or metastatic PD-L1-positive gastric cancer, pembrolizumab had a manageable toxicity profile and promising antitumour activity, warranting further study in phase 2 and 3 trials. Funding: Merck & Co.
Article
We previously showed that LIGHT and its receptor herpes virus entry mediator (HVEM) are important for development of optimal CD4(+) Th1 cell immunity and resistance to primary Leishmania major infection in mice. In this study, we further characterized the contributions of this molecule in dendritic cell (DC) maturation, initiation, and maintenance of primary immunity and secondary anti-Leishmania immunity. Flow-cytometric studies showed that CD8α(+) DC subset was mostly affected by HVEM-Ig and lymphotoxin β receptor-Ig treatment. LIGHT signaling is required at both the priming and the maintenance stages of primary anti-Leishmania immunity but is completely dispensable during secondary immunity in wild type mice. However, LIGHT blockade led to impaired IL-12 and IFN-γ responses and loss of resistance in healed CD40-deficient mice after L. major challenge. The protective effect of LIGHT was mediated primarily via its interaction with lymphotoxin β receptor on CD8α(+) DCs. Collectively, our results show that although LIGHT is critical for maintenance of primary Th1 response, it is dispensable during secondary anti-Leishmania immunity in the presence of functional CD40 signaling as seen in wild type mice. Copyright © 2015 by The American Association of Immunologists, Inc.
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How neoplastic cells respond to therapy is not solely dependent on the complexity of the genomic aberrations they harbor but is also regulated by numerous dynamic properties of the tumor microenvironment. Identifying and targeting critical pathways that improve therapeutic efficacy by bolstering anti-tumor immune responses holds great potential for improving outcomes and impacting long-term patient survival. Macrophages are key regulators of homeostatic tissue and tumor microenvironments. Therefore, therapeutics impacting macrophage presence and/or bioactivity have shown promise in preclinical models and are now being evaluated in the clinic. This review discusses the molecular/cellular pathways identified so far whereby macrophages mediate therapeutic responses. Copyright © 2015 Elsevier Inc. All rights reserved.
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Treatment of cancer patients with taxane-based chemotherapeutics, such as paclitaxel (PTX), is complicated by their narrow therapeutic index. Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of PTX, as they can be tailored to encapsulate large amounts of hydrophobic drugs and achieve prolonged circulation kinetics. As a result, PTX deposition in tumors is increased while drug exposure to healthy tissues is reduced. However, many PTX-loaded micelle formulations suffer from low stability and fast drug release in the circulation, limiting their suitability systemic drug targeting. To overcome these limitations, we have developed paclitaxel (PTX)-loaded micelles which are stable without chemical crosslinking and covalent drug attachment, and characterized by excellent loading capacity and strong drug retention, attributed to π-π stacking interaction between PTX and the aromatic groups of the polymer chains in the micellar core. The micelles are based on methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl) methacrylamide)) (mPEG-b-p(HPMAm-Bz)) block copolymers, which improve the pharmacokinetics and the biodistribution of PTX, and substantially increased PTX tumor accumulation (by more than 2000%; as compared to Taxol® or control micelle formulations). Improved biodistribution and tumor accumulation were confirmed by hybrid CT-FMT imaging using near-infrared labeled micelles and payload. The PTX-loaded micelles were well tolerated at different doses while they induced complete tumor regression in two different xenograft models (i.e. A431 and MDA-MB-468). Our findings consequently indicate that π-π stacking-stabilized polymeric micelles are promising carriers to improve the delivery of highly hydrophobic drugs to tumors and to increase their therapeutic index.
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Background: Docetaxel is a widely used cytotoxic agent. This study evaluates the impact of docetaxel toxicities on patient's health-related quality of life (QoL). Patients and methods: We conducted a multicenter, prospective, non-interventional trial, in which the QoL was assessed using the EORTC QLQ-C30 questionnaires at baseline and every 4 weeks up to 40 weeks in patients receiving a docetaxel-based chemotherapy for metastatic disease. Treatment-related adverse events were correlated with the corresponding QoL scores. Uni- and multivariate analyses were applied. Results: From January 2008 to June 2011, a total of 2659 patients were included. The majority of patients (48.1%) had prostate cancer, followed by breast (17.1%) and non-small-cell-lung cancer (15.8%). Patients received a median of 5 docetaxel cycles with the median dose of 75 mg/m(2). The presence of grade 3/4 diarrhea showed the strongest effect on global health status/QoL average scores (50.91 versus 33.06), followed by vomiting (50.91 versus 35.17), dyspnea (50.94 versus 35.81), mucositis/stomatitis (50.88 versus 36.41), nausea (50.91 versus 36.68), infection (50.90 versus 37.14), fatigue (50.90 versus 43.82) and anemia (50.91 versus 41.03), P < 0.05 for all comparisons. Grade 3/4 leukopenia/neutropenia, alopecia, constipation, neurotoxicity and nail disorders had no significant impact on the global health status/QoL or other items. Conclusion: In this large non-interventional trial, docetaxel-associated grade 3 or 4 toxicities were shown to have a strong detrimental effect on patient's QoL. Notably, diarrhea and vomiting had the strongest negative impact on QoL measures. This has to be kept in mind while making therapeutic decisions and providing optimized supportive treatment measures. Clinical trials number: This study was registered at Deutsches Krebsstudienregister (DKSR, primary registry in the WHO Registry Network) with the ID 527.
Article
Background The aim of our study was to evaluate retrospectively in a large single institution setting all cases of lung resections for colorectal metastases from 1998 to 2008 and to assess clinicopathologic factors influencing outcome. Methods In all, 199 patients, 125 men and 74 women, with lung metastases of colorectal cancer, 120 colon and 79 rectum, underwent resection with curative intent; mean interval between primary surgery and lung metastasis was 35 months. Carcinoembryonic antigen preoperative value was abnormal in 52 patients; K-RAS wild-type was detected in 60 of 97 examined cases; 75 patients received preoperative or postoperative chemotherapy or both. A solitary lesion was described in 95 patients (47.7%), two or three metastases in 72 (36.2%), and more than three metastases in 26 (13.1%). Nodal status was reported in 130 patients (73%). One hundred twenty patients (60.3%) underwent wedge resection, 27 (13.6%) underwent segmentectomy, and 52 (26.1%) had lobectomy. An R0 resection was achieved in 178 cases (89.4%). Results Median overall survival was 4.2 years (95% confidence interval: 3.1 to 5.1) with a 5-year overall survival of 43% (95% confidence interval: 36% to 50%). An R1 resection (log rank p = 0.0001), thoracic nodal involvement (log rank p = 0.0002), and preoperative abnormal carcinoembryonic antigen value (log rank p < 0.001) were significantly associated with poor outcome in univariate analysis. In multivariate analysis, the same variables plus the number of lesions (single versus multiple, p = 0.04) were shown to affect outcome. Conclusions An R0 resection, preoperative carcinoembryonic antigen, nodal involvement, and number of lesions represent strong prognostic factors in patient with lung metastases of colorectal cancer. The role of systemic treatments and biomolecular tests deserve future prospective investigations.
Article
The tumor microenvironment is a complex ecology of cells that evolves with and provides support to tumor cells during the transition to malignancy. Among the innate and adaptive immune cells recruited to the tumor site, macrophages are particularly abundant and are present at all stages of tumor progression. Clinical studies and experimental mouse models indicate that these macrophages generally play a protumoral role. In the primary tumor, macrophages can stimulate angiogenesis and enhance tumor cell invasion, motility, and intravasation. During monocytes and/or metastasis, macrophages prime the premetastatic site and promote tumor cell extravasation, survival, and persistent growth. Macrophages are also immunosuppressive, preventing tumor cell attack by natural killer and T cells during tumor progression and after recovery from chemo- or immunotherapy. Therapeutic success in targeting these protumoral roles in preclinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment.
Article
In recent years, polymeric nanoparticles have appeared as a most viable and versatile delivery system for targeted cancer therapy. Various in vivo studies have demonstrated that virus-sized stealth particles are able to circulate for a prolonged time and preferentially accumulate in the tumor site via the enhanced permeability and retention (EPR) effect (so called 'passive tumor-targeting'). The surface decoration of stealth nanoparticles by a specific tumor-homing ligand such as antibody, antibody fragment, peptide, aptamer, polysaccharide, saccharide, folic acid, etc. might further lead to increased retention and accumulation of nanoparticles in the tumor vasculature as well as selective and efficient internalization by target tumor cells (termed as 'active tumor-targeting'). Notably, these active targeting nanoparticulate drug formulations have shown improved, though to varying degrees, therapeutic performances in different tumor models as compared to their passive targeting counterparts. In addition to type of ligands, several other factors such as in vivo stability of nanoparticles, particle shape and size, and ligand density also play an important role in targeted cancer chemotherapy. In this review, concept and recent development of polymeric nanoparticles conjugated with specific targeting ligands, ranging from proteins (e.g. antibodies, antibody fragments, growth factors, and transferrin), peptides (e.g. cyclic RGD, octreotide, AP peptide, and tLyp-1 peptide), aptamers (e.g. A10 and AS1411), polysaccharides (e.g. hyaluronic acid), to small biomolecules (e.g. folic acid, galactose, bisphosphonates, and biotin), for active tumor-targeting drug delivery in vitro and in vivo are highlighted and discussed. With promise to maximize therapeutic efficacy while minimize systemic side effects, ligand-mediated active tumor-targeting treatment modality has become an emerging and indispensable platform for safe and efficient cancer therapy.
Article
Despite new insight into the pathogenesis and development of cancer, most novel therapies fail upon reaching Phase III clinical trials. This occurs even though millions of dollars are spent on target validation and drug optimization in preclinical models. When evaluating our approach to target discovery, we should consider if our current, powerful genomic technologies are being used on model systems that have poor clinical predictive power."Tumor graft models" (also known as Patient-Derived Xenografts or PDXs) are based on the transfer of primary tumors directly from the patient into an immunodeficient mouse. This review examines the development, challenges and broad utility of these attractive cancer models.
Article
Thermosensitive amphiphilic block copolymers self-assemble into micelles above their lower critical solution temperature in water, however the micelles generally display mediocre physical stability. To stabilize such micelles and increase their loading capacity for chemotherapeutic drugs, block copolymers with novel aromatic monomers were synthesized by free radical polymerization of N-(2-benzoyloxypropyl methacrylamide (HPMAm-Bz) or the corresponding naphthoyl analogue (HPMAm-Nt), with N-(2-hydroxypropyl) methacrylamide monolactate, using a polyethylene glycol based macroinitiator. The critical micelle temperatures and critical micelle concentrations decreased with increasing the HPMAm-Bz/Nt content. The micelles of 30 to 50 nm were prepared by heating the polymer aqueous solutions from 0 to 50 oC and were colloidally stable for at least 48 h at pH 7.4 and 37 oC. Paclitaxel and docetaxel encapsulation was performed by mixing drug solutions in ethanol with polymer aqueous solutions and heating from 0 to 50 oC. The micelles had a drug loading capacity up to 34 weight % for docetaxel, which is amongst the highest loadings reported for polymeric micelles, with loaded micelle sizes ranging from 60 to 80 nm. The micelles without aromatic groups almost completely released loaded paclitaxel in 10 days, whereas the HPMAm-Bz/Nt containing micelles released 50% of the paclitaxel at the same time, which showed a better retention for the drug of the latter micelles. 1H solid-state NMR spectroscopy data are compatible with π-π stacking between aromatic groups. The empty micelles demonstrated good cytocompatibility, and paclitaxel loaded micelles showed high cytotoxicity to tumor cells. In conclusion, the π-π stacking effect introduced by aromatic groups increases the stability and loading capacity of polymeric micelles.