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Helicobacter pylori ( H. pylori ) infection is considered to be the main cause of most digestive diseases,such as chronic active gastritis, gastroduodenal ulcers, or even gastric cancer. Oral medication is a transformative approach to treat H. pylori -induced infections. However, unlike intravenous administration, orally administrated drugs have to overcome various barriers before reaching the infected sites, which significantly limits the therapeutic efficacy. These challenges may be addressed by emerging nanomedicine that is equipped with nanotechnology approaches to enable efficient and effective targeted delivery of drugs. Herein, in this review, we first discuss the conventional therapy for the eradication of H. pylori . Through the introduction of the critical barriers of oral administration, the benefits of nanomedicine are highlighted. Recently-published examples of nanocarriers for combating H. pylori in terms of design, preparation, and antimicrobial mechanisms are then presented, followed by our perspective on potential future research directions of oral nanomedicines.

Traditional herbal medicine (THM), an ancient science, is a gift from nature. For thousands of years, it has helped humans fight diseases and protect life, health, and reproduction. Nanomedicine, a newer discipline has evolved from exploitation of the unique nanoscale morphology and is widely used in diagnosis, imaging, drug delivery, and other biomedical fields. Although THM and nanomedicine differ greatly in time span and discipline dimensions, they are closely related and are even evolving toward integration and convergence. This review begins with the history and latest research progress of THM and nanomedicine, expounding their respective developmental trajectory. It then discusses the overlapping connectivity and relevance of the two fields, including nanoaggregates generated in herbal medicine decoctions, the application of nanotechnology in the delivery and treatment of natural active ingredients, and the influence of physiological regulatory capability of THM on the in vivo fate of nanoparticles. Finally, future development trends, challenges, and research directions are discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

With the rapid increase in the use of nanotechnology and immunotherapy for cancer management in the recent past, there are great implications for using nanotechnology in immuno-oncology. However, to deliver clinical success, the scientific and clinical rationale must be critically evaluated when applying nanotechnology to immuno-oncology challenges. This opinion article distinguishes between designing nanotherapeutics for immunotherapy and the past focus on the placement of chemotherapy agents in nanoparticles. We believe the integration of nanotechnology with cancer immunotherapy for nano-immunotherapeutics provides unique opportunities for both fields, paving the way for entirely new therapeutic paradigms. As a particular focus in our article, we envision the necessities and challenges of nanotechnology in the development of in situ cancer vaccines, immune checkpoint inhibitors, adoptive cell transfer, and bispecific antibody therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The microbiome is emerging as a key player and driver of cancer. Traditional modalities to manipulate the microbiome (for example, antibiotics, probiotics and microbiota transplants) have been shown to improve efficacy of cancer therapies in some cases, but issues such as collateral damage to the commensal microbiota and consistency of these approaches motivates efforts towards developing new technologies specifically designed for the microbiome-cancer interface. Considering the success of nanotechnology in transforming cancer diagnostics and treatment, nanotechnologies capable of manipulating interactions that occur across microscopic and molecular length scales in the microbiome and the tumour microenvironment have the potential to provide innovative strategies for cancer treatment. As such, opportunities at the intersection of nanotechnology, the microbiome and cancer are massive. In this Review, we highlight key opportunistic areas for applying nanotechnologies towards manipulating the microbiome for the treatment of cancer, give an overview of seminal work and discuss future challenges and our perspective on this emerging area.

Nanomedicine (NM) cannot penetrate deeply into solid tumors, which is partly attributed to the heterogeneous microenvironment and high interstitial fluid pressure of solid tumors. To improve NM efficacy, there has been tremendous effort developing tumor-penetrating NMs by miniaturizing NM sizes or controlling NM surface properties. But progress along the direction of developing tumor penetrating nanoparticle has been slow and improvement of the overall antitumor efficacy has been limited. Herein, a novel strategy of inhibiting solid tumor with high efficiency by dual-functional, nontumor-penetrating NM is demonstrated. The intended NM contains 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a vascular-disrupting agent, and doxorubicin (DOX), a cytotoxic drug. Upon arriving at the target tumor site, sustained release of DMXAA from NMs results in disruption of tumor vessel functions, greatly inhibiting the interior tumor cells by cutting off nutritional supply. Meanwhile, the released DOX kills the residual cells at the tumor exterior regions. The in vivo studies demonstrate that this dual-functional, nontumor penetrating NM exhibits superior anticancer activity, revealing an alternative strategy of effective tumor growth inhibition., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A strategy for enhancing the treatment efficacy of nanomedicines within the central region of solid tumors is developed by combining nanomedicines and free small-molecule vascular disrupting agents (VDAs). The nanomedicines (cis-diamminedichloroplatinum-loaded nanoparticles) primarily target cells at the tumor periphery whereas the free small-molecule VDA (combretastatin A4 disodium phosphate) efficiently kills the cancer cells within the central regions of the tumor., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Self‐assembled polymeric nanoparticle (NP) drug carriers are capable of encapsulated and controlled delivery, facilitating improvements in the therapeutic efficiency of drugs. Here we report a series of poly(l‐glutamic acid)‐g‐methoxy poly(ethylene glycol)/4‐phenylbutyl ester (PLG‐g‐mPEG/PB) copolymers, which were synthesized by esterification of 4‐phenylbutanol (PB) and PLG‐g‐mPEG in different feed ratios. The copolymers obtained form into nano‐sized micelles in aqueous solution by a self‐assembly process, with lower critical micelle concentration value for higher PB ratio in the copolymers. Variable temperature infrared spectroscopy and circular dichroism were used to prove the breaking of intermolecular hydrogen bonds after PB modification. Podophyllotoxin (PPT), an effective anticancer agent, was incorporated into the inner core of the micelle system by physical entrapment through hydrophobic interaction between the drug and the PB‐modified copolymers. Both the drug loading content and the loading efficiency increased with PB content in the PLG‐g‐mPEG/PB copolymers and reached an ultrahigh value of 28.2 wt% and 94%, respectively. The PPT‐encapsulated micelles (PPT‐NPs) were stable at pH 7.4 but dissociated and released 80% of loaded PPT in a weak acidic environment (pH 5.0). The in vitro proliferation of non‐small‐cell lung cancer cells (A549) was significantly inhibited by PPT‐NPs in a cytotoxicity assay. These results demonstrate that hydrophobic modification is an efficient route for tuning the self‐assembly behaviour and drug encapsulation of PLG‐g‐mPEG copolymers, and our PLG‐g‐mPEG/PB will serve as a promising carrier for hydrophobic anticancer drug delivery. © 2021 Society of Industrial Chemistry. [ABSTRACT FROM AUTHOR]

Solid tumors especially desmoplastic tumors are complex organ-like structures. Tumor-associated fibroblasts (TAFs), one type of the stromal cells, support the initiation, progression, and metastasis of carcinomas. TAFs also contribute to immunosuppressive tumor microenvironment (TME) and hinder T lymphocytes in killing tumors. Here, the role of TAFs in TME is discussed. In specific, TAFs form barriers for the penetration of T lymphocytes. TAFs also act as negative regulators for T lymphocytes. These findings suggest that targeting TAFs is a promising strategy for improving cancer immunotherapy. Our previous studies have indicated the ability of therapeutic nanoparticles to distribute into, and deplete or inactivate TAFs. This approach is discussed in the context of developing specific and effective immunotherapies for cancer. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy is quickly growing to be the fourth most important cancer therapy, after surgery, radiation therapy, and chemotherapy. Immunotherapy is the most promising cancer management strategy because it orchestrates the body’s own immune system to target and eradicate cancer cells, which may result in durable antitumor responses and reduce metastasis and recurrence more than traditional treatments. Nanomaterials hold great promise in further improving the efficiency of cancer immunotherapy - in many cases, they are even necessary for effective delivery. In this review, we briefly summarize the basic principles of cancer immunotherapy and explain why and where to apply nanomaterials in cancer immunotherapy, with special emphasis on cancer vaccines and tumor microenvironment modulation. [ABSTRACT FROM AUTHOR]

Combretastatin A4 (CA4) is a leading agent in vascular disrupting strategies for tumor therapy. Although many small-molecule prodrugs of CA4 have been developed to improve its solubility, the overall therapeutic efficiency is moderate. A key reason for this is the reversible effect that CA4 has on tubulin as well as its rapid clearance from plasma and tissues. In this study, we proposed a poly( l- glutamic acid)-CA4 conjugate (PLG-CA4) nanomedicine to fulfill the requirements for fully liberating the potential of CA4 on tumor therapy. Enhanced accumulation and retention of CA4 in tumor tissue, especially, high distribution and gradual release around tumor blood vessels resulted in prolonged vascular disruption and markedly enhanced therapeutic efficiency. We examined and compared the therapeutic effect of PLG-CA4 and commercial combretastatin-A4 phosphate (CA4P) in a murine colon C26 tumor. PLG-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, the PLG-CA4 was mainly distributed around the tumor vessels because of its low tissue penetration in solid tumor. Pathology tests showed that PLG-CA4 treatment resulted in persistent vascular disruption and tumor damage 72 h after a single injection, this in contrast to CA4P treatment, which showed quick relapse at an equal dose. Tumor suppression tests showed that PLG-CA4 treatment resulted in a tumor suppression rate of 74%, which indicates a significant advantage when compared to tumor suppression rate of the CA4P group, which was 24%. This is the first time that an advantage of the polymeric CA4 nanomedicine with low tissue penetration for solid tumor therapy has been shown. Thus, the results presented in this study provide a new idea for enhancing the tumor therapeutic effect of vascular disrupting agents. Statement of Significance Nanomedicine usually has low tissue penetration in solid tumors, which limits the efficacy of nanomedicine in most cases. But herein, we demonstrate a nanosized vascular disruptive agent (VDA) PLG-CA4 has supper advantages over small molecular combretastatin-A4 phosphate (CA4P) because the PLG-CA4 was mainly distributed around the tumor vessels due to its low tissue penetration in solid tumor. [ABSTRACT FROM AUTHOR]

Disulfiram (DSF) showed great potential in an in vitro tumor therapy study; however, those results could not be applied to an in vivo study due to the extreme instability of DSF in blood. Here, we describe a system of methoxy poly(ethylene glycol)- b -poly(lactide- co -glycolide)/poly(ε-caprolactone) (mPEG-PLGA/PCL) mixed nanoparticles (NPs) for DSF loading and delivery. By adjusting the mPEG-PLGA/PCL content ratios, the DSF loading capacity increased to 7.8%, while the hydrodynamic radii of the NPs were around 50-100 nm. The DSF-loaded NPs showed high stability in distilled water and 10% serum-containing phosphate buffered saline. The NPs efficiently protected DSF from degradation while maintaining its anti-tumor properties. Furthermore, a pharmacokinetics study demonstrated that NP delivery system enhanced the DSF concentration in the blood after tail vein injection. Finally, DSF delivery using this model effectively slowed the growth of a 4T1 murine xenograft tumor. From the Clinical Editor The anti-tumor efficacy of the anti-alcoholic drug disulfiram has been known for some time. However, its use in the clinical setting is limited due to the underlying instability of the drug. In this study, the authors utilized a nanocarrier system of mPEG-PLGA/PCL for the delivery of this drug. The promising results may allow encapsulation of other drugs. [ABSTRACT FROM AUTHOR]

An amphiphilic anionic copolymer, methoxy poly(ethylene glycol)-b-poly(l-glutamic acid-co-l-phenylalanine) (mPEG-b-P(Glu-co-Phe)), with three functionalized domains, was synthesized and used as a nanovehicle for cationic anticancer drug doxorubicin hydrochloride (DOX·HCl) delivery via electrostatic interactions for cancer treatment. The three domains displayed distinct functions: PEG block chain for prolonged circulation; poly(phenylalanine) domain for stabilizing the nanoparticle construct through hydrophobic/aromatic interactions; and the poly(glutamic acid) domain for providing electrostatic interactions with the cationic drug to be loaded. The copolymer could self-assemble into micellar-type nanoparticles, and DOX was successfully loaded into the interior of nanoparticles by simple mixing of DOX·HCl and the copolymer in the aqueous phase. DOX-loaded mPEG-b-P(Glu-co-Phe) nanoparticles (DOX-NP) had a superior drug-loading content (DLC) (21.7%), a high loading efficiency (almost 98%) and a pH-triggered release of DOX. The size of DOX-NP was ∼140nm, as determined by dynamic light scattering measurements and transmission electron microscopy. In vitro assays showed that DOX-NP exhibited higher cell proliferation inhibition and higher cell uptake in A549 cell lines compared with free DOX·HCl. Maximum tolerated dose (MTD) studies showed that DOX-NP demonstrated an excellent safety profile with a significantly higher MTD (15mg DOX kg−1) than that of free DOX·HCl (5mg DOX kg−1). The in vivo studies on the subcutaneous non-small cell lung cancer (A549) xenograft nude mice model confirmed that DOX-NP showed significant antitumor activity and reduced side effects, and then enhanced tumor accumulation as a result of the prolonged circulation in blood and the enhanced permeation and retention effect, compared with free DOX, indicating its great potential for cancer therapy. [ABSTRACT FROM AUTHOR]

Reversing the aggravated immunosuppression hence overgrowth of colorectal cancer (CRC) caused by the gut inflammation and microbiota dysbiosis is pivotal for effective CRC therapy and metastasis inhibition. However, the low delivery efficiency and severe dose-limiting off-target toxicities caused by unsatisfied drug delivery systems remain the major obstacles in precisely modulating gut inflammation and microbiota in CRC therapy. Herein, a multifunctional oral dextran-aspirin nanomedicine (P3C-Asp) was utilized for oral treatment of primary CRC, as it could release salicylic acid (SA) while scavenging reactive oxygen species (ROS) and held great potential in modulating gut microbiota with prebiotic (dextran). Oral P3C-Asp retained in CRC tissues for over 12 h and significantly increased SA accumulation in CRC tissues over free aspirin (10.8-fold at 24 h). The enhanced SA accumulation and ROS scavenging of P3C-Asp cooperatively induced more potent inflammation relief over free aspirin, characterized as lower level of cyclooxygenase-2 and immunosuppressive cytokines. Remarkably, P3C-Asp promoted the microbiota homeostasis and notably increased the relative abundance of strengthening systemic anti-cancer immune response associated microbiota, especially lactobacillus and Akkermansia to 6.66- and 103- fold over the control group. Additionally, a demonstrable reduction in pathogens associated microbiota (among 96% to 79%) including Bacteroides could be detected. In line with our findings, inflammation relief along with enhanced abundance of lactobacillus was positively correlated with CRC inhibition. In primary CRC model, P3C-Asp achieved 2.1-fold tumor suppression rate over free aspirin, with an overall tumor suppression rate of 85%. Moreover, P3C-Asp cooperated with αPD-L1 further reduced the tumor weight of each mouse and extended the median survival of mice by 29 days over αPD-L1 alone. This study unravels the synergistic effect of gut inflammation and microbiota modulation in primary CRC treatment, and unlocks an unconventional route for immune regulation in TME with oral nanomedicine. [Display omitted] • P3C-Asp is constructed with aspirin, ROS scavenging moiety, and prebiotic for primary colorectal cancer treatment. • P3C-Asp can simultaneously improve tumor microenvironment and enhance probiotics to reinvigorate antitumor immune responses. • The noninvasive and functional-rich P3C-Asp provides a promising candidate for gastrointestinal diseases treatment. [ABSTRACT FROM AUTHOR]

Platinum-based polymeric nano-drugs, especially cisplatin-loaded polymeric nanoparticles (CDDP-NPs), have been extensively exploited for the treatment of solid tumors. However, it is still unclear what role the processing procedure and the properties of the polymeric carrier materials may play in influencing the plasma pharmacokinetics, biodistribution and in vivo efficacy of CDDP-NPs. In this study, a series of poly( l -glutamic acid)- g -methoxy poly(ethylene glycol) (PLG- g -mPEG) copolymers were synthesized for the preparation of CDDP-loaded PLG- g -mPEG (CDDP/PLG- g -mPEG) nanoparticles. All of the parameters, including PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length, ultrafiltration purification and cisplatin loading content, were found to have a significant influence on the plasma pharmacokinetics of the CDDP/PLG- g -mPEG nanoparticles. The blood circulation time of the nanoparticles was prolonged with increases in PLG molecular weight, mPEG/PLG weight ratio, mPEG chain length and CDDP loading content. The use of ultrafiltration purification could prolong the blood circulation time of the nanoparticles as well. Experiments to measure the pharmacokinetics and biodistribution demonstrated that the selected CDDP/PLG- g -mPEG nanoparticles, NP10, had a long blood circulation time and could achieve selective and significant accumulation in Lewis lung carcinoma (LLC) tumors. The platinum plasma concentrations in the LLC tumor-bearing mice receiving NP10 remained up to 46-fold higher than that of mice receiving equivalent doses of free CDDP. In addition, the plasma area under the concentration time curve (AUC) of NP10 was 31-fold higher than that of free CDDP in 48 h. The platinum concentration ratio of NP10 to free CDDP in tumors reached as high as 9.4. The tumor AUC ratio of NP10 to CDDP was 6. Using a mouse C26 tumor model, here we demonstrate that NP10 improves the safety and tolerance in vivo when compared to CDDP and effectively inhibits the growth of C26 tumors. Furthermore, increasing the dosage of NP10 by 2 or 3-fold of free CCDP improved its anticancer efficacy to comparable or higher levels. These results indicate that CDDP/PLG- g -mPEG nanoparticles have greater potential for the treatment of solid tumors in clinical application. [ABSTRACT FROM AUTHOR]

Abstract: pH responsive cisplatin prodrug crosslinked polysaccharide-based nanoparticles were developed from succinic acid decorated dextran (Dex-SA) for active loading and triggered intracellular release of doxorubicin (DOX). Nanoparticles with uniform size were formed spontaneously in aqueous medium via electrostatic interaction between anionic Dex-SA and cationic DOX, and subsequently transformed into crosslinked nanoparticles (CL-Nanoparticles) in situ by readily crosslinking the micelles via chelate interactions between the ionic polymeric carrier and the platinum (II) antitumor drug. This strategy eliminated the need of organic solvents and sophisticated processes in the drug loading procedure. The in vitro release studies showed that DOX was released from the CL-Nanoparticles in a controlled and pH-dependent manner. Furthermore, the pharmacokinetics and biodistribution investigations indicated that, as compared to the non-crosslinked nanoparticles (NCL-Nanoparticles) and free DOX, the CL-Nanoparticles significantly prolonged the blood circulation time of drug, decreased accumulation in the normal tissues and enriched drug into the tumors. As a consequence, the DOX-loaded CL-Nanoparticles exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with the NCL-Nanoparticles and free DOX, which were further confirmed by the histological and immunohistochemical analyses. These cisplatin prodrug crosslinked polysaccharide nanoparticles proved to be a promising nanomedicine drug delivery system for tumor-targeted delivery of DOX. [Copyright &y& Elsevier]

STING (stimulator of interferon genes) signaling pathway has attracted considerable attention in cancer immunotherapy due to its capacity to boost vigorous antitumor immunity. However, the shortage of effective STING agonists limits the promotion of STING pathway in cancer treatment. Herein, we present an approach for in situ activation of STING pathway with nanoparticles delivered DNA-targeting chemo agents, based on the understanding that cytosol DNA is a pre-requisite for STING pathway activation. Through in vitro screening among several DNA-targeting chemo agents, we identified 7-ethyl-10-hydroxycamptothecin (SN38) as the most potent drug for stimulating interferon (IFN)-β secretion and proved that this process is mediated by the passage of DNA-containing exosomes from treated tumor cells to bone marrow-derived dendritic cells (BMDCs) and subsequent activation of the STING pathway. Furthermore, we designed a polymeric-SN38 conjugate that could self-assemble into nanoparticles (SN38-NPs) for in vivo application. The SN38-NPs formulation reduced toxicity of free SN38, effectively stimulated the activation of STING pathway in E0771 tumors, and resulted in a tumor suppression rate (TSR%) of 82.6%. Our results revealed a new mechanism of SN38 in cancer treatment and should inspire using more DNA-targeting agents, especially in nanoformulation, for activating STING pathway and cancer chemoimmunotherapy. Image 1 [ABSTRACT FROM AUTHOR]