Recent advances of nanotechnology in the diagnosis and therapy of triple-negative breast cancer (TNBC)

Background: The development of advanced treatment of triple-negative breast cancer (TNBC) is the utmost need of an era. TNBC is recognized as the most aggressive, metastatic cancer and the leading cause of mortality in females worldwide. The lack of expression of triple receptors namely, estrogen, progesterone, and human epidermal receptor2 defined TNBC. Objective: The current review introduced the novel biomarkers such as miRNA and family, PD1, EGFR, VEGF, TILs, P53, AR and PI3K, etc. contributed significantly to the prognosis and diagnosis of TNBC. Once diagnosed the utilization advanced approaches available for TNBC because of the limitations of chemotherapy. Novel approaches include lipid-based (liposomes, SLN, NLC, and SNEDDS), polymer-based (micelle, nanoparticles, dendrimers, and quantum dots), advanced nanocarriers such as (exosomes, antibody and peptide-drug conjugates), carbon-based nanocarriers (Carbon nanotubes, and graphene oxide). Lipid-based delivery is used for excellent carriers for hydrophobic drugs, biocompatibility, and lesser systemic toxicities than chemotherapeutic agents. Polymer-based approaches are preferred over lipids for providing longer circulation time, nanosize, high loading efficiency, high linking; avoiding the expulsion of drugs, targeted action, diagnostic and biosensing abilities. Advanced approaches like exosomes, conjugated moieties are preferred over polymeric for possessing potency, high penetrability, biomarkers, and avoiding the toxicity of tissues. Carbon-based gained wide applicability for their unique properties like a versatile carrier, prognostic, diagnostic, sensing, photodynamic, and photothermal characteristics. Conclusion: The survival rate can be increased by utilizing several kinds of biomarkers. The advanced approaches can also be significantly useful in the prognosis and theranostic of triple-negative breast cancer. One of the biggest successes in treating with nanotechnology-based approaches is the marked reduction of systemic toxicity with high therapeutic effectiveness compared with chemotherapy, surgery, etc. The requirements such as prompt diagnosis, longer circulation time, high efficiency, and high potency, can be fulfilled with these nanocarriers.

Effect of Size on Magnetic Polyelectrolyte Microcapsules Behavior: Biodistribution, Circulation Time, Interactions with Blood Cells and Immune System

Drug carriers based on polyelectrolyte microcapsules remotely controlled with an external magnetic field are a promising drug delivery system. However, the influence of capsule parameters on microcapsules’ behavior in vivo is still ambiguous and requires additional study. Here, we discuss how the processes occurring in the blood flow influence the circulation time of magnetic polyelectrolyte microcapsules in mouse blood after injection into the blood circulatory system and their interaction with different blood components, such as WBCs and RBCs. The investigation of microcapsules ranging in diameter 1–5.5 μm allowed us to reveal the dynamics of their filtration by vital organs, cytotoxicity, and hemotoxicity, which is dependent on their size, alongside the efficiency of their interaction with the magnetic field. Our results show that small capsules have a long circulation time and do not affect blood cells. In contrast, the injection of large 5.5 μm microcapsules leads to fast filtration from the blood flow, induces the inhibition of macrophage cell line proliferation after 48 h, and causes an increase in hemolysis, depending on the carrier concentration. The obtained results reveal the possible directions of fine-tuning microcapsule parameters, maximizing capsule payload without the side effects for the blood flow or the blood cells.

Self-Assembled Nanomicelles of Affibody-Drug Conjugate with Excellent Therapeutic Property to Cure Ovary and Breast Cancers

Affibody molecules are small non-immunoglobulin affinity proteins, which can precisely target to some cancer cells with specific overexpressed molecular signatures. However, the relatively short in vivo half-life of them seriously limited their application in drug targeted delivery for cancer therapy. Here an amphiphilic affibody-drug conjugate is self-assembled into nanomicelles to prolong circulation time for targeted cancer therapy. As an example of the concept, the nanoagent was prepared through molecular self-assembly of the amphiphilic conjugate of ZHER2:342-Cys with auristatin E derivate, where the affibody used is capable of binding to the human epidermal growth factor receptor 2 (HER2). Such a nanodrug not only increased the blood circulation time, but also enhanced the tumor targeting capacity (abundant affibody arms on the nanoagent surface) and the drug accumulation in tumor. As a result, this affibody-based nanoagent showed excellent antitumor activity in vivo to HER2-positive ovary and breast tumor models, which nearly eradicated both small solid tumors (about 100 mm3) and large established tumors (exceed 500 mm3). The relative tumor proliferation inhibition ratio reaches 99.8% for both models.

Role of 12-LOX in the Platelet Storage Lesion

Background: 12-lipoxygenase (12-LOX) is an enzyme abundant in platelets which can contribute to the platelet storage lesion by oxidizing polyunsaturated fatty acids (PUFAs) released from phospholipid membranes. We and others have shown that the PUFA arachidonic acid (AA) and its lipid oxidation products, such as 12-hydroxyeicosatetraenoic acid (12-HETE), accumulate during storage and have inhibitory effects on platelet recovery, survival, and function. However, several PUFAs are substrates for 12-LOX, and their resulting oxylipins may have different effects. We used targeted metabolomics to quantify PUFAs and oxylipins and platelet function assays to characterize function of fresh and stored wild-type (WT) and 12-LOX -/- platelets. Methods: Blood from WT and 12-LOX -/- mice was collected by retro-orbital bleeding. Platelet-rich plasma (PRP) was generated from whole blood. After fresh samples were aliquoted, the remaining PRP was separated in two groups. One group was stored at room temperature with agitation (RT) for 24 hours, and the other for 48 hours. Metabolites were extracted from samples and quantified by targeted metabolomics as described previously. We assessed platelet function by αIIbβ3 integrin activation by flow cytometry. In vivo recovery of function was measured by transfusing stored platelets into UBiC-GFP mice and stimulating platelets with agonists, followed by gating for transfused (GFP-negative) platelets by flow cytometry. For recovery and survival, we traced biotinylated fresh, 24h, or 48h-stored platelets after transfusion in vivo. Results: We quantified metabolites present in platelets by targeted metabolomics to monitor their changes in concentration over storage time. Among the 10 PUFAs and 28 related oxylipins we analyzed, 15 of 38 analytes showed a significant difference in PRP from WT and 12-LOX-/- mouse samples. The major metabolites of 12-LOX include 12-HETE, 12-hydroxyeicosapentaenoic acid (12-HEPE) and 14-hydroxydocosahexaenoic acid (14-HDHA), from AA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). 12-HETE, 12-HEPE, and 14-HDHA were only detected at <8 nmol/L levels in fresh PRP from 12-LOX -/- mice compared to 668 ± 409nM, 149 ± 85nM, and 295 ± 154nM from WT mice, respectively. After 24 hours of storage at RT, 12-HETE, 12-HEPE, and 14-HDHA dramatically increased to 29.0±4.2µM, 3.7±1.1µM, and 6.3±0.8µM in PRP from WT mice, respectively. As expected, these same metabolites remained at low nmol/L levels in 12-LOX-/- samples during storage accompanied by a significant increase of their precursors AA, EPA, and DHA due to lack of 12-LOX activity. Interestingly, there was also a significant reduction in 15-HETE, 17-HDHA, and 13-hydroxyoctadecadienoic acid (13-HODE) in the 12-LOX -/- mice compared to the WT mice, which are primarily produced by the 15-LOX enzyme. Additionally, we observed a significant decrease of metabolites mediated via the cyclooxygenase (COX) pathway in PRP from 12-LOX-/- mice, including prostaglandin E2 (PGE2), PGD2, thromboxane B2, and 12-hydroxyheptadecatrienoic acid (12-HHTrE). Function-wise, fresh 12-LOX -/- platelets were less responsive to agonists compared to WT platelets. Surprisingly, after transfusion of fresh 12-LOX -/- platelets, we found comparable αIIbβ3-integrin activation results after 1, 4, and 24h of circulation time. In contrast, 24h and 48h of storage of 12-LOX -/- platelets led to significantly lower pre-activation at baseline and a significantly lower activation response than WT platelets after 1h and 4h of circulation time. No significant differences were observed after 24h of circulation time. We observed a clear trend for longer survival after 24 and 48h of storage. Conclusions: We found many metabolic changes between 12-LOX -/- and WT mice during storage. While the 12-LOX -/- mouse model highlights the primary metabolic differences that occur without 12-LOX activity, other changes, such as differences in COX or additional LOX isoform activity, may attenuate oxylipin production. Functionally, we observed less pre-activation and better survival in functional studies, but this may be due to a combined effect of each of these individual metabolites. Future studies will have to determine the roles of individual oxylipins. Disclosures Stolla: Cerus: Research Funding.

Recent Advances in Gadolinium Based Contrast Agents for Bioimaging Applications

Gadolinium (Gd) based contrast agents (CAs) (Gd-CAs) represent one of the most advanced developments in the application of Gd for magnetic resonance imaging (MRI). Current challenges with existing CAs generated an urgent requirement to develop multimodal CAs with good biocompatibility, low toxicity, and prolonged circulation time. This review discussed the Gd-CAs used in bioimaging applications, addressing their advantages and limitations. Future research is required to establish the safety, efficacy and theragnostic capabilities of Gd-CAs. Nevertheless, these Gd-CAs offer extraordinary potential as imaging CAs and promise to benefit bioimaging applications significantly.

Corona protein impacts on alternating current biosusceptometry signal and circulation times of differently coated MnFe2O4 nanoparticles

Background: We evaluated the impacts of corona protein (CP) formation on the alternating current biosusceptometry (ACB) signal intensity and in vivo circulation times of three differently coated magnetic nanoparticles (MNP): bare, citrate-coated and bovine serum albumin-coated MNPs. Methods: We employed the ACB system, gel electrophoresis and mass spectrometry analysis. Results: Higher CP formation led to a greater reduction in the in vitro ACB signal intensity and circulation time. We found fewer proteins forming the CP for the bovine serum albumin-coated MNPs, which presented the highest circulation time in vivo among the MNPs studied. Conclusion: These data showed better biocompatibility, stability and magnetic signal uniformity in biological media for bovine serum albumin-coated MNPs than for citrate-coated MNPs and bare MNPs.