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Metastatic cancers are responsible for 90% of cancer related deaths and melanoma is known as one of the deadliest cancers. Dacarbazine (DTIC) for metastatic melanoma has become an approved first-line treatment in routine clinical practice. However, response rates to single-drug therapy with dacarbazine are quite low. Therefore, combination drug therapy as a method of treatment that combines two or more therapeutic agents is the cornerstone of cancer therapy. Here, we examined the effects of the combination of ornidazole, a derivative of 5-nitroimidazole which is active against protozoa and anaerobic bacteria, and DTIC on melanoma cells to investigate novel advanced combination therapies for melanoma. Doses in this study are 0, 800 and 1200µg/mL for ornidazole, 0, 5, 25, 50, 100, 200, 300, 600, 1200μM/L for DTIC and 800µg/mL+100μM/L, 800µg/mL+200μM/L, 1200µg/mL+100μM/L, 1200µg/mL+200μM/L for ornidazole+DTIC combination. Treatment effect of ornidazole and DTIC as a single-agents and in combination on cell viability was investigated with crystal violet and MTT assays. As well as the effect of them on migration ability was assessed by wound healing assay, the effect of them on DNA damage induction was evaluated by comet assay in B16F10 melanoma cells in vitro. Our data showed that combination treatment with ornidazole and DTIC markedly inhibited cancer cell proliferation and migration. DNA damage was also significantly induced by this combination treatment. Our study showed that ornidazole/DTIC combination drug therapy has more effective therapeutic potential for melanoma compared to DTIC therapy alone. In conclusion, our findings suggest that combination therapy with ornidazole/ DTIC could serve as a new and valuable approach for melanoma treatment. [ABSTRACT FROM AUTHOR]

ABSTRACTThe RNA molecule plays a pivotal role in many biological processes by relaying genetic information, regulating gene expression, and serving as molecular machines and catalyzers. This inherent versatility of RNA has fueled significant advancements in the field of RNA nanotechnology, driving the engineering of complex nanoscale architectures toward biomedical applications, including targeted drug delivery and bioimaging. RNA polymers, serving as building blocks, offer programmability and predictability of Watson-Crick base pairing, as well as non-canonical base pairing, for the construction of nanostructures with high precision and stoichiometry. Leveraging the ease of chemical modifications to protect the RNA from degradation, researchers have developed highly functional and biocompatible RNA architectures and integrated them into preclinical studies for the delivery of payloads and imaging agents. This review offers an educational introduction to the use of RNA as a biopolymer in the design of multifunctional nanostructures applied to targeted delivery in vivo, summarizing physical and biological barriers along with strategies to overcome them. Furthermore, we highlight the most recent progress in the development of both small and larger RNA nanostructures, with a particular focus on imaging reagents and targeted cancer therapeutics in pre-clinical models and provide insights into the prospects of this rapidly evolving field.

Dehydrocurvularin (DCV) is a promising lead compound for anti-cancer therapy. Unfortunately, the development of DCV-based drugs has been hampered by its poor solubility and bioavailability. Herein, we prepared a DCV-loaded mPEG-PLGA nanoparticles (DCV-NPs) with improved drug properties and therapeutic efficacy. The spherical and discrete particles of DCV-NPs had a uniform diameter of 101.8 ± 0.45 nm and negative zeta potential of −22.5 ± 1.12 mV (pH = 7.4), and its entrapment efficiency (EE) and drug loading (DL) were ∼53.28 ± 1.12 and 10.23 ± 0.30%, respectively. In vitro the release of DCV-NPs lasted for more than 120 h in a sustained-release pattern, its antiproliferation efficacy towards breast cancer cell lines (MCF-7, MDA-MB-231, and 4T1) was better than that of starting drug DCV, and it could be efficiently and rapidly internalised by breast cancer cells. In vivo DCV-NPs were gradually accumulated in tumour areas of mice and significantly suppressed tumour growth. In summary, loading water-insoluble DCV onto nanoparticles has the potential to be an effective agent for breast cancer therapy with injectable property and tumour targeting capacity. [ABSTRACT FROM AUTHOR]

Naseer F, Ahmad T, Kousar K, et al. Int J Nanomedicine. 2023;18:185–205. We, the Editor and Publisher of the journal International Journal of Nanomedicine are retracting the published article. Following publication of the article, concerns were raised about the duplication of images from Figures 8, 10 and 13 with images from other unrelated articles. Specifically, The image for Figure 8A, blank NF temperatures, has been duplicated with the image for Figure 13C, SEM of lyophilized NF after 3 months storage. The image for Figure 8C, HA-coated OMV loaded TC, has been duplicated with the image for Figure 16C, lyophilized NFs after 3 months, from Kousar K, Naseer F, Abduh MS, Anjum S and Ahmad T. CD44 targeted delivery of oncolytic Newcastle disease virus encapsulated in thiolated chitosan for sustained release in cervical cancer: a targeted immunotherapy approach. Front. Immunol. 2023;14:1175535. https://doi.org/10.3389/fimmu.2023.1175535. The image for Figure 8D, HA-coated OMV loaded TCs, has been duplicated with the image for Figure 6B, CsA-loaded ThC-HA NF, from Abduh MS. Anticancer Analysis of CD44 Targeted Cyclosporine Loaded Thiolated Chitosan Nanoformulations for Sustained Release in Triple-Negative Breast Cancer. Int J Nanomedicine. 2023;18:5713-5732. https://doi.org/10.2147/IJN.S424932. The image for Figure 9D, HA-coated OMV-loaded TCs, has been duplicated with the image for Figure 10B, HA-ThCs-Cis NFs, from Kousar K, Naseer F, Abduh MS, et al. Green synthesis of hyaluronic acid coated, thiolated chitosan nanoparticles for CD44 targeted delivery and sustained release of Cisplatin in cervical carcinoma. Front. Pharmacol. 2023;13:1073004. https://doi.org/10.3389/fphar.2022.1073004. The entire Figure 10 has been duplicated with Figure 6 from Naseer F, Kousar K, Abduh MS, et al. Evaluation of the anticancer potential of CD44 targeted vincristine nanoformulation in prostate cancer xenograft model: a multi-dynamic approach for advanced pharmacokinetic evaluation. Cancer Nano. 2023;14:65. https://doi.org/10.1186/s12645-023-00218-2. The images for Figure 10, Pure MV 12h, 90µg/ml and OMV-loaded TCs 24h, 50µg/ml have been duplicated. The image for Figure 10, OMV-loaded TCs 24h, 90µg/ml has been duplicated with the image for Figure 10, MCF-10A, Pure CsA, 90µg/ml from Abduh MS, 2023. The image for Figure 10, Pure MV 12h, 50µg/ml has been duplicated with the image for Figure 10, MCF-10A, CsA-NF, 60µg/ml from Abduh MS, 2023. The images for Figure 13C, lyophilized NF after 3 months storage, has been duplicated with the image for Figure 7A, SEM image of spherical HA-ThCs-Cis loaded nanoparticles, from Kousar K, et al (2023). The corresponding author responded to our queries but was unable to provide a satisfactory explanation for how the images came to be duplicated and the editor no longer has confidence in the reported findings. As verifying the validity of published work is core to the integrity of the scholarly record, the Publisher and Editor requested to retract the article and the corresponding author does not agree with this decision. We have been informed in our decision-making by our editorial policies and COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Payal Deepak,1 Praveen Kumar,2,3 Prashant Pandey,1 Dilip Kumar Arya,1 Shweta Jaiswal,1 Anand Kumar,1 Archana Bharti Sonkar,1 Daoud Ali,4 Saud Alarifi,4 Mohankumar Ramar,5 P S Rajinikanth1 1Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India; 2Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, Madhya Pradesh, India; 3S.D College of Pharmacy and Vocational Studies, Muzaffarnagar, Uttar Pradesh, India; 4Department of Zoology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia; 5Department of Pharmacology and Toxicology, School of Pharmacy, University of Connecticut, Storrs, CT, 02903, USACorrespondence: P S Rajinikanth, Department of Pharmaceutical Sciences Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, 226025, India, Email psrajinikanth222@gmail.comBackground: Antitumor research aims to efficiently target hepatocarcinoma cells (HCC) for drug delivery. Nanostructured lipid carriers (NLCs) are promising for active tumour targeting. Cell-penetrating peptides are feasible ligands for targeted cancer treatment.Methods: In this study, we optimized gefitinib-loaded NLCs (GF-NLC) for HCC treatment. The NLCs contained cholesterol, oleic acid, Pluronic F-68, and Phospholipon 90G. The NLC surface was functionalized to enhance targeting with the cRGDfK-pentapeptide, which binds to the αvβ 3 integrin receptor overexpressed on hepatocarcinoma cells.Results: GF-NLC formulation was thoroughly characterized for various parameters using differential scanning calorimetry and X-ray diffraction analysis. In-vitro and in-vivo studies on the HepG2 cell line showed cRGDfK@GF-NLC’s superiority over GF-NLC and free gefitinib. cRGDfK@GF-NLC exhibited significantly higher cytotoxicity, growth inhibition, and cellular internalization. Biodistribution studies demonstrated enhanced tumour site accumulation without organ toxicity. The findings highlight cRGDfK@GF-NLC as a highly efficient carrier for targeted drug delivery, surpassing non-functionalized NLCs. These functionalized NLCs offer promising prospects for improving hepatocarcinoma therapy outcomes by specifically targeting HCC cells.Conclusion: Based on these findings, cRGDfK@GF-NLC holds immense potential as a highly efficient carrier for targeted drug delivery of anticancer agents, surpassing the capabilities of non-functionalized NLCs. This research opens up new avenues for effective treatment strategies in hepatocarcinoma. Keywords: nanostructured lipid carrier, αvβ 3 integrin receptor, cRGDfK-pentapeptide, hepatocellular carcinoma, tumour targeting

Triple-negative breast cancer (TNBC), a subtype of breast cancer that lacks expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), has clinical features including a high degree of invasiveness, an elevated risk of metastasis, tendency to relapse, and poor prognosis. It constitutes around 10-15% of all breast cancer, and having heredity of BRCA1 mutated breast cancer could be a reason for the occurrence of TNBC in women. Overexpression of cellular and molecular targets, i.e. CD44 receptor, EGFR receptor, Folate receptor, Transferrin receptor, VEGF receptor, and Androgen receptor, have emerged as promising targets for treating TNBC. Signalling pathways such as Notch signalling and PI3K/AKT/mTOR also play a significant role in carrying out and managing crucial pro-survival and pro-growth cellular processes that can be utilised for targeted therapy against triple-negative breast cancer. This review sheds light on various targeting strategies, including cellular and molecular targets, signalling pathways, poly (ADP-ribose) polymerase inhibitors, antibody-drug conjugates, and immune checkpoint inhibitors PARP, immunotherapy, ADCs have all found a place in the current TNBC therapeutic paradigm. The role of photothermal therapy (PTT) and photodynamic therapy (PDT) has also been explored briefly. [ABSTRACT FROM AUTHOR]

Tumours, with increasing mortality around the world, have bothered human beings for decades. Enhancing the targeting of antitumor drugs to tumour tissues is the key to enhancing their antitumor effects. The tumour microenvironment is characterised by a relatively low pH, overexpression of certain enzymes, redox imbalance, etc. Therefore, smart drug delivery systems that respond to the tumour microenvironment have been proposed to selectively release antitumor drugs. Among them, peptide hydrogels as a local drug delivery system have received much attention due to advantages such as high biocompatibility, degradability and high water-absorbing capacity. The combination of peptide segments with different physiological functions allows for tumour targeting, self-aggregation, responsiveness, etc. Morphological and microstructural changes in peptide hydrogels can occur when utilising the inherent pathological microenvironment of tumours to trigger drug release, which endows such systems with limited adverse effects and improved therapeutic efficiency. Herein, this review outlined the driving forces, impact factors, and sequence design in peptide hydrogels. We also discussed the triggers to induce the transformation of peptide-based hydrogels in the tumour microenvironment and described the advancements of peptide-based hydrogels for local drug delivery in tumour treatment. Finally, we gave a brief perspective on the prospects and challenges in this field. [ABSTRACT FROM AUTHOR]

Bone morphogenetic protein (BMP)-9 is considered a member of the transforming growth factor (TGF)β superfamily. It was first found as an inducer of bone and cartilage formation and then discovered that this factor mediates several physiologic functions and hemostasis. Besides physiological conditions, BMP9 has also been elucidated that it is involved in several pathological situations, especially cancer. In various cancers, dysregulation of BMP9 has raised the issue that BMP9 might play a conflicting role in tumour development. BMP9 binding to its receptors (BMPRs), including ALKs and BMPRII, induces canonical SMAD-dependent and non-canonical PI3K/AKT and MAPK signalling pathways in tumour cells. BMP9, via inducing apoptosis, inhibiting tumour-promoting cell signalling pathways, suppressing epithelial-mesenchymal transition (EMT) process, blocking angiogenesis, and preventing cross-talk in the tumour microenvironment, mainly exerts tumour-suppressive functions. In contrast, BMP9 triggers tumour-supportive signalling pathways, promotes EMT, and enhances angiogenesis, suggesting that BMP9 is also involved in tumour development. It has been demonstrated that modulating BMP9 expression and functions might be a promising approach to cancer treatment. It has also been indicated that evaluating BMP9 expression in cancers might be a biomarker for predicting cancer prognosis. Overall, BMP9 would provide a promising target in cancer management. [ABSTRACT FROM AUTHOR]

Pharmaceutical peptide Octreotide is a somatostatin analog with targeting and therapeutic abilities. Over the last decades, Octreotide has been developed and approved to treat acromegaly and neuroendocrine tumours, and Octreotide-based radioactive conjugates have been leveraged clinically to detect small neuroendocrine tumour sites. Meanwhile, variety of Octreotide-derived delivery strategies have been proposed and explored for tumour targeted therapeutics or diagnostics in preclinical or clinical settings. In this review, we especially focus on the preclinical development and applications of Octreotide-derived drug delivery systems, diagnostic nanosystems, therapeutic nanosystems and multifunctional nanosystems, we also briefly discuss challenges and prospects of these Octreotide-derived delivery systems. [ABSTRACT FROM AUTHOR]

Faiza Naseer,1,2 Tahir Ahmad,1 Kousain Kousar,1 Salik Kakar,3 Rabia Gul,2 Sadia Anjum,4 Usman Shareef2 1Industrial Biotechnology, Atta-ur-Rehman School of Applied Biosciences, National University of Science and Technology, Islamabad, Pakistan; 2Shifa College of Pharmaceutical Sciences, Shifa Tameer e Millat University, Islamabad, Pakistan; 3Healthcare Biotechnology, Atta-ur-Rehman School of Applied Biosciences, National University of Science and Technology, Islamabad, Pakistan; 4Department of Biology, University of Hail, Hail, Saudia ArabiaCorrespondence: Faiza Naseer; Tahir Ahmad, Email faiza.naseer@ymail.com; tahir@asab.nust.edu.pkBackground: Oncolytic viruses are reported as dynamite against cancer treatment nowadays.Methodology: In the present work, a live attenuated oral measles vaccine (OMV) strain was used to formulate a polymeric surface-functionalized ligand-based nanoformulation (NF). OMV (half dose: not less than 500 TCID units; 0.25 mL) was encapsulated in thiolated chitosan and outermost coating with hyaluronic acid by ionic gelation method characterizing parameters was performed.Results and Discussion: CD44 high expression was confirmed in prostatic adenocarcinoma (PRAD) by GEPIA which extracted data of normal and cancer tissue from GTEx and TCGA. Bioinformatics tools confirmed the viral hemagglutinin capsid protein interaction with human Caspase-I, NLRP3, and TNF-α and viral fusion protein interaction with COX-II and Caspase-I after successful delivery of MV encapsulated in NFs due to high affinity of hyaluronic acid with CD44 on the surface of prostate cancer cells. Particle size = 275.6 mm, PDI = 0.372, and ± 11.5 zeta potential were shown by zeta analysis, while the thiolated group in NFs was confirmed by FTIR and Raman analysis. SEM and XRD showed a spherical smooth surface and crystalline nature, respectively, while TEM confirmed virus encapsulation within nanoparticles, which makes it very useful in targeted virus delivery systems. The virus was released from NFs in a sustained but continuous release pattern till 48 h. The encapsulated virus titer was calculated as 2.34× 107 TCID50/mL units, which showed syncytia formation on post-day infection 7. Multiplicities of infection 0.1, 0.5, 1, 3, 5, 10, 15, and 20 of HA-coated OMV-loaded NFs as compared to MV vaccine on PC3 was inoculated with IC50 of 5.1 and 3.52, respectively, and growth inhibition was seen after 72 h via MTT assay which showed apoptotic cancer cell death.Conclusion: Active targeted, efficacious, and sustained delivery of formulated oncolytic MV is a potent moiety in cancer treatment at lower doses with safe potential for normal prostate cells.Graphical Abstract: Keywords: green synthesis, controlled release, immunotherapeutic agent, in vitro studies, oncolytic activity, oncolytic measles virus, prostate cancer, targeted virus/drug delivery system, thiolated chitosan, tumour targeting, vaccine-based nanoformulation

Treatment of metastatic cancer is one of the biggest challenges in anticancer therapy. Curcumin is interesting nature polyphenolic compound with unique biological and medicinal effects, including repression of metastases. High impact studies imply that curcumin can modulate the immune system, independently target various metastatic signalling pathways, and repress migration and invasiveness of cancer cells. This review discusses the potential of curcumin as an antimetastatic agent and describes potential mechanisms of its antimetastatic activity. In addition, possible strategies (curcumin formulation, optimization of the method of administration and modification of its structure motif) to overcome its limitation such as low solubility and bioactivity are also presented. These strategies are discussed in the context of clinical trials and relevant biological studies.

Liposomal drugs exhibit advantages for cancer therapy, but efficacy is often limited by their rapid clearance from the blood by the reticuloendothelial system, and an inability to target and penetrate tumours. Interestingly, a 21-amino acid SIRP-α- (signal regulatory protein-α) interacting 'self' peptide is reported to inhibit uptake by phagocytes. Also, 'iRGD' a 9-amino acid cyclic peptide that binds αvβ3 integrins and neuropilin-1 (NRP-1), promotes targeting and penetration of the drug into tumours. Here we explore the potential of nitrilotriacetic acid-ditetra-decylamine (NTA3-DTDA)-containing liposomes (NTA-liposomes) engrafted with His-tagged forms of 'self' peptide (pCD47) to prolong circulation time in blood after iv administration, and of iRGD peptide (piRGD) to enhance treatment efficacy of doxorubicin-containing liposomes (Caelyx). Our results show that pre-incubation of murine phagocytic DC2.4 and RAW246.7 cells with pCD47 inhibits the uptake of NTA-liposomes in vitro, but engraftment of pCD47 surprisingly reduces liposome lifetime in blood. Engraftment of piRGD promoted binding of NTA-liposomes to murine B16 melanoma and CT26 colorectal carcinoma cells in vitro. Importantly, iv administration of piRGD-engrafted Caelyx was found to significantly inhibit tumour growth and prolong survival in both B16 and CT26 murine tumour models. Our results show that engraftment of piRGD onto Caelyx is a convenient strategy to enhance treatment efficacy. [ABSTRACT FROM AUTHOR]

Multi-drug resistance (MDR) is the major hindrance towards the successful treatment of malignant lung cancer. The aim of this study was to develop a novel nanoparticle co-loaded with docetaxel (DTX) and si-colon cancer-associated transcript-2 (siCCAT2) (NP-DTX/siCCAT2) for overcoming the DTX-resistant non-small cell lung cancer (NSCLC). The NP-DTX/siCCAT2, developed by DTX-conjugated poly (D,L-lactic-co-glycolic acid) (PLGA) copolymers, has an average size of t 87.26 nm. Further modification of Transferrin (Tf) peptides on the surface of NP-DTX/siCCAT2 did not significantly change the particle size with an average diameter of 96.81 nm. The present study demonstrated that TfNP-DTX/siCCAT2 has excellent tumour targeting ability and resulted in an enhanced anti-tumour effect both in vitro and in vivo experiments. Not unexpectedly, a more excellent anti-tumour effect of NP-DTX/siCCAT2 was obtained than the NP-DTX because the silencing of CCAT2 levels in lung cancer cells resulted in down-regulated expressions of P-glycoprotein (P-gp) and multidrug-resistance-associated proteins 1 (MRP1). Further investigation revealed that inhibition of CCAT2 expression dramatically increased the activity of miR-204-3p and thereby signally suppressed the IGFBP2/AKT/Bcl2 pathway. [ABSTRACT FROM AUTHOR]

Abstract Gas-filled ultrasound (US) contrast agents easily collapse in the body, and the gas can easily overflow, which limits the effectiveness of US imaging. To address this issue, an injectable gas-generating multi-mode system was developed that carries the MR negative contrast agent Fe3O4, the fluorescent dye Cy5.5, and the CO2 releasing donor (Na2CO3). The nanoparticles can continuously generate carbon dioxide (CO2) gas in acidic tumour tissue in the body, giving the tumour a strong echo signal under ultrasonic imaging. In addition, the nanoparticles confer excellent effects for MR and fluorescence imaging of the tumour tissue. The results indicate that this pH-responsive NP system provides good effects in MR/US/fluorescent imaging. This study provides a useful reference for multi-mode tumour imaging.

Polymeric micelles (PMs) play a vital role in multidrug co-delivery and cancer treatment. However, development of intelligent PMs further allows PMs to accurately target tumour, selectively release cargo multidrug and increase uptake. Therefore, targets, controlled release and uptake of intelligent PMs should be paid more attention to improvement of synergistic therapeutic outcomes and minimize side effects. In this review, tumour targeting of co-delivery intelligent PMs and its intracellular trafficking mechanisms were overviewed. And this review provides a comprehensive summarization of several intelligent co-delivery PMs. Such a system could control the multidrug to be released simultaneously or sequentially by special properties of tumour microenvironment (TME) (including acidic PH, redox, overexpressed enzyme, excessive temperature) and external environment trigger. Additionally, limitations, clinical translation and future perspectives of intelligent co-delivery PMs were also being discussed in this article.

The present study was aimed to develop a novel combination therapeutic strategy of gene therapy and immunotherapy for efficiently treatment of colorectal cancer (CRC). To achieve that goal, the polyethylene glycol-modified poly (2-(N,N-dimethylamino) ethyl methacrylate) (PEG-PDMAEMA)-based nanoparticles loaded with protein tyrosine phosphatase non-receptor type 6 (PTPN6) (NP-PTPN6) was developed first followed by conjugation with anti-PD-L1 monoclonal antibodies (aPD-L1) atezolizumab (aPD-L1NP-PTPN6). Importantly, the aPD-L1 was conjugated on the surface of NP-PTPN6 by the matrix metalloproteinases (MMPs)-cleavable linkage PLGLAG. Therefore, the aPD-L1 would be completely released once the aPD-L1NP-PTPN6 was entrapped into tumour tissues as demonstrated by the release assay. Tumour targeting assay demonstrated the aPD-L1NP-PTPN6 have high affinity to CRC cells and resulted in excellent tumour targeting drug delivery efficacy. Additionally, anti-tumour effect evaluation revealed that the aPD-L1NP-PTPN6 has greater ability to inhibit the growth, invasion and migration of CRC cells and finally led to longer survival time of tumour-bearing mice than other treatments. Further mechanisms studies demonstrated that treatment of CRC cells with aPD-L1NP-PTPN6 contributed to significant suppression of the MAPK/ERK signalling pathway. Besides, it was further demonstrated that treating CRC with aPD-L1NP-PTPN6 resulted in up-regulation of NK cells and T cells percentage within the tumour tissues. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB) and complex tumour immunosuppressive micro-environment posed austere challenges for combatting brain tumours such as the glioblastoma. In this study, we have developed a novel dual functional dendrimer drug delivery system (DDS) by the PAMAM and loaded with siLSINCT5 (NP- siRNA) for efficiently across the BBB to inhibit glioblastoma. To achieve the goal of BBB crossing, on the surface of NP-siRNA was decorated with the cell penetrating peptides tLyp-1 (tLypNP-siRNA). Moreover, to overcome the immunosuppressive microenvironment within the glioblastoma (GBM) tissues, a checkpoint inhibitor named as anti-NKG2A monoclonal antibody (aNKG2A), which was able of promoting anti-tumour immunity by unleashing both T and NK Cells, was further conjugated on the surface of siLSINCT5-loaded nanoparticles via the pH-sensitive linkage. Therefore, the developed dual functional and siLSINCT5-loaded dendrimer nanoparticles (tLyp/aNKNP-siRNA) was supposed to have the ability to efficiently cross the BBB and inhibit GBM by simultaneously inhibit the LSINCT5-activated signalling pathways and activate the anti-tumour immunity. The hypothesis was thoroughly confirmed by in vitro cellular and in vivo animal experiments, and provided a novel strategy for combating glioblastoma. [ABSTRACT FROM AUTHOR]

Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin analogues. The O-methyl group of the unit B D-tyrosine analogue was replaced by an O-(allyloxyethyl) moiety, an O-(hydroxyethyl) group, or an O-(((azidoethoxy)ethoxy)ethoyxethyl) substituent. While the former two maintain cytotoxicity in the subnanomolar range, the attachment of the triethylene glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of the novel cryptophycin analogues to β-tubulin provided a rationale for the observed cytotoxicities.

Dongyu Duan,1,* Aiping Wang,1,* Ling Ni,2 Liping Zhang,1 Xiuju Yan,1 Ying Jiang,1 Hongjie Mu,1 Zimei Wu,1 Kaoxiang Sun,1 Youxin Li1,2 1School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, People’s Republic of China; 2State Key Laboratory of Long Acting and Targeting Drug Delivery System, Shandong Luye Pharmaceutical Co., Ltd, Yantai, People’s Republic of China *These authors contributed equally to this work Introduction: Nanoparticles (NPs) modified with bio-ligands represent a promising strategy for active targeted drug delivery to tumour. However, many targeted ligands, such as trastuzumab (TMAB), have high molecular weight, limiting their application for targeting. In this study, we prepared Fab’ (antigen-binding fragments cut from TMAB)-modified NPs (Fab'-NPs) with curcumin (Cur) as a model drug for more effective targeting of human epidermal growth factor receptor 2 (HER2/ErbB2/Neu), which is overexpressed on breast cancer cells. Material and methods: The release kinetics was conducted by dialysis bags. The ability to kill HER2-overexpressing BT-474 cells of Fab'-Cur-NPs compared with TMAB-Cur-NPs was conducted by cytotoxicity experiments. Qualitative and quantitative cell uptake studies using coumarin-6 (fluorescent probe)-loaded NPs were performed by fluorescence microscopy and flow cytometry. Pharmacokinetics and biodistribution experiments in vivo were assessed by liquid chromatography–tandem mass spectrometry (LC-MS/MS).Results: The release kinetics showed that both Fab'-Cur-NPs and TMAB-Cur-NPs provided continuous, slow release of curcumin for 72 h, with no significant difference. In vitro cytotoxicity experiments showed that Fab'-Cur-NPs manifested prominent ability to kill HER2-overexpressing BT-474 cells compared with TMAB-Cur-NPs. Qualitative and quantitative cell uptake studies indicated that the accumulation of Fab'-NPs was greater than that of TMAB-NPs in BT-474 (HER2+) cells; However, there was no significant difference in MDA-MB-231 (HER2-) cells. Pharmacokinetics and biodistribution experiments in vivo demonstrated that the half-life (t1/2) and area under the blood concentration-time curve (AUC0-t) of Fab'-Cur-NPs increased 5.30-fold and 1.76-fold relative to those of TMAB-Cur-NPs, respectively. Furthermore, the tumor accumulation of Fab'-Cur-NPs was higher than that of TMAB-Cur-NPs. Conclusion: Fab' fragment has greater capacity than the intact antibody to achieve tumor targeting through NP-based delivery. Keywords: trastuzumab-modified curcumin nanoparticles, Fab'-modified curcumin nanoparticles, pharmacokinetics, biodistribution, tumour targeting, breast cancer

The tumour microenvironment (TME) plays a pivotal role in tumour fate determination. The TME acts together with the genetic material of tumour cells to determine their initiation, metastasis and drug resistance. Stromal cells in the TME promote the growth and metastasis of tumour cells by secreting soluble molecules or exosomes. The abnormal microenvironment reduces immune surveillance and tumour killing. The TME causes low anti‐tumour drug penetration and reactivity and high drug resistance. Tumour angiogenesis and microenvironmental hypoxia limit the drug concentration within the TME and enhance the stemness of tumour cells. Therefore, modifying the TME to effectively attack tumour cells could represent a comprehensive and effective anti‐tumour strategy. Normal cells, such as stem cells and immune cells, can penetrate and disrupt the abnormal TME. Reconstruction of the TME with healthy cells is an exciting new direction for tumour treatment. We will elaborate on the mechanism of the TME to support tumours and the current cell therapies for targeting tumours and the TME—such as immune cell therapies, haematopoietic stem cell (HSC) transplantation therapies, mesenchymal stem cell (MSC) transfer and embryonic stem cell‐based microenvironment therapies—to provide novel ideas for producing breakthroughs in tumour therapy strategies. [ABSTRACT FROM AUTHOR]

β-Cyclodextrine-based polyester was coated on the surface of gadolinium oxide nanoparticles (NPs) and then functionalised with folic acid to produce an efficient pH-sensitive targeted theranostic system (Gd2O3@PCD-FA) for doxorubicin delivery and magnetic resonance imaging (MRI). Gd2O3@PCD-FA was fully characterised by FTIR, vibrating sample magnetometer, TGA, XRD, SEM and TEM analyses. The dissolution profile of DOX showed a pH sensitive release. No significant toxicity was observed for the targeted NPs (Gd2O3@PCD-FA) and DOX-loaded NPs inhibiting M109 cells viability more efficiently than free DOX. Moreover, the negligible hemolytic activity of the targeted NPs showed their appropriate hemocompatibility. The preferential uptake was observed for the developed Gd2O3@PCD-FA-DOX NPs in comparison with Dotarem using T1- and T2-weighted MRI in the presence of folate receptor-positive and folate receptor-negative cancer cells (M109 and 4T1, respectively). Furthermore, in vivo studies revealed that Gd2O3@PCD-FA-DOX not only exhibited considerably relaxivity performance as a contrast agent for MRI, but also improved in vivo anti-tumour efficacy of the system. The results suggest that Gd2O3@PCD-FA-DOX improves its therapeutic efficacy in the treatment of solid tumours and also reduces the adverse effects, so it could be proposed as a promising drug delivery system for chemotherapy and molecular imaging diagnosis in MRI. [ABSTRACT FROM AUTHOR]

Gas-filled ultrasound (US) contrast agents easily collapse in the body, and the gas can easily overflow, which limits the effectiveness of US imaging. To address this issue, an injectable gas-generating multi-mode system was developed that carries the MR negative contrast agent Fe3O4, the fluorescent dye Cy5.5, and the CO2 releasing donor (Na2CO3). The nanoparticles can continuously generate carbon dioxide (CO2) gas in acidic tumour tissue in the body, giving the tumour a strong echo signal under ultrasonic imaging. In addition, the nanoparticles confer excellent effects for MR and fluorescence imaging of the tumour tissue. The results indicate that this pH-responsive NP system provides good effects in MR/US/fluorescent imaging. This study provides a useful reference for multi-mode tumour imaging. [ABSTRACT FROM AUTHOR]

The objective of this work was to develop micelles of D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), conjugated with glucosamine for non-invasive targeted delivery of curcumin (CRM) for tumour targeting. The micelles with and without glucosamine conjugation were prepared by the solvent casting method and characterised for their particle size, surface morphology, drug entrapment efficiency, drug loading and in vitro drug release study. The molecule sizes of the functionalised micelles were 189.9 nm and for non- functionalised micelles were146.8nm. Drug entrapment was found 98.19 ± 1.2% and 92.81 ± 1.4% with non- functionalised and t functionalised micelles respectively. The in vitro release revealed that curcumin stacked glucosamine TPGS micelles could be a promising bearer for tumour targeting due to nanosized medication delivery, which gave an enhanced and prolonged tumour targeting of curcumin. [ABSTRACT FROM AUTHOR]

Fluorescent proteins are useful imaging and theranostic agents, but their potential superiority over alternative dyes is weakened by substantial photobleaching under irradiation. Enhancing protein photostability has been attempted through diverse strategies, with irregular results and limited applicability. In this context, we wondered if the controlled oligomerization of Green Fluorescent Protein (GFP) as nanoscale supramolecular complexes could stabilize the fluorophore through the newly formed protein-protein contacts, and thus, enhance its global photostability. For that, we have here analyzed the photobleaching profile of several GFP versions, engineered to self-assemble as tumour-homing nanoparticles with different targeting, size and structural stability. This has been done under prolonged irradiation in confocal laser scanning microscopy and by small-angle X-ray scattering. The results show that the oligomerization of GFP at the nanoscale enhances, by more than seven-fold, the stability of fluorescence emission. Interestingly, GFP nanoparticles are much more resistant to X-ray damage than the building block counterparts, indicating that the gained photostability is linked to enhanced structural resistance to radiation. Therefore, the controlled oligomerization of self-assembling fluorescent proteins as protein nanoparticles is a simple, versatile and powerful method to enhance their photostability for uses in precision imaging and therapy. Fluorescent protein assembly into regular and highly symmetric nanoscale structures has been identified to confer enhanced structural stability against radiation stresses dramatically reducing their photobleaching. Being this the main bottleneck in the use of fluorescent proteins for imaging and theranostics, this protein architecture engineering principle appears as a powerful method to enhance their photostability for a broad applicability in precision imaging, drug delivery and theranostics. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Polymeric micelles (PMs) play a vital role in multidrug co-delivery and cancer treatment. However, development of intelligent PMs further allows PMs to accurately target tumour, selectively release cargo multidrug and increase uptake. Therefore, targets, controlled release and uptake of intelligent PMs should be paid more attention to improvement of synergistic therapeutic outcomes and minimize side effects. In this review, tumour targeting of co-delivery intelligent PMs and its intracellular trafficking mechanisms were overviewed. And this review provides a comprehensive summarization of several intelligent co-delivery PMs. Such a system could control the multidrug to be released simultaneously or sequentially by special properties of tumour microenvironment (TME) (including acidic PH, redox, overexpressed enzyme, excessive temperature) and external environment trigger. Additionally, limitations, clinical translation and future perspectives of intelligent co-delivery PMs were also being discussed in this article. [ABSTRACT FROM AUTHOR]

Diagnostic imaging of aggressive cancer with a high stroma content may benefit from the use of imaging contrast agents targeted with peptides that have high binding affinity to the extracellular matrix (ECM). In this study, we report the use of superparamagnetic iron-oxide nanoparticles (IO-NP) conjugated to a nonapeptide, CSGRRSSKC (CSG), which specifically binds to the laminin-nidogen-1 complex in tumours. We show that CSG-IO-NP accumulate in tumours, predominantly in the tumour ECM, following intravenous injection into a murine model of pancreatic neuroendocrine tumour (PNET). In contrast, a control untargeted IO-NP consistently show poor tumour uptake, and IO-NP conjugated to a pentapeptide. CREKA that bind fibrin clots in blood vessels show restricted uptake in the angiogenic vessels of the tumours. CSG-IO-NP show three-fold higher intratumoral accumulation compared to CREKA-IO-NP. Magnetic resonance imaging (MRI) T2-weighted scans and T2 relaxation times indicate significant uptake of CSG-IO-NP irrespective of tumour size, whereas the uptake of CREKA-IO-NP is only consistent in small tumours of less than 3 mm in diameter. Larger tumours with significantly reduced tumour blood vessels show a lack of CREKA-IO-NP uptake. Our data suggest CSG-IO-NP are particularly useful for detecting stroma in early and advanced solid tumours.

The RNA molecule plays a pivotal role in many biological processes by relaying genetic information, regulating gene expression, and serving as molecular machines and catalyzers. This inherent versatility of RNA has fueled significant advancements in the field of RNA nanotechnology, driving the engineering of complex nanoscale architectures toward biomedical applications, including targeted drug delivery and bioimaging. RNA polymers, serving as building blocks, offer programmability and predictability of Watson-Crick base pairing, as well as non-canonical base pairing, for the construction of nanostructures with high precision and stoichiometry. Leveraging the ease of chemical modifications to protect the RNA from degradation, researchers have developed highly functional and biocompatible RNA architectures and integrated them into preclinical studies for the delivery of payloads and imaging agents. This review offers an educational introduction to the use of RNA as a biopolymer in the design of multifunctional nanostructures applied to targeted delivery in vivo , summarizing physical and biological barriers along with strategies to overcome them. Furthermore, we highlight the most recent progress in the development of both small and larger RNA nanostructures, with a particular focus on imaging reagents and targeted cancer therapeutics in pre-clinical models and provide insights into the prospects of this rapidly evolving field.

Purpose: Conjugation of nanocarriers with antibodies that bind to specific membrane receptors that are overexpressed in cancer cells enables targeted delivery. In the present study, we developed and synthesised two PAMAM dendrimer-trastuzumab conjugates that carried docetaxel or paclitaxel, specifically targeted to cells which overexpressed HER-2. Methods: The 1H NMR, 13C NMR, FTIR and RP-HPLC were used to analyse the characteristics of the products and assess their purity. The toxicity of PAMAM-trastuzumab, PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined using MTT assay and compared with free trastuzumab, docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. The cellular uptake and internal localisation were studied using flow cytometry and confocal microscopy, respectively. Results: The PAMAM-drug-trastuzumab conjugates in particular showed extremely high toxicity toward the HER-2-positive SKBR-3 cells and very low toxicity towards to HER-2-negative MCF-7 cells. As expected, the HER-2-positive SKBR-3 cell line accumulated trastuzumab from both conjugates rapidly; but surprisingly, although a large amount of PAMAM-ptx-trastuzumab conjugate was observed in the HER-2-negative MCF-7 cells. Confocal microscopy confirmed the intracellular localisation of analysed compounds. The key result of fluorescent imaging was the identification of strong selective binding of the PAMAM-doc-trastuzumab conjugate with HER-2-positive SKBR-3 cells only. Conclusions: Our results confirm the high selectivity of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates for HER-2-positive cells, and demonstrate the utility of trastuzumab as a targeting agent. Therefore, the analysed conjugates present an promising approach for the improvement of efficacy of targeted delivery of anticancer drugs such as docetaxel or paclitaxel. [ABSTRACT FROM AUTHOR]

The therapeutic potential of plumbagin, a naphthoquinone extracted from the officinal leadwort with anticancer properties, is hampered by its failure to specifically reach tumours at a therapeutic concentration after intravenous administration, without secondary effects on normal tissues. Its use in clinic is further limited by its poor aqueous solubility, its spontaneous sublimation, and its rapid elimination in vivo. We hypothesize that the entrapment of plumbagin within liposomes grafted with transferrin, whose receptors are overexpressed on many cancer cells, could result in a selective delivery to tumours after intravenous administration. The objectives of this study were therefore to prepare and characterize transferrin‐targeted liposomes entrapping plumbagin and to evaluate their therapeutic efficacy in vitro and in vivo. The entrapment of plumbagin in transferrin‐bearing liposomes led to an increase in plumbagin uptake by cancer cells and improved antiproliferative efficacy and apoptosis activity in B16‐F10, A431, and T98G cell lines compared with that observed with the drug solution. In vivo, the intravenous injection of transferrin‐bearing liposomes entrapping plumbagin led to tumour suppression for 10% of B16‐F10 tumours and tumour regression for a further 10% of the tumours. By contrast, all the tumours treated with plumbagin solution or left untreated were progressive. The animals did not show any signs of toxicity. Transferrin‐bearing liposomes entrapping plumbagin are therefore highly promising therapeutic systems that should be further optimized as a therapeutic tool for cancer treatment. [ABSTRACT FROM AUTHOR]

Single-chain Fv (scFv) molecules exhibit highly specific tumour-targeting properties in tumour-bearing mice. However, because of their smaller size and monovalent binding, the quantities of radiolabelled scFv retained in tumours limit their therapeutic applications. Diabodies are dimeric antibody-based molecules composed of two non-covalently associated scFv that bind to antigen in a divalent manner. In vitro, diabodies produced from the anti-HER2/neu (c-erbB-2) scFv C6.5 displayed approximately 40-fold greater affinity for HER2/neu by surface plasmon resonance biosensor measurements and significantly prolonged association with antigen on the surface of SK-OV-3 cells (t1/2 cell surface retention of > 5 h vs 5 min) compared with C6.5 scFv. In SK-OV-3 tumour-bearing scid mice, radioiodinated C6.5 diabody displayed a highly favourable balance of quantitative tumour retention and specificity. By as early as 4 h after i.v. administration, significantly more diabody was retained in tumour (10 %ID g(-1)) than in blood (6.7 %ID ml(-1)) or normal tissue (liver, 2.8 %ID g(-1); lung, 7.1 %ID g(-1); kidney, 5.2 %ID g(-1)). Over the next 20 h, the quantity present in blood and most tissues dropped approximately tenfold, while the tumour retained 6.5 %ID g(-1) or about two-thirds of its 4-h value. In contrast, the 24-h tumour retention of radioiodinated C6.5 scFv monomer was only 1 %ID g(-1). When diabody retentions were examined over the course of a 72-h study and cumulative area under the curve (AUC) values were determined, the resulting tumor-organ AUC ratios were found to be superior to those previously reported for other monovalent or divalent scFv molecules. In conclusion, the diabody format provides the C6.5 molecule with a distinct in vitro and in vivo targeting advantage and has promise as a delivery vehicle for therapeutic agents.

This paper proposes a novel type of multifunctional envelope-type mesoporous silica nanoparticle (MSN) to achieve cancer cell targeting and drug-controlled release. In this system, MSNs were first modified by active targeting moiety hyaluronic acid (HA) for breast cancer cell targeting and hyaluronidases (Hyal)-induced intracellular drug release. Then gelatin, a proteinaceous biopolymer, was grafted onto the MSNs to form a capping layer via glutaraldehyde-mediated cross-linking. To shield against unspecific uptake of cells and prolong circulation time, the nanoparticles were further decorated with poly(ethylene glycol) polymers (PEG) to obtain MSN@HA-gelatin-PEG (MHGP). Doxorubicin (DOX), as a model drug, was loaded into PEMSN to assess the breast cancer cell targeting and drug release behaviours. In vitro study revealed that PEG chains protect the targeting ligand and shield against normal cells. After reaching the breast cancer cells, MMP-2 overpressed by cells hydrolyses gelatin layer to deshield PEG and switch on the function of HA. As a result, DOX-loaded MHGP was selectively trapped by cancer cells through HA receptor-mediated endocytosis and subsequently release DOX due to Hyal-catalysed degradation of HA. This system presents successful bienzyme-responsive targeting drug delivery in an optimal fashion and provides potential applications for targeted cancer therapy.

A series of three dual-responsive ‘thermosonic’ (thermo- and ultrasound-responsive) injectable organogels (TIOs) based on crosslinked N -(isopropyl acrylamide) (NIPAM) bearing biocompatible polymeric constituents were investigated for strong gelation in response to tumour temperature, and sol-like fluid gel formation upon the application of an ultrasonic stimulus. A time-efficient free radical polymerisation reaction of ˂15 min resulted in TIO formation. Moreover, the formulation of the TIOs integrated green chemistry principles to ensure enhanced biocompatibility. Fourier Transform Infrared (FTIR) spectral analysis revealed the presence of new molecular vibrations at 847 and 771 cm −1 ( CH deformation), which were indicative of the functionalisation of the NIPAM backbone with hydrophobic and ultrasound-responsive aromatic moieties. Thermo- and ultrasound-response analysis and rheological analysis demonstrated that the TIOs displayed a temperature-induced transition to a strong highly-structured gel, and an ultrasound-triggered increase in gel flowability dependant on the composition of the formulation. Cell proliferation studies were undertaken for the TIOs, which verified that the designed TIOs were all non-cytotoxic and promoted cell proliferation over 1, 3, and 5 day intervals. The rational design and formulation of a biocompatible injectable in-situ depot drug delivery system for ultimate application in tumour targeting was successfully achieved and warrant further investigation. [ABSTRACT FROM AUTHOR]

It is well known that Arginine-Glycine-Aspartic acid (RGD) and Asparagine-Glycine-Arginine (NGR) peptides preferentially bind to integrin receptors and aminopeptidase N respectively and these two receptors play important roles in angiogenesis. Therefore ketoprofen as a non-selective cox Inhibitor was conjugated with linear RGD and NGR to take advantage of targeting capability of these two motifs and delivering ketoprofen to these cancer cells with overexpression of integrin and aminopeptidase N. In order to investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six carbon (hexanoic acid) linker was also used as a spacer. Cytotoxic effect of the synthesized compounds was evaluated against a group of cancer cell lines, including MCF-7, A2780 (αvβ3 positive), OVCAR3 (high αvβ3), HT-1-80 (high CD13) and SKOV-3 (CD13 positive). Both NGR and RGD conjugated forms of ketoprofen showed higher cytotoxic activity against OVCAR3 and HT-1-80 respectively. [ABSTRACT FROM AUTHOR]

Exosomes are endogenous nanocarriers that can deliver biological information between cells. They are secreted by all cell types, including immune cells such as natural killer (NK) cells. However, mammalian cells release low quantities of exosomes, and the purification of exosomes is difficult. Here, nanovesicles were developed by extrusion of NK cells through filters with progressively smaller pore sizes to obtain exosome mimetics (NK-EM). The anti-tumour effect of the NK-EM was confirmed in vitro and in vivo. The morphological features of the NK-EM were revealed by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blot. In vitro, the cytotoxicity of the NK-EM to cancer cells (glioblastoma, breast carcinoma, anaplastic thyroid cancer and hepatic carcinoma) was assessed using bioluminescence imaging (BLI) and CCK-8 assay. For in vivo study, a xenograft glioblastoma mouse model was established. The anti-tumour activity of NK-EM was confirmed in vivo by the significant decreases of BLI, size and weight (all p < .001) of the tumour compared with the control group. Moreover, NK-EM cytotoxicity for glioblastoma cells that related with decreased levels of the cell survival markers p-ERK and p-AKT, and increased levels of apoptosis protein markers cleaved-caspase 3, cytochrome-c and cleaved-PARP was confirmed. All those results suggest that NK-EM exert stronger killing effects to cancer cells compared with the traditional NK-Exo, at the same time, the tumour targeting ability of the NK-EM was obtained in vivo. Therefore, NK-EM might be a promising immunotherapeutic agent for treatment of cancer. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX), as an anthracycline, plays an important role in chemotherapy. But multidrug resistance (MDR) tremendously retards the anticancer effect of DOX and results in the failure of chemotherapy. Multifunctional micelles emerge as a valid strategy to load DOX by physical encapsulation or chemical binding to be delivered to cancer cells against MDR. In this review, mechanism of MDR of DOX is simply described. Multifunctional co-delivery micelles of DOX and main MDR modulators have been summarised in detail. DOX-loaded multifunctional polymeric micelles are also introduced to alleviate MDR of DOX, in which polymers act as MDR modulators. [ABSTRACT FROM PUBLISHER]

We describe the selection of Anticalins against a common tumour surface antigen, human Hsp70, using functional display on live Escherichia coli cells as fusion with a truncated EspP autotransporter. While found intracellularly in normal cells, Hsp70 is frequently exposed in a membrane-bound state on the surface of tumour cells and, even more pronounced, in metastases or after radiochemotherapy. Employing a recombinant Hsp70 fragment comprising residues 383-548 as the target, Anticalins were selected from a naïve bacterial library. The Anticalin with the highest affinity (KD = 13 nm), as determined towards recombinant full-length Hsp70 by real-time surface plasmon resonance analysis, was improved to KD = 510 pm by doped random mutagenesis and another cycle of E. coli surface display, followed by rational combination of mutations. This Anticalin, which recognises a linear peptide epitope located in the interdomain linker of Hsp70, was demonstrated to specifically bind Hsp70 in its membrane-associated form in immunofluorescence microscopy and via flow cytometry using the FaDu cell line, which is positive for surface Hsp70. The radiolabelled and PASylated Anticalin revealed specific tumour accumulation in xenograft mice using positron emission tomography (PET) imaging. Furthermore, after enzymatic coupling to the protein toxin gelonin, the Anticalin showed potent cytotoxicity on FaDu cells in vitro. [ABSTRACT FROM AUTHOR]

Treatment of metastatic cancer is one of the biggest challenges in anticancer therapy. Curcumin is interesting nature polyphenolic compound with unique biological and medicinal effects, including repression of metastases. High impact studies imply that curcumin can modulate the immune system, independently target various metastatic signalling pathways, and repress migration and invasiveness of cancer cells. This review discusses the potential of curcumin as an antimetastatic agent and describes potential mechanisms of its antimetastatic activity. In addition, possible strategies (curcumin formulation, optimization of the method of administration and modification of its structure motif) to overcome its limitation such as low solubility and bioactivity are also presented. These strategies are discussed in the context of clinical trials and relevant biological studies. [Display omitted] • Curcumin (nature polyphenol) is promising antitumour / antimetastatic agents. • Low curcumin bioavability single repress its therapeutic applicability. • DDS and curcumin formulation increase its blood and tumour level. • Curcumin combination with other agents display strong synergic effect. • Alternative curcumin routes increase its anticancer efficiency. [ABSTRACT FROM AUTHOR]

Taxanes are considered fundamental drugs in the treatment of breast cancer, but despite the similarities, docetaxel (doc) and paclitaxel (ptx) work differently. For this reason, it is interesting to identify mechanisms of antitumor activity of PAMAM dendrimer conjugates that carry docetaxel or paclitaxel and monoclonal antibody trastuzumab, specifically targeted to cells which overexpressed HER-2. For this purpose, the impact on the level of reactive oxygen species, the mitochondrial membrane potential, cell cycle distribution and the activity of caspases-3/7, -8 and -9 of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined and compared with free docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. Moreover, apoptosis and necrosis were studied using flow cytometry and confocal microscopy, respectively. Our studies show the complexity of the potential mechanism of cytotoxic action of PAMAM-drug-trastuzumab conjugates that should be sought as a resultant of oxidative stress, mitochondrial activation of the caspase cascade and the HER-2 receptor blockade.