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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.

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

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.

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.

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]

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]

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.

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.

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]

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.

[Display omitted] Breast carcinoma is among the most commonly diagnosed cancer in females, responsible for 15% of all cancer affiliated mortalities and 23% of all cancer incidence. Based on the recent GLOBOCAN 2020 figures, malignancy of breast is responsible for One in every-Eight cancer identified and 2.3 million newly diagnosed incidences in both gender coupled. Thus, making it the one of the deadliest illnesses. Even though the conventional cancer treatments like radiotherapy, surgery, and chemotherapy manage the condition and minimise the chances of relapse. But they produce severe side effects and poor chemotherapeutic efficacy due to reasons like cytotoxicity to healthy cells, low specificity, resistance to multiple drugs, and fast drug clearance. The use of nanotechnology has emerged as an innovative and successful approach for optimising medicine delivery for cancer management and detection. Magnetic nanoparticles (MNPs), in particular, have sparked significant attention in recent years because to their small size, excellent colloidal stability, high cytocompatibility, selective tumour targeting, and very effective hyperthermia under the influence of magnetic field. Here we summarize various applications of MNP in cancer therapy. Further, different research studies that have been conducted to assess the potential of MNPs in the therapy of breast cancer has also been reviewed. [ABSTRACT FROM AUTHOR]

In this study, a pH-dependent thermo-responsive polymer (poly ( N -isopropyl acrylamide- co -methacrylic acid -co- ethyl methacrylate, P(NIPAAm- co -MAA- co -EMA)), which was used as a masking functional module was designed and prepared. Its LCST was pH-dependent, leading to a sensitive isothermal phase transition between the blood and the extracellular environment of solid tumours. This masking polymer had a LCST of 36.4 °C at pH 6.5, and remained hydrophilic at pH 7.4 even when the temperature was increased to 50 °C. The liver-targeted nanoparticles (NPs) were then obtained by co-grafting the masking functional module and the targeting ligands glycyrrhetinic acid (GA) onto the gold nanoparticles (Au NPs). Their surface properties and targeting ability could be switched based on the expanding or shrinking behaviour of the polymers. The shielding/deshielding effect of GA was confirmed by the bovine serum albumin adsorption and cellular uptake. The results indicated that GA could be shielded by the hydrophilic P(NIPAAm- co -MAA- co -EMA) in the normal physiological environment (pH 7.4, 37 °C) and deshielded in the tumour microenvironment of pH 6.5, 40 °C, leading to an increase in cellular uptake as high as 2.3-fold compared with that observed at pH 7.4, 37 °C. More importantly, the ultrasensitive phase transition of the polymer was reversible, which means that the targeting ability of the deshielded Au NPs could be reshielded if they come back to the blood circulation. [ABSTRACT FROM AUTHOR]

Treatment with chemotherapy such as docetaxel (DTX) is associated with significant toxicity and tumour recurrence. In this study, we developed DTX-entrapped core-cross-linked polymeric micelles (DTX-CCL-PMs, 66 nm size) by covalently conjugating DTX to CCL-PMs via a hydrolysable ester bond. The covalent conjugation allowed for sustained release of DTX under physiological conditions in vitro . In vivo , DTX-CCL-PMs demonstrated superior therapeutic efficacy in mice bearing MDA-MB-231 tumour xenografts as compared to the marketed formulation of DTX (Taxotere ® ). Strikingly, a single intravenous injection of DTX-CCL-PMs enabled complete regression of both small (∼150 mm 3 ) and established (∼550 mm 3 ) tumours, leading to 100% survival of the animals. These remarkable antitumour effects of DTX-CCL-PMs are attributed to its enhanced tumour accumulation and anti-stromal activity. Furthermore, DTX-CCL-PMs exhibited superior tolerability in healthy rats as compared to Taxotere. These preclinical data strongly support clinical translation of this novel nanomedicinal product for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Activatable cell-penetrating peptides (aCPPs) allow non-viral, low cytotoxic and selective delivery of compounds into target cells for cancer therapy. In tumour cells, up-regulation of human telomerase reverse transcriptase (hTERT) frequently occurs and is being considered as a target in cancer diagnosis and treatment. siRNA sequence that target hTERT mRNA can silence the gene and reduce hTERT protein expression to reduce cell proliferation and inhibit cell growth. In our study, we tested a matrix metalloproteinase-2 (MPP2) aCPP in delivering hTERT siRNA into hepatocellular carcinoma cells (SMMC-7721) to silence the hTERT gene. Cultured SMMC-7721 cells were transfected with a complex of aCPPs and hTERT-specific siRNA-encoding or control plasmids. Compared with cells treated with the complex of control plasmid-CPPs, cells treated with the hTERT-specific siRNA-encoding plasmid-CPP complex had a prolonged G1-phase, but a shorter G2/S-phase, indicating a G1-arrest. Treatment with the hTERT-specific siRNA resulted in a significant decrease (by 26%; P<0.05) in hTERT mRNA levels. The aCPPs tested in this study provides a non-viral delivery of siRNA into cancer cells to silence target genes in cancer therapy. [ABSTRACT FROM AUTHOR]

Nuclear-receptors are often overexpressed in tumours and can thereby be used as targets when designing novel selective chemotherapeutic agents. To date, many conjugates incorporating an estrogen receptor (ER) ligand have been synthesised in order to direct chemical agents to tissue sites containing ERs. A series of ER ligand conjugates were synthesised incorporating an antagonistic ER ligand scaffold based on endoxifen, covalently-bound via an amide linkage to a variety of combretastatin-based analogues, which may act as antimitotic agents. These novel endoxifen-combretastatin hybrid scaffold analogues were biochemically evaluated in order to determine their antiproliferative and cytotoxicity effects in both the ER-positive MCF-7 and the ER-negative MDA-MB-231 human breast cancer cell lines. ER competitive binding assays were carried out to assess the binding affinity of the lead conjugate 28 towards both the ERα and ERβ isoforms. In results from the NCI 60-cell line screen, the lead conjugate 28 displayed potent and highly selective antiproliferative activity towards the MCF-7 human cancer cell line (IC50 = 5 nM). In the ER-binding assays, the lead conjugate 28 demonstrated potent ER competitive binding in ERα (IC50 value: 0.9 nM) and ERβ (IC50 value: 4.7 nM). Preliminary biochemical results also demonstrate that the lead conjugate 28 may exhibit pure antagonism. This series makes an important addition to the class of ER antagonists and may have potential applications in anticancer therapy.

Abstract: Tumour targeting nanoparticles (NPs) have demonstrated great potential for enhancing anticancer drug delivery to tumour sites and for reducing the side effects of chemotherapy. However, many nanoparticulate delivery systems still lack efficient tumour accumulation. In this work, we present a porous silicon (PSi) nanovector functionalized with a tumour-homing peptide, which targets the mammary-derived growth inhibitor (MDGI) expressing cancer cells both in vitro and in vivo, thereby enhancing the accumulation of the NPs in the tumours. We demonstrated that the tumour homing peptide (herein designated as CooP) functionalized thermally hydrocarbonized PSi (THCPSi) NPs homed specifically to the subcutaneous MDGI-expressing xenograft tumours. The THCPSi-CooP NPs were stable in human plasma and their uptake by MDGI-expressing cancer cells measured by confocal microscopy and flow cytometry was significantly increased compared to the non-functionalized THCPSi NPs. After intravenous injections into nude mice bearing MDGI-expressing tumours, effective targeting was detected and THCPSi-CooP NPs showed ∼9-fold higher accumulation in the tumour site compared to the control THCPSi NPs. Accumulation of both NPs in the vital organs was negligible. [Copyright &y& Elsevier]