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Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Due to the complexity of the disorder and the presence of the blood-brain barrier (BBB), its drug discovery and development are facing enormous challenges, especially after several failures of monoclonal antibody (mAb) trials. Nevertheless, the Food and Drug Administration's approval of the mAb aducanumab has ushered in a new day. As we better understand the disease's pathogenesis and identify novel intracerebral therapeutic targets, antibody-based therapies have advanced over the past few years. The mAb drugs targeting β-amyloid or hyperphosphorylated tau protein are the focus of the current research. Massive neuronal loss and glial cell-mediated inflammation are also the vital pathological hallmarks of AD, signaling a new direction for research on mAb drugs. We have elucidated the mechanisms by which AD-specific mAbs cross the BBB to bind to targets. In order to investigate therapeutic approaches to treat AD, this review focuses on the promising mAbs targeting intracerebral dysfunction and related strategies to cross the BBB.

Tumor immunotherapy has become a new hotspot for cancer treatment. Various immunotherapies, such as immune checkpoint inhibitors, oncolytic viruses (OVs), cytokines, and cancer vaccines, have been used to treat tumors. They operate through different mechanisms, along with certain toxicities and side effects. Understanding the mechanisms by which immunotherapy modulates the immune system is essential for improving the efficacy and managing these adverse effects. This article discusses various currently approved cancer immunotherapy mechanisms and related agents approved by the Food and Drug Administration, the European Medicines Agency, and the Medicines and Medical Devices Agency. We also review the latest progress in immune drugs approved by the National Medical Products Administration, including monoclonal antibodies, cytokines, OVs, and chimeric antigen receptor-T cell therapy, to help understand the clinical application of tumor immunotherapy., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

RNA polymerase mitochondria (POLRMT) is essential for mitochondrial transcription machinery and other mitochondrial functions. Its expression and potential functions in prostate cancer were explored here. The Cancer Genome Atlas prostate cancer cohort (TCGA PRAD) shows that POLRMT mRNA expression is upregulated in prostate cancer tissues and POLRMT upregulation is correlated with poor patients' survival. POLRMT mRNA and protein levels were upregulated in local prostate cancer tissues and different primary/immortalized prostate cancer cells. Genetic depletion of POLRMT, using viral shRNA or CRISPR/Cas9 gene editing methods, impaired mitochondrial functions in prostate cancer cells, leading to mitochondrial depolarization, oxidative stress, mitochondria complex I inhibition, and ATP depletion. Moreover, POLRMT depletion resulted in robust inhibition of prostate cancer cell viability, proliferation, and migration, and provoked apoptosis. Conversely, prostate cancer cell proliferation, migration, and ATP contents were strengthened following ectopic POLRMT overexpression. In vivo, intratumoral injection of POLRMT shRNA adeno-associated virus impeded prostate cancer xenograft growth in nude mice. POLRMT silencing, oxidative stress, and ATP depletion were detected in POLRMT shRNA-treated prostate cancer xenograft tissues. IMT1 (inhibitor of mitochondrial transcription 1), the first-in-class POLRMT inhibitor, inhibited prostate cancer cell growth in vitro and in vivo. Together, overexpressed POLRMT is an important mitochondrial protein for prostate cancer cell growth, representing a novel and promising diagnostic and therapeutic oncotarget., (© 2023. The Author(s).)

Titanium and its alloys have become the most excellent structure materials for naval seawater pipelines due to their high strength and good corrosion resistance. However, marine biofouling poses a serious threat to titanium alloy piping systems because of their good biocompatibility. Recently, the biomimetic antifouling coating, a novel antifouling method, has received great attention. Here, based on this biomimetic idea, we develop a nontoxic antifouling slippery surface (AFSS) using silicone oil, silane coupling agent, nanosilica, nanoceramic coating, epoxy resin, and capsaicin. The developed AFSS has excellent slippery performance for various droplets, good durability, and a superior self-cleaning property. Additionally, the antifouling performance of the AFSS was significantly enhanced, as confirmed by the reduced adhesion of proteins (70.7%), bacteria (97.2%), and algae (97.7%) compared to the ordinary titanium alloy. With these excellent properties, the AFSS was expected to be a promising candidate for protecting titanium alloy piping systems from marine biofouling.

China's birth rates hit a record low in 2021. The high demand for having children has spawned a massive market for surrogacy, which, however, is a dilemma in China involving a series of moral and legal issues under the current circumstances. First, special populations, including infertile patients, families who have lost their sole child, and homosexuals, wanted to have children, giving rise to surrogacy. Then, the development of and innovation in assisted reproductive technology allowed surrogacy to mature. A high return offsets a high risk, and consequently, an underground surrogacy market has emerged, causing various social issues for the Chinese Government, such as civil disputes, gender disproportion, crime, and the spread of disease. At the same time, surrogacy violates moral ethics, traditional Chinese culture, and the rights and interests of vulnerable groups.

This paper presents a magnetic resonance image deblurring and denoising model named the isotropic total variation regularized least absolute deviations measure (LADTV). More specifically, the least absolute deviations term is first adopted to measure the violation of the relation between the desired magnetic resonance image and the observed image, and to simultaneously suppress the noise that may corrupt the desired image. Then, in order to preserve the smoothness of the desired image, we introduce an isotropic total variation constraint, yielding the proposed restoration model LADTV. Finally, an alternating optimization algorithm is developed to solve the associated minimization problem. Comparative experiments on clinical data demonstrate the effectiveness of our approach to synchronously deblur and denoise magnetic resonance image.

On June 24, 2022, the US Supreme Court overturned Roe v. Wade, which marked a further restriction on women's abortion rights in the US. It has sparked a wide range of societal reactions around the world. Women in different countries enjoy diverse abortion rights due to conditions in their respective nations and cultures. Abortion protects women's rights to a certain extent, and especially in the event of unintended pregnancy. An inappropriate abortion ban will affect women's health and lives and all aspects of medicine, including the lives of doctors, patient access, and the development of medical technology. This review provides a gynecologist's perspective on the impact of abortion policies on women's health and the medical system. This review also attempts to determine the reason for the government's abortion ban.

Zhi-Zi Hou-Po Decoction (ZHD) has been widely used in the treatment of depression for centuries. This study aimed to investigate the antidepressant effects of the water extract of ZHD (ZHD-WE) and ethanol extract of ZHD (ZHD-EE) using behavioral despair tests in mice, and to further explore the neuroprotective effects in a PC12 cell injury model induced by corticosterone (CORT). Mice were divided into a control group (normal saline), ZHD-WE groups (4, 8, and 16 g kg -1 ), ZHD-EE groups (4, 8, and 16 g kg -1 ) and the fluoxetine group (20 mg kg -1 ). The forced swimming test (FST) and tail suspension test (TST) were used to screen the antidepressant effects of ZHD-WE and ZHD-EE after oral administration for seven consecutive days. The level of brain-derived neurotrophic factor (BDNF) in the hippocampus was determined by ELISA. The MTT, lactate dehydrogenase (LDH) and flow cytometry analysis were performed to elucidate the neuroprotective effect of ZHD-EE on a PC12 cell injury model. Additionally, the mRNA and proteins expression of apoptotic molecules Bax, Bcl-2 and BDNF were detected by RT-PCR and western blot assay. It showed that ZHD-EE at concentrations of 8 and 16 g kg -1 significantly decreased the immobility time in the TST and FST, and increased the BDNF levels in the hippocampus. While ZHD-WE at concentrations of 4, 8, and 16 g kg -1 had no significant effect on the immobility time in the TST, and only the 16 g kg -1 of extract group significantly decreased the immobility time in the FST. In vitro, the obtained results showed that PC12 cells pre-incubated with ZHD-EE at concentrations of 100 and 400 μg ml -1 improved cell viability, decreased LDH release, and reduced apoptosis rate of PC12 cells. Moreover, ZHD-EE significantly increased the mRNA and proteins expression of Bcl-2 and BDNF, while decreased the mRNA and protein expression of Bax. ZHD-EE significantly improved despair-like behavior in mice, and its mechanism may be related to BDNF upregulation in the hippocampus. This study also showed that ZHD-EE had a protective effect on CORT-induced injury in PC12 cells by upregulating the expression of BDNF and restoring Bcl-2/Bax balance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bai, Dai, Song, Gu, Ba, Ju and Zhang.)

Objective: To investigate the value of quick sequential organ failure assessment (qSOFA) score in early identification for sepsis patients of different ages., Methods: A retrospective study was conducted. The clinical data of 1 529 patients with suspected infection in emergency department of Changshu No.2 People's Hospital from September 2017 to March 2020 were collected. All patients were assessed for qSOFA score, and the diagnosis and treatment were recorded. Sepsis-3 was defined as the diagnostic criteria for sepsis. All the patients were divided into five groups according to age, youth group (< 45 years old), middle-aged group (45-59 years old), presenile group (60-74 years old), elderly group (75-89 years old), and longevity group (≥ 90 years old). The patients' examination results, diagnosis and treatment status were collected. The distribution of different scores of qSOFA was analyzed to calculate the sensitivity, specificity, positive predictive value and negative predictive value of different qSOFA scores for the diagnosis of sepsis in patients with suspected infection of different ages. The receiver operator characteristic curve (ROC curve) was drawn to analyze the diagnostic value of qSOFA score for sepsis in patients with suspected infection at different ages., Results: Of 1 529 suspected infection patients, there were 67 patients in youth group, 129 patients in middle-aged group, 465 patients in presenile group, 778 patients in elderly group and 90 patients in longevity group. There were significant differences in lactic acid (Lac), total bilirubin (TBil), creatinine (Cr), qSOFA score and the increased value of SOFA score compared with the basic value (ΔSOFA) among the suspected infection patients at different ages. Among suspected infection patients at different ages, the patients with qSOFA score ≥ 1 were the most, and the proportion of sepsis patients was larger. Further analysis showed that qSOFA score ≥ 1 had a high diagnostic sensitivity in patients with suspected infection at different ages. In the youth group, the sensitivity was 84.4%, and the specificity was the highest (74.3%). Although qSOFA score ≥ 2 had a high specificity in the diagnosis of sepsis (all > 97%), its sensitivity was very low (all < 44%). In this study, all patients with a qSOFA score of 3 were sepsis, and the positive predictive value of the diagnosis of sepsis in each group was 100%. ROC curve analysis showed that the area under ROC curve (AUC) of qSOFA score for the diagnosis of sepsis in all suspected infection patients was 0.771 [95% confidence interval (95%CI) was 0.747-0.794], when the best cut-off value was 0.5, the sensitivity was 93.4% and the specificity was 45.6%. Among suspected infection patients of all ages, the accuracy of qSOFA score in the diagnosis of sepsis in the youth group and the longevity group was relatively high, with AUC (95%CI) of 0.825 (0.724-0.927) and 0.837 (0.756-0.917), respectively; when the best cut-off value was 0.5, the sensitivity was 84.4% or 92.2%, and the specificity was 74.3% or 56.4%, respectively., Conclusions: qSOFA score has an early diagnosis value for sepsis, especially in the patients aged < 45 years old or ≥ 90 years old. Using qSOFA score ≥ 2 to screen patients with suspected infection is likely to cause missed diagnosis.

Transferrin receptor (TfR) is a promising target validated in the clinical trials for managing various malignancies. Transferrin (Tf) and single chain antibody fragment can target TfR and are typically conjugated to nanomedicines via post-modification, which poses significant production challenges. Here, we report that the polymersomes functionalized with a Tf-binding peptide CGGGHKYLRW (TBP-Ps) can selectively and stably bind Tf and subsequently mediate targeted doxorubicin (Dox) delivery to TfR over-expressing HCT-116 colorectal cancer cells in vitro and in vivo. The Tf surface density of the polymersomes could be controlled by the surface content of TBP. Interestingly, modifying Dox-loaded TBP-Ps with Tf led to greatly increased cellular uptake and inhibitory effect of HCT-116 cells. Tf-bound TBP-Ps demonstrated rapid accumulation in the tumor xenografts in nude mice following i.v. injection. More importantly, Dox-loaded Ps with Tf binding significantly enhanced the antitumor efficacy in mice bearing HCT-116 tumors compared to polymersomes without Tf binding. Surface functionalization of the nanoparticles with Tf-binding peptide provides an appealing strategy in formulating Tf-targeted nanomedicines., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Metastasis is responsible for >90% of the deaths of breast cancer patients in the clinic. Here, we report on cross-linked multifunctional hyaluronic acid nanoparticles carrying docetaxel (DTX-CMHN) for enhanced suppression of highly metastatic 4T1 breast tumors in vivo . DTX-CMHN was formed from a single and all-natural hyaluronic acid- g -polytyrosine-lipoic acid conjugate (HA- g -PTyr-LA; HA, 20 kDa; PTyr, 2.2 kDa), and the size of DTX-CMHN increased from 69 to 78 to 96 nm as the increasing degree of substitution (DS) of PTyr increased from 4 to 11 to 15, respectively. Robust encapsulation of DTX was obtained when DS ≥ 11. DTX-CMHN while steady in a nonreducing environment was destabilized under 10 mM glutathione releasing ∼90% of the DTX within 24 h. It is noteworthy that DTX-CMHN exhibited better antitumor, antimigration, and anti-invasion activity in CD44-overexpressed 4T1-Luc breast cancer cells than free DTX. Interestingly, DTX-CMHN displayed a long elimination half-life of 5.75 h, in contrast to half-lives of 2.11 and 0.75 h for its non-cross-linked counterpart (DTX-MHN) and free DTX, respectively. In vivo therapeutic studies showed significantly better inhibition of primary 4T1-Luc tumor growth and lung metastasis and lower toxicity of DTX-CMHN compared with that of free DTX. These multifunctional nanoformulations based on a single and all-natural hyaluronic acid conjugate emerge as a potential nanoplatform for targeted treatment of CD44-positive metastatic tumors.

Nanomedicines are deemed as the most promising treatment modality for malignant cancers. Particularly, cancer nanomedicines based on synthetic polypeptides have gained interest because they possess excellent safety, unique hierarchical structure, and tailorable functionalities to suit for delivery of diverse drugs including synthetic drugs, peptides, proteins, and nucleic acids. A few polypeptide-based nanoformulations (e.g., NK105, NC6004, NK911, CT2103) are under phases I-III clinical investigation for treating patients with advanced solid tumors. In recent years, progress has been made in the development of robust and high drug loading, tumor-targeting, membrane-disrupting, and stimuli-sensitive nanomedicines from de novo functional polypeptides, which afford not only better safety and reduced adverse effects, but also further improved anticancer efficacy over clinical formulations. Moreover, virus-mimicking vehicles have been devised from polypeptides for efficient nonviral delivery of highly potent peptides, proteins, and nucleic acids, greatly advancing biotherapy for cancers. In this Perspective, we highlight the state-of-the-art design and fabrication of cancer nanomedicines based on synthetic polypeptides and, at the end, give our viewpoints on their future development for targeted cancer therapy and potential challenges for clinical translation.

Future healthcare requires development of novel theranostic agents that are capable of not only enhancing diagnosis and monitoring therapeutic responses but also augmenting therapeutic outcomes. Here, a versatile and stable nanoagent is reported based on poly(ethylene glycol)-b-poly(l-thyroxine) (PEG-PThy) block copolypeptide for enhanced single photon emission computed tomography/computed tomography (SPECT/CT) dual-modality imaging and targeted tumor radiotherapy in vivo. PEG-PThy acquired by polymerization of l-thyroxine-N-carboxyanhydride (Thy-NCA) displays a controlled M n , high iodine content of ≈49.2 wt%, and can spontaneously form 65 nm-sized nanoparticles (PThyN). In contrast to clinically used contrast agents like iohexol and iodixanol, PThyN reveals iso-osmolality, low viscosity, and long circulation time. While PThyN exhibits comparable in vitro CT attenuation efficacy to iohexol, it greatly enhances in vivo CT imaging of vascular systems and soft tissues. PThyN allows for surface decoration with the cRGD peptide achieving enhanced CT imaging of subcutaneous B16F10 melanoma and orthotopic A549 lung tumor. Taking advantages of a facile iodine exchange reaction, 125 I-labeled PThyN enables SPECT/CT imaging of tumors and monitoring of PThyN biodistribution in vivo. Besides, 131 I-labeled and cRGD-functionalized PThyN displays remarkable growth inhibition of the B16F10 tumor in mice (tumor inhibition rate > 89%). These poly(l-thyroxine) nanoparticles provide a unique and versatile theranostic platform for varying diseases., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies. The current chemotherapy with typically low tumor uptake and high toxicity reveals a poor anti-HCC efficacy. Here, we report transferrin-guided polycarbonate-based polymersomal doxorubicin (Tf-Ps-Dox) as a low-toxic and potent nanotherapeutic agent for effective treatment of liver tumor using a transferrin receptor (TfR)-positive human liver tumor SMMC-7721 model. Tf-Ps-Dox was facilely fabricated with small size of ca. 75 nm and varying Tf densities from 2.2% to 7.0%, by postmodification of maleimide-functionalized Ps-Dox (Dox loading content of 10.6 wt%) with thiolated transferrin. MTT assays showed that Tf-Ps-Dox had an optimal Tf surface density of 3.9%. The cellular uptake, intracellular Dox level, and anticancer efficacy of Tf-Ps-Dox to SMMC-7721 cells were inhibited by supplementing free transferrin, which supports that Tf-Ps-Dox is endocytosed through TfR. Interestingly, Tf-Ps-Dox exhibited a high accumulation of 8.5%ID/g (percent injected dose per gram of tissue) in subcutaneous SMMC-7721 tumors, which was 2- and 3-fold higher than that of nontargeted Ps-Dox and clinically used liposomal Dox formulation (Lipo-Dox), respectively. The median survival times of mice bearing orthotopic SMMC-7721 tumors increased from 82, 88 to 96 days when treated with Tf-Ps-Dox at Dox doses from 8, 12 to 16 mg/kg, which was significantly longer than that of Ps-Dox at 8 mg/kg (58 days) and Lipo-Dox at 4 mg/kg (48 days) or PBS (36 days). Notably, unlike Lipo-Dox, no body weight loss and damage to major organs could be discerned for all Tf-Ps-Dox groups, indicating that Tf-Ps-Dox caused low systemic toxicity. This transferrin-dressed polymersomal doxorubicin provides a potent and low-toxic treatment modality for human hepatocellular carcinoma. STATEMENT OF SIGNIFICANCE: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Vast work has focused on developing HCC-targeted nanotherapeutics. However, none of the nanotherapeutics has advanced to clinics, partly because the ligands used have not been validated in patients. Transferrin (Tf) is a natural ligand for transferrin receptor (TfR) that is overexpressed on cancerous cells, and it is currently under clinical trials (MBP-426 and CALAA-01) for the treatment of solid tumors. We designed Tf-functionalized polymersomal doxorubicin (Tf-Ps-Dox) for targeted therapy of orthotopic SMMC-7721 tumor in nude mice. Tf-Ps-Dox showed potent anti-HCC efficacy and significantly improved survival time with low toxicity as compared with nontargeted Ps-Dox and clinical liposomal Dox (Lipo-Dox). Hence, Tf-Ps-Dox is very appealing for targeted treatment of HCC., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Prostate cancer (PCa) incidence was increased substantially in the last two decades in China. We evaluated the performance of prostate health index (PHI) in predicting the presence of PCa in Chinese people., Methods: A total of 108 consecutive patients were recruited to develop a PHI-based nomogram to predict PCa. Serum total prostate specific antigen (tPSA), free PSA (fPSA), and p2PSA were measured by Beckman Coulter's DxI 800 Immunoassay System. PHI was calculated by [p2PSA/fPSA]×. Performance of individual PSA and PHI measurements in discriminating clinical outcomes was measured using the detection rate of PCa, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC)., Results: Among all patients, PHI was a better predictor of PCa compared with tPSA. PHI achieved the highest AUC of 76.6% in discriminating PCa from non-PCa compare to tPSA measurement, the difference of AUC area between PHI and PSA was about 6% in the entire cohort. The PHI-based nomogram reduced the number of biopsies. With the cutoff value (tPSA >4 ng/mL, PHI >40), there were 37 patients need to do biopsies in tPSA >4 ng/mL group, while with PHI >40, only 30 patients need to do. Seven patients could avoid unnecessary biopsies. When combined with the two values (tPSA >4 ng/mL, PHI >40) only 24 patients remained., Conclusions: Our finding has implication PHI and provides added value over tPSA for PCa detecting in Chinese people., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2019.05.08). The authors have no conflicts of interest to declare., (2019 Translational Cancer Research. All rights reserved.)

The clinical success of nanomedicines demands on the development of simple biodegradable nanocarriers that can efficiently and stably encapsulate chemotherapeutics while quickly release the payloads into target cancer cells. Herein, we report that cRGD-decorated biodegradable polytyrosine nanoparticles (cRGD-PTN) boost encapsulation and targeted delivery of doxorubicin (DOX) to colorectal cancer in vivo. The co-assembly of poly(ethylene glycol)-poly(L-tyrosine) (PEG-PTyr) and cRGD-functionalized PEG-PTyr (mol/mol, 80/20) yielded small-sized cRGD-PTN of 70 nm. Interestingly, cRGD-PTN exhibited an ultra-high DOX encapsulation with drug loading contents ranging from 18.5 to 54.1 wt%. DOX-loaded cRGD-PTN (cRGD-PTN-DOX) was highly stable against dilution, serum, and Triton X-100 surfactant, while quickly released DOX in HCT-116 cancer cells, likely resulting from enzymatic degradation of PTyr. Flow cytometry, confocal microscopy and MTT assays displayed that cRGD-PTN-DOX was efficiently internalized into α v β 5 overexpressing HCT-116 colorectal cancer cells, rapidly released DOX into the nuclei, and induced several folds better antitumor activity than non-targeted PTN-DOX and clinically used liposomal DOX (Lipo-DOX). SPECT/CT imaging revealed strong tumor accumulation of 125 I-labeled cRGD-PTN, which was 2.8-fold higher than 125 I-labeled PTN. Notably, cRGD-PTN-DOX exhibited over 5 times better toleration than Lipo-DOX and significantly more effective inhibition of HCT-116 colorectal tumor than non-targeted PTN-DOX control, affording markedly improved survival rate in HCT-116 tumor-bearing mice with depleting side effects at 6 or 12 mg DOX equiv./kg. cRGD-PTN-DOX with great simplicity, robust drug encapsulation and efficient nucleic drug release appears promising for targeted chemotherapy of colorectal tumor., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Polypeptide micelles, though having been proved to be an appealing nanoplatform for cancer chemotherapy, are met with issues like inefficient drug encapsulation, gradual drug release, and low tumor cell selectivity and uptake. Here, we report on cRGD-decorated, small-sized, robust, and reduction-responsive polytyrosine micelles (cRGD-rPTM) based on poly(ethylene glycol)- b-poly(l-tyrosine)-lipoic acid (PEG- b-PTyr-LA) conjugate for high loading and targeted delivery of doxorubicin (Dox). Notably, cRGD-rPTM exhibited efficient loading of Dox, giving cRGD-rPTM-Dox with a drug loading content (DLC) of 18.5 wt % and a small size of 45 nm at a theoretical DLC of 20 wt %. cRGD-rPTM-Dox displayed reduction-triggered drug release, high selectivity and superior antiproliferative activity toward α v β 3 integrin positive MDA-MB-231 breast cancer cells (IC 50 = 1.5 μg/mL) to both nontargeted rPTM-Dox and clinical liposomal formulation (LP-Dox). cRGD-rPTM-Dox demonstrated a prolonged circulation time compared with the noncrosslinked cRGD-PTM-Dox control and significantly better accumulation in MDA-MB-231 breast tumor xenografts than nontargeted rPTM-Dox. Moreover, cRGD-rPTM-Dox at 6 mg Dox equiv/kg could remarkably suppress growth of MDA-MB-231 human breast tumor without inducing obvious side effects, outperforming both rPTM-Dox and LP-Dox. These reduction-responsive multifunctional polytyrosine micelles appear to be a viable and versatile nanoplatform for targeted chemotherapy.

Despite the great significance of clinically viable nanovehicles, very few of them exhibit stability and high anticancer drug loading with fast intracellular drug release. Herein, we report that polytyrosine nanoparticles (PTNs) self-assembled from poly(ethylene glycol)-b-poly(l-tyrosine) block copolymer enable the ultra-high loading and rapid enzyme-responsive release of doxorubicin (DOX). Notably, PTNs achieve a remarkably high DOX loading of 63.1 wt% likely due to the existence of strong π-π stacking between polytyrosine and DOX, as shown by UV-vis analysis. Additionally, PTNs present a high docetaxel loading of 17.5 wt%. Furthermore, PTNs exhibit good colloidal stability in 10% FBS, but are quickly de-stabilized by proteinase K. Interestingly, ca. 90% of DOX is released under 6 U mL-1 proteinase K in 24 h or in RAW 264.7 cells in 8 h. The DOX-loaded PTNs display efficient delivery and release of DOX in both RAW 264.7 cells and HCT-116 human colorectal cancer cells, achieving a better in vitro antiproliferative effect than the clinically used liposomal DOX formulation. Thus, these polytyrosine nanoparticles appear to be a potentially viable platform for the controlled delivery of anthraquinone anticancer agents.

Antibody-mertansine (DM1) conjugates (AMCs) are among the very few active targeting therapeutics that are approved or clinically investigated for treating various cancers including metastatic breast cancer. However, none of the AMCs are effective for the treatment of triple-negative breast cancers (TNBCs). Here, we show that cRGD-decorated, redox-activatable micellar mertansine prodrug (cRGD-MMP) can effectively target and deliver DM1 to α v β 3 integrin overexpressing MDA-MB-231 TNBC xenografts in nude mice, resulting in potent tumor growth inhibition. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that cRGD-MMP had obvious targetability to MDA-MB-231 cells with a low half-maximal inhibitory concentration (IC 50 ) of 0.18 μM, which was close to that of free DM1 and 2.2-fold lower than that of micellar mertansine prodrug (MMP; nontargeting control). The confocal microscopy studies demonstrated that cRGD-MMP mediated a clearly more efficient cellular uptake and intracellular release of doxorubicin (used as a fluorescent anticancer drug model) in MDA-MB-231 cells. Notably, cRGD-MMP loaded with 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide (DiR; a hydrophobic near-infrared dye) was shown to quickly accumulate in the MDA-MB-231 tumor with strong DiR fluorescence from 2 to 24 h post injection. MMP loaded with DiR could also accumulate in the tumor, although significantly less than cRGD-MMP. The biodistribution studies revealed a high DM1 accumulation of 8.1%ID/g in the tumor for cRGD-MMP at 12 h post injection. The therapeutic results demonstrated that cRGD-MMP effectively suppressed MDA-MB-231 tumor growth at 1.6 mg DM1 equiv./kg without causing noticeable side effects, as shown by little body weight loss and histological analysis. This MMP has appeared as a promising platform for potent treatment of TNBCs., Competing Interests: Disclosure The authors report no conflicts of interest in this work.