The role of Chinese medicine in COVID-19 pneumonia: A systematic review and meta-analysis.

INTRODUCTION: Chinese medicine (CM) has been used to treat Novel Coronavirus 2019 (COVID-19) pneumonia in China. This meta-analysis was conducted to evaluate the clinical efficacy and safety of CM in the treatment of COVID-19 pneumonia. METHODS: Randomized controlled trials (RCTs) involving CM in the treatment of COVID-19 pneumonia were identified from Cochrane Central Register of Controlled Trials, PubMed, EMBASE, Chinese National Knowledge Infrastructure, Chinese Biomedical Database, Wanfang Database and VIP Information Database. The methodological quality of trials was evaluated with Cochrane Hanadbook criteria, and the Cochrane Collaboration's Review Manager 5.3 software was used for meta-analysis. RESULTS: A total of 7 valid studies involving 681 patients were included. The meta-analysis exhibited in comparison to conventional treatment, CM combined with conventional treatment significantly improved clinical efficacy (RR = 1.21, 95% CI [1.08,1.36]), and significantly increased viral nucleic acid negative conversion rate (RR = 1.49, 95% CI [1.13,1.97]). CM also prominently reduced pulmonary inflammation (RR = 1.27, 95% CI [1.12,1.44]), and improved host immune function (WBC, MD = 0.92, 95% CI [0.07,1.76]; LYM, MD = 0.33, 95% CI [0.08,0.57]; LYM%, MD = 2.90, 95% CI [2.09,3.71]; CRP, MD = -12.66, 95% CI [-24.40, -0.92]). Meanwhile, CM did not increase the incidence of adverse reactions (RR = 1.17, 95% CI [0.39,3.52]). CONCLUSION: According to the allocated data, CM has demonstrated clinical efficacy and safety on COVID-19 pneumonia, which need to be confirmed by high quality, multiple-center, large sample randomized controlled trials.

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy.

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.

Facile Generation of Tumor-pH-Labile Linkage-Bridged Block Copolymers for Chemotherapeutic Delivery.

Successful bench-to-bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor-pH-labile linkage-bridged copolymers of clinically validated poly(D,L-lactide) and poly(ethylene glycol) (PEG-Dlink(m)-PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG-Dlink(m)-PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1% in comparison to 47.8% of the non-responsive control. Furthermore, PEG-Dlink(m)-PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG-b-PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies.

Tumor Acidity-Sensitive Polymeric Vector for Active Targeted siRNA Delivery.

Although surface PEGylation of siRNA vectors is effective for preventing protein adsorption and thereby helps these vectors to evade the reticuloendothelial system (RES) in vivo, it also suppresses the cellular uptake of these vectors by target cells. This dilemma could be overcome by employing stimuli-responsive shell-detachable nanovectors to achieve enhanced cellular internalization while maintaining prolonged blood circulation. Among the possible stimuli, dysregulated pH in tumor (pHe) is the most universal and practical. However, the design of pHe-sensitive system is problematic because of the subtle differences between the pHe and pH in other tissues. Here, a simple acid-sensitive bridged copolymer is developed and used for tumor-targeted systemic delivery of siRNA. After forming the micelleplex delivery system, the corresponding nanoparticles (Dm-NP) might undergo several modifications as follows: (i) a poly(ethylene glycol) (PEG) corona, which is stable in the circulatory system and protects nanovectors from RES clearance; (ii) a pHe responsive linkage breakage, which induces PEG detachment at tumor sites and thereby facilitates cell targeting; and (iii) a cell-penetration peptide, which is exposed upon the removal of PEG and further enhances cellular uptake. Thus, Dm-NP achieved both prolonged circulation and effective accumulation in tumor cells and resulted in the safe and enhanced inhibition of non-small cell lung cancer growth.

Achieving a new controllable male contraception by the photothermal effect of gold nanorods.

During the process of human civilization, owning household pets has become increasingly popular. However, dogs and cats may be reservoirs or vectors of transmissible diseases to humans. Confronted with the overpopulation of pets, traditional contraception methods, surgical methods of sterilization, for animals are used, namely, ovariohysterectomy and orchidectomy. Therefore, a simple, nonsurgical, controllable, more effective and less expensive contraception method is highly desirable. In this study, we show that in situ testicular injection of methoxy poly(ethylene glycol)-modified gold nanorods with near-infrared irradiation in male mice can achieve short-lived or permanent male infertility. In a lower hyperthermia treatment, the morphology of testes and seminiferous tubules is only partly injured, and fertility indices are decreased to 10% at day 7, then recovered to 50% at day 60. In a higher hyperthermia treatment, the morphology of testes and seminiferous tubules are totally destroyed, and fertility indices are decreased to 0 at day 7. Overall, our results indicate a potential application of plasmonic nanomaterials for male contraception.

Tumor pH-triggered "charge conversion" nanocarriers with on-demand drug release for precise cancer therapy.

Combined X-ray-induced photodynamic therapy (X-PDT) and chemotherapy are of great interest for tumor treatment, but their outcome is still hindered by insufficient drug delivery without tumor specificity and the difficulty of switching to chemotherapy during the X-PDT process. Herein, we report an efficient strategy for preparing a nanocarrier, DANPVP&DOX, with slight-acidity-induced charge conversion and hypoxia-motivated doxorubicin (DOX) release properties to achieve a more precise and synchronous therapeutic effect. Upon a change in the extracellular pH (pHe) in the tumor matrix, the surface charge of DANPVP&DOX converted from negative to positive via dimethyl maleate degradation. Following the increased internalization by tumoral cells, exposure of verteporfin (VP) in DANPVP&DOX to low-dose X-ray radiation resulted in O2 consumption in the cytoplasm to produce cytotoxic reactive oxygen species (ROS), which caused cell killing. Moreover, the hypoxic conditions formed in the tumor area specifically promoted DANPVP&DOX dissociation and on-demand DOX release. Consequently, DANPVP&DOX significantly increased the therapeutic efficacy through X-PDT and cascade chemotherapy. More importantly, this strategy could potentially be extended to various therapeutic agents other than anticancer drugs for precise drug delivery and cancer treatment.

Light-activated drug release from a hyaluronic acid targeted nanoconjugate for cancer therapy.

Hyaluronic acid (HA)-based nanocarriers are of great interest in the drug delivery field due to the tumor targetability via CD44-mediated recognition and endocytosis. However, sufficient tumor-specific release of encapsulated cargoes with steady controllability is necessary to optimize their outcome for cancer therapy. In this study, we constructed a light-activated nanocarrier TKHCENPDOX to enable on-demand drug release at the desired site (tumor). Particularly, TKHCENPDOX encapsulating doxorubicin (DOX) was self-assembled from a HA-photosensitizer conjugate (HA-TK-Ce6) containing reactive oxygen species (ROS)-sensitive thioketal (TK) linkers. Following i.v. injection, TKHCENPDOX was accumulated in the MDA-MB-231 breast tumor xenograft more efficiently through preventing drug leakage in the bloodstream and the HA-mediated targeting effect. Upon internalization into tumoral cells, 660 nm laser irradiation generated ROS during a photodynamic (PDT) process to cleave the TK linker next to Ce6, resulting in light-induced TKHCENPDOX dissociation and selective DOX release in the tumor area. Consequently, TKHCENPDOX showed a remarkable therapeutic effect and minimized toxicity in vivo. This strategy might provide new insight for designing cancer-selective nanoplatforms with active targeting and locoregional drug release simultaneously.

Cascade-amplifying synergistic effects of chemo-photodynamic therapy using ROS-responsive polymeric nanocarriers.

The simple integration of chemotherapeutic drugs and photosensitizers (PSs) into the same nanocarriers only achieves a combination of chemo-photodynamic therapy but may not confer synergistic effects. The boosted intracellular release of chemotherapeutic drugs during the photodynamic therapy (PDT) process is necessary to achieve a cascade of amplified synergistic therapeutic effects of chemo-photodynamic therapy. Methods: In this study, we explored an innovative hyperbranched polyphosphate (RHPPE) containing a singlet oxygen (SO)-labile crosslinker to boost drug release during the PDT process. The photosensitizer chlorin e6 (Ce6) and doxorubicin (DOX) were simultaneously loaded into RHPPE nanoparticles (denoted as SOHNPCe6/DOX). The therapeutic efficacy of SOHNPCe6/DOX against drug-resistant cancer was evaluated in vitro and in vivo. Results: Under 660-nm light irradiation, SOHNPCe6/DOX can produce SO, which not only induces PDT against cancer but also cleaves the thioketal linkers to destroy the nanoparticles. Subsequently, boosted DOX release can be achieved, activating a chemotherapy cascade to synergistically destroy the remaining tumor cells after the initial round of PDT. Furthermore, SOHNPCe6/DOX also efficiently detected the tumor area by photoacoustic/magnetic resonance bimodal imaging. Under the guidance of bimodal imaging, the laser beam was precisely focused on the tumor areas, and subsequently, SOHNPCe6/DOX realized a cascade of amplified synergistic chemo-photodynamic therapeutic effects. High antitumor efficacy was achieved even in a drug-resistant tumor model. Conclusion: The designed SOHNPCe6/DOX with great biocompatibility is promising for use as a co-delivery carrier for combined chemo-photodynamic therapy, providing an alternative avenue to achieve a cascade of amplified synergistic effects of chemo-photodynamic therapy for cancer treatment.

A micellar cisplatin prodrug simultaneously eliminates both cancer cells and cancer stem cells in lung cancer.

Platinum-based chemotherapy as first-line treatment for lung cancers encounters insufficient selectivity, severe side effects and drug resistance in clinics. In this study, we developed an amphiphilic prodrug of cisplatin-poly(ethylene glycol)-block-polycaprolactone and demonstrated that the prodrug formed micellar nanoparticles, NPPt(IV), with an average diameter of ∼100 nm. NPPt(IV) released platinum in response to the intracellular acidic and reductive environment, and in turn induced significant anti-proliferative activity in lung cancer cells. More importantly, NPPt(IV) exhibited a prominent inhibitory effect on CD133+ lung cancer stem cells (CSCs) and suppressed tumor growth in vivo. Unlike cisplatin treatment which eventually enriches CSCs, NPPt(IV) treatment prevents the accumulation of CD133+ lung CSCs in tumors. Therefore, NPPt(IV) simutaneously targeting CSCs and non-CSCs might represent a superior strategy to improve conventional anticancer therapy directed predominantly to tumor bulk populations.

Tumor acidity-sensitive linkage-bridged block copolymer for therapeutic siRNA delivery.

The design of ideal nanoparticle delivery systems should be capable of meeting the requirements of several stages of drug delivery, including prolonged circulation, enhanced accumulation and penetration in the tumor, facilitated cellular internalization and rapid release of the active drug in the tumor cells. However, among the current design strategies, meeting the requirements of one stage often conflicts with the other. Herein, a tumor pH-labile linkage-bridged block copolymer of poly(ethylene glycol) with poly(lacide-co-glycolide) (PEG-Dlinkm-PLGA) was used for siRNA delivery to fulfill all aforementioned requirements of these delivery stages. The obtained siRNA-encapsulating PEG-Dlinkm-PLGA nanoparticle gained efficiently prolonged circulation in the blood and preferential accumulation in tumor sites via the PEGylation. Furthermore, the PEG surface layer was detached in response to the tumor acidic microenvironment to facilitate cellular uptake, and the siRNA was rapidly released within tumor cells due to the hydrophobic PLGA layer. Hence, PEG-Dlinkm-PLGA nanoparticles met the requirements of several stages of drug delivery, and resulted in the enhanced therapeutic effect of the nanoparticular delivery systems.

Three-Dimensional Nanofiber Hybrid Scaffold Directs and Enhances Axonal Regeneration after Spinal Cord Injury.

Spinal cord injuries (SCIs) are followed by a complex series of events that contribute to the failure of regeneration. To date, there is no robust treatment that can restore the injury-induced loss of function. Since damaged spinal axons do not spontaneously regenerate in their native inhibitory microenvironment, a combined application of biomaterials and neurotrophic factors that induce nerve regeneration emerges as an attractive treatment for SCIs. In this study, we report the novel use of a three-dimensional (3D) hybrid scaffold to provide contact guidance for regrowth of axons in vivo. The scaffold comprises 3D aligned sparsely distributed poly(ε-caprolactone-co-ethyl ethylene phosphate) nanofibers that are supported and dispersed within a collagen hydrogel. Neurotrophin-3 was incorporated into the scaffold as an additional biochemical signal. To evaluate the efficacy of the scaffold in supporting nerve regeneration after SCIs, the construct was implanted into an incision injury, which was created at level C5 in the rat spinal cord. After 3 months of implantation, scaffolds with NT-3 incorporation showed the highest average neurite length (391.9 ± 12.9 µm, p ≤ 0.001) as compared to all the other experimental groups. In addition, these regenerated axons formed along the direction of the aligned nanofibers, regardless of their orientation. Moreover, the presence of the hybrid scaffolds did not affect tissue scarring and inflammatory reaction. Taken together, these findings demonstrate that our scaffold design can serve as a potential platform to support axonal regeneration following SCIs.

Overcoming tumor resistance to cisplatin by cationic lipid-assisted prodrug nanoparticles.

Chemotherapy resistance has become a major challenge in the clinical treatment of lung cancer which is the leading cancer type for the estimated deaths. Recent studies have shown that nanoparticles as drug carriers can raise intracellular drug concentration by achieving effectively cellular uptake and rapid drug release, and therefore reverse the acquired chemoresistance of tumors. In this context, nanoparticles-based chemotherapy represents a promising strategy for treating malignancies with chemoresistance. In the present study, we developed cationic lipid assisted nanoparticles (CLAN) to deliver polylactide-cisplatin prodrugs to drug resistant lung cancer cells. The nanoparticles were formulated through self-assembly of a biodegradable poly(ethylene glycol)-block-poly(lactide) (PEG-PLA), a hydrophobic polylactide-cisplatin prodrug, and a cationic lipid. The cationic nanoparticles were proven to significantly improve cell uptake of cisplatin, leading to an increased DNA-Pt adduct and significantly promoted DNA damage in vitro. Moreover, our study reveals that cationic nanoparticles, although are slightly inferior in blood circulation and tumor accumulation, are more effective in blood vessel extravasation. The CLANs ultimately enhances the cellular drug availability and leads to the reversal of cisplatin resistance.

Delivery of mitogen-activated protein kinase inhibitor for hepatocellular carcinoma stem cell therapy.

Hepatocellular carcinoma (HCC) is one of the most common malignant human tumors worldwide, but no effective therapeutic options are currently available. The cancer stem cell (CSC) has proven to play a central role in the development, metastasis, and recurrence of HCC. In this study, we report a dual functional mitogen-activated protein kinase inhibitor (U0126)-based therapy for treating both bulk HCC and HCC CSCs, using poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) nanoparticles as the drug carrier. It is demonstrated that nanoparticle encapsulation enhanced the cell uptake of U0126 in HCC CSCs and that enhanced endocytosis lead to augmented cytotoxicity of U0126 in HCC CSCs. Moreover, the nanoparticle encapsulation increased the inhibition of self-renewal capability, prolonged the circulation time, and increased the tumor accumulation of U0126 when compared with the use of the free inhibitor. The systemic delivery of U0126 remarkably enhanced the suppression of tumor development with decreased CSCs in the HepG2 xenograft simultaneously with reduced systemic toxicity.

Redox-Responsive Polyphosphoester-Based Micellar Nanomedicines for Overriding Chemoresistance in Breast Cancer Cells.

Multidrug resistance (MDR) has been recognized as a key factor contributing to the failure of chemotherapy for cancer in the clinic, often due to insufficient delivery of anticancer drugs to target cells. For addressing this issue, a redox-responsive polyphosphoester-based micellar nanomedicine, which can be triggered to release transported drugs in tumor cells, has been developed. The micelles are composed of diblock copolymers with a hydrophilic PEG block and a hydrophobic polyphosphoester (PPE) block bearing a disulfide bond in a side group. After incubating the redox-responsive micelles with drug-resistant tumor cells, the intracellular accumulation and retention of DOX were significantly enhanced. Moreover, after internalization by MDR cancer cells, the disulfide bond in the side group was cleaved by the high intracellular glutathione levels, resulting in a hydrophobic to hydrophilic transition of the PPE block and subsequent disassembly of the micelles. Thus, the encapsulated DOX was rapidly released, and abrogation of drug resistance in the cancer cells was observed in vitro. Moreover, the DOX-loaded redox-responsive micelles exhibited significantly enhanced inhibition of tumor growth in nude mice bearing MCF-7/ADR xenograft tumors via tail vein injection, indicating that such micelles have great potential in overcoming MDR for cancer therapy.

A block copolymer of zwitterionic polyphosphoester and polylactic acid for drug delivery.

Polymeric nanoparticles have been widely used as nano-drug delivery systems in preclinical and clinical trials for cancer therapy, and these systems usually need to be sterically stabilized by poly(ethylene glycol) (PEG) to maintain stability and avoid rapid clearance by the immune system. Recently, zwitterionic materials have been demonstrated to be potential alternatives to the classic PEG. Herein, we developed two drug delivery systems stabilized by zwitterionic polyphosphoesters. These nanoparticles showed favourable stability and anti-protein absorption ability in vitro. Meanwhile, as drug carriers, these zwitterionic polyphosphoester-stabilized nanoparticles significantly prolonged drug circulation half-lives and increased drug accumulation in tumors, which was comparable to PEG-stabilized nanoparticles. Systemic delivery of doxorubicin (DOX) by zwitterionic polyphosphoester-stabilized nanoparticles significantly inhibited tumor growth in a MDA-MB-231 tumor model, suggesting the potential of zwitterionic polyphosphoester-based nanoparticles in anticancer drug delivery.

Co-delivery of platinum drug and siNotch1 with micelleplex for enhanced hepatocellular carcinoma therapy.

As part of HCC tumor cellularity, cancer stem cells (CSCs) are considered a major obstacle to eradicate hepatocellular carcinoma (HCC), which is the third most common cause of cancer-related death worldwide, and the accumulation of chemotherapeutic drug-resistant CSCs invariably accounts for poor prognosis and HCC relapse. In the present study, we explored the efficacy of co-delivery of platinum drug and siRNA targeting Notch1 to treat CSCs-harboring HCC. To overcome the challenging obstacles of platinum drug and siRNA in the systemic administration, we developed a micellar nanoparticle (MNP) to deliver platinum(IV) prodrug and siNotch1, hereafter referred to as (Pt(IV))MNP/siNotch1. We demonstrated that (Pt(IV))MNP/siNotch1 was able to efficiently deliver two drugs into both non-CSCs and CSCs of SMMC7721, a HCC cell line. We further found that siRNA-mediated inhibition of Notch1 suppression can increase the sensitivity of HCC cells to platinum drugs and decrease the percentage of HCC CSCs, and consequently resulting in enhanced proliferation inhibition and apoptosis induction in HCC cells in vitro. Moreover, our results indicated that the combined drug delivery system can remarkably augment drug enrichment in tumor tissues, substantially suppressing the tumor growth while avoiding the accumulation of CSCs in a synergistic manner in the SMMC7721 xenograft model.

Regulating the surface poly(ethylene glycol) density of polymeric nanoparticles and evaluating its role in drug delivery in vivo.

Poly(ethylene glycol) (PEG) is usually used to protect nanoparticles from rapid clearance in blood. The effects are highly dependent on the surface PEG density of nanoparticles. However, there lacks a detailed and informative study in PEG density and in vivo drug delivery due to the critical techniques to precisely control the surface PEG density when maintaining other nano-properties. Here, we regulated the polymeric nanoparticles' size and surface PEG density by incorporating poly(ε-caprolactone) (PCL) homopolymer into poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) and adjusting the mass ratio of PCL to PEG-PCL during the nanoparticles preparation. We further developed a library of polymeric nanoparticles with different but controllable sizes and surface PEG densities by changing the molecular weight of the PCL block in PEG-PCL and tuning the molar ratio of repeating units of PCL (CL) to that of PEG (EG). We thus obtained a group of nanoparticles with variable surface PEG densities but with other nano-properties identical, and investigated the effects of surface PEG densities on the biological behaviors of nanoparticles in mice. We found that, high surface PEG density made the nanoparticles resistant to absorption of serum protein and uptake by macrophages, leading to a greater accumulation of nanoparticles in tumor tissue, which recuperated the defects of decreased internalization by tumor cells, resulting in superior antitumor efficacy when carrying docetaxel.

Doxorubicin conjugate of poly(ethylene glycol)-block-polyphosphoester for cancer therapy.

Polyphosphoesters with repeating phosphoester linkages in the backbone can be easily functionalized, are biodegradable and potentially biocompatible, and may be potential candidates as polymer carriers of drug conjugates. Here, the efficacy of a polyphosphoester drug conjugate as an anticancer agent in vivo is assessed for the first time. With controlled synthesis, doxorubicin conjugated to poly(ethylene glycol)-block-polyphosphoester (PPEH-DOX) via labile hydrazone bonds form spherical nanoparticles in aqueous solution with an average diameter of ≈60 nm. These nanoparticles are effectively internalized by MDA-MB-231 breast cancer cells and release the conjugated doxorubicin in response to the intracellular pH of endosomes and lysosomes, resulting in significant antiproliferative activity in cancer cells. Compared with free doxorubicin injection, PPEH-DOX injection exhibits much longer circulation behavior in the plasma of mice and leads to enhanced drug accumulation in tumor cells. In an MDA-MB-231 xenograft murine model, inhibition of tumor growth with systemic delivery of PPEH-DOX nanoparticles is more pronounced compared with free doxorubicin injection, suggesting the potential of polyphosphoesters as carriers of drug conjugates in cancer therapy.

Effect of hydrophobicity of core on the anticancer efficiency of micelles as drug delivery carriers.

Recently, micelles, which are self-assembled by amphiphilic copolymers, have attracted tremendous attention as promising drug delivery systems for cancer treatment. Thus, the hydrophobic core of the micelles, which could efficiently encapsulate small molecular drug, will play a significant role for the anticancer efficiency. Unfortunately, the effect of hydrophobicity of micellar core on its anticancer efficiency was rarely reported. Herein, the amphiphilic diblock polymers of poly(ethylene glycol) and polyphosphoester with different side groups (butyl, hexyl, octyl) were synthesized to tune the hydrophobicity of the micellar core. We found that the in vitro cytotoxicity of the DOX-loaded micelles decreased with the increasing hydrophobicity of micellar core due to the drug release rate. However, following systemic delivery, the DOX-loaded micelles with the most hydrophobic core exhibited the most significant inhibition of tumor growth in a MDA-MB-231 tumor model, indicating the importance of hydrophobicity of core on the antitumor efficacy of drug delivery systems.