Postoperative Multimodal Analgesia Strategy for Enhanced Recovery After Surgery in Elderly Colorectal Cancer Patients.

Enhanced Recovery After Surgery (ERAS) protocols have substantially proven their merit in diminishing recuperation durations and mitigating postoperative adverse events in geriatric populations undergoing colorectal cancer procedures. Despite this, the pivotal aspect of postoperative pain control has not garnered the commensurate attention it deserves. Typically, employing a multimodal analgesia regimen that weaves together nonsteroidal anti-inflammatory drugs, opioids, local anesthetics, and nerve blocks stands paramount in curtailing surgical complications and facilitating reduced convalescence within hospital confines. Nevertheless, this integrative pain strategy is not devoid of pitfalls; the specter of organ dysfunction looms over the geriatric cohort, rooted in the abuse of analgesics or the complex interplay of polypharmacy. Revolutionary research is delving into alternative delivery and release modalities, seeking to allay the inadvertent consequences of analgesia and thereby potentially elevating postoperative outcomes for the elderly post-colorectal cancer surgery populace. This review examines the dual aspects of multimodal analgesia regimens by comparing their established benefits with potential limitations and offers insight into the evolving strategies of drug administration and release.

An infection-microenvironment-targeted and responsive peptide-drug nanosystem for sepsis emergency by suppressing infection and inflammation.

Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation. Nevertheless, current therapeutic regimens are inadequate to promptly address the vast diversity of potential pathogens. Omiganan, an antimicrobial peptide, has shown promise for neutralizing endotoxins and eliminating diverse pathogens. However, its clinical application is hindered by safety and stability concerns. Herein, we present a nanoscale drug delivery system (Omi-hyd-Dex@HA NPs) that selectively targets infectious microenvironments (IMEs) and responds to specific stimuli for efficient intervention in sepsis. The system consists of omiganan-dexamethasone conjugates linked by hydrazone bonds which self-assemble into nanoparticles coated with a hyaluronic acid (HA). The HA coating not only facilitates IMEs-targeting through interaction with intercellular-adhesion-molecule-1 on inflamed endotheliocytes, but also improves the biosafety of the nanosystem and enhances drug accumulation in primary infection sites triggered by hyaluronidase. The nanoparticles release dual drugs in IMEs through pH-sensitive cleavage of hydrazone bonds to eradicate pathogens and suppress inflammation. In multiple tissue infection and sepsis animal models, Omi-hyd-Dex@HA NPs exhibited rapid source control and comprehensive inflammation reduction, thereby preventing subsequent fatal complications and significantly improving survival outcomes. The bio-responsive and self-delivering nanosystem offers a promising strategy for systemic sepsis treatment in emergencies.

Rapid and Visual Detection of SARS-CoV-2 Using Multiplex Reverse Transcription Loop-Mediated Isothermal Amplification Linked With Gold Nanoparticle-Based Lateral Flow Biosensor.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that has caused the outbreak of coronavirus disease 2019 (COVID-19) all over the world. In the absence of appropriate antiviral drugs or vaccines, developing a simple, rapid, and reliable assay for SARS-CoV-2 is necessary for the prevention and control of the COVID-19 transmission. Methods: A novel molecular diagnosis technique, named multiplex reverse transcription loop-mediated isothermal amplification, that has been linked to a nanoparticle-based lateral flow biosensor (mRT-LAMP-LFB) was applied to detect SARS-CoV-2 based on the SARS-CoV-2 RdRp and N genes, and the mRT-LAMP products were analyzed using nanoparticle-based lateral flow biosensor. The mRT-LAMP-LFB amplification conditions, including the target RNA concentration, amplification temperature, and time were optimized. The sensitivity and specificity of the mRT-LAMP-LFB method were tested in the current study, and the mRT-LAMP-LFB assay was applied to detect the SARS-CoV-2 virus from clinical samples and artificial sputum samples. Results: The SARS-CoV-2 specific primers based on the RdRp and N genes were valid for the establishment of mRT-LAMP-LFB assay to detect the SARS-CoV-2 virus. The multiple-RT-LAMP amplification condition was optimized at 63°C for 30 min. The full process, including reaction preparation, viral RNA extraction, RT-LAMP, and product identification, could be achieved in 80 min. The limit of detection (LoD) of the mRT-LAMP-LFB technology was 20 copies per reaction. The specificity of mRT-LAMP-LFB detection was 100%, and no cross-reactions to other respiratory pathogens were observed. Conclusion: The mRT-LAMP-LFB technique developed in the current study is a simple, rapid, and reliable method with great specificity and sensitivity when it comes to identifying SARS-CoV-2 virus for prevention and control of the COVID-19 disease, especially in resource-constrained regions of the world.

Functional extracellular vesicles engineered with lipid-grafted hyaluronic acid effectively reverse cancer drug resistance.

Multidrug resistance (MDR) is a key issue accounting for ineffectiveness of cancer chemotherapy. Numerous multifunctional nanocarriers have been developed to increase drug delivery efficacy and inhibit drug efflux for overcoming cancer drug resistance. However, limited success has been achieved in clinic because of nanocarriers' complicated multi-step fabrication procedures and their undesired side toxicity as well as potential immunogenicity. Here, hyaluronic acid (HA) functionalized extracellular vesicles (EVs) are generated as natural vehicles to efficiently deliver doxorubicin (DOX) and reverse MDR. The EVs isolated from noncancerous HEK293T cells (hEVs) reduce P-glycoprotein (P-gp) expression in drug resistant MCF7/ADR cells. To acquire tumor-targeting capability, hEVs are modified with lipidomimetic chains-grafted HA (lipHA) by a simple incubation. Owing to CD44-mediated cancer-specific targeting and P-gp suppressive capability, the HA-functionalized hEVs (lipHA-hEVs) remarkably promote the intracellular DOX accumulation in drug resistant breast cancer cells. In preclinical MDR tumor models, lipHA-hEVs deeply penetrate into tumor tissue and effectively transport DOX into tumor local, while eliminating DOX's systemic toxicity. Importantly, DOX@lipHA-hEVs inhibited MDR tumor growth by 89% and extend animal survival time by approximately 50%. Thus, our engineered tumor-targeting hEVs are promising natural carriers for overcoming cancer MDR.

Redox-Responsive Dual Drug Delivery Nanosystem Suppresses Cancer Repopulation by Abrogating Doxorubicin-Promoted Cancer Stemness, Metastasis, and Drug Resistance.

Chemotherapy is a major therapeutic option for cancer patients. However, its effectiveness is challenged by chemodrugs' intrinsic pathological interactions with residual cancer cells. While inducing cancer cell death, chemodrugs enhance cancer stemness, invasiveness, and drug resistance of remaining cancer cells through upregulating cyclooxygenase-2/prostaglandin-E2 (COX-2/PGE2) signaling, therefore facilitating cancer repopulation and relapse. Toward tumor eradication, it is necessary to improve chemotherapy by abrogating these chemotherapy-induced effects. Herein, redox-responsive, celecoxib-modified mesoporous silica nanoparticles with poly(ß-cyclodextrin) wrapping (MSCPs) for sealing doxorubicin (DOX) are synthesized. Celecoxib, an FDA-approved COX-2 inhibitor, is employed as a structural and functional element to confer MSCPs with redox-responsiveness and COX-2/PGE2 inhibitory activity. MSCPs efficiently codeliver DOX and celecoxib into the tumor location, minimizing systemic toxicity. Importantly, through blocking chemotherapy-activated COX-2/PGE2 signaling, MSCPs drastically enhance DOX's antitumor activity by suppressing enhancement of cancer stemness and invasiveness as well as drug resistance induced by DOX-based chemotherapy in vitro. This is also remarkably achieved in three preclinical tumor models in vivo. DOX-loaded MSCPs effectively inhibit tumor repopulation by blocking COX-2/PGE2 signaling, which eliminates DOX-induced expansion of cancer stem-like cells, distant metastasis, and acquired drug resistance. Thus, this drug delivery nanosystem is capable of effectively suppressing tumor repopulation and has potential clinical translational value.

Synergized Multimodal Therapy for Safe and Effective Reversal of Cancer Multidrug Resistance Based on Low-Level Photothermal and Photodynamic Effects.

Despite the therapeutic usefulness of near-infrared irradiation (NIR)-induced potent photothermal effects (PTE) and photodynamic effects (PDE), they inevitably damage normal tissues, often posing threat to life when treating tumors adjacent to key organs or major blood vessels. In this study, the frequently overlooked, "weak" PTE and PDE (no killing capability) are employed to synergize chemotherapy against multidrug resistance (MDR) without impairing normal tissues. An NIR-responsive nanosystem, gold (Au)-nanodot-decorated hollow carbon nanospheres coated with hyaluronic acid, is synthesized as a doxorubicin (DOX) carrier with excellent photothermal and photodynamic properties. Upon low-level infrared irradiation, the mild heat of weak PTE moderately boosts DOX unloading, meanwhile the weak PDE moderately disturbs the P-glycoprotein function for retaining intracellular DOX by impairing mitochondrial ATP production. These two "moderate" alterations are quantitatively and functionally sufficient to augment the efficacy of chemotherapy in reversing MDR without damaging neighboring tissue. Thus, this work creates a gold-dot-decorated nanocarbon spheres based nanosystem for trimodal therapy, reveals the therapeutic value of the frequently ignored weak PTE/PDE, and demonstrates that synergizing with chemotherapy to overcome drug resistance does not necessarily require potent PTE/PDE.

Supramolecular Modular Approach toward Conveniently Constructing and Multifunctioning a pH/Redox Dual-Responsive Drug Delivery Nanoplatform for Improved Cancer Chemotherapy.

Because heterogeneity affects many functional aspects of a tumor, a way to overcome it is to arm nanosized drug delivery systems (nanoDDS) with diverse functions required to shatter heterogeneity. However, it remains technically challenging to fabricate a nanocarrier possessing all required functions. Here, we propose a modular strategy for generating a supramolecular, multifunctional, and stimuli-responsive nanoDDS through docking a parental core nanoDDS with various daughter function-prebuilt modules. Doxorubicin (DOX)-loaded mesoporous silica nanoparticles (MSNs) as the parental nanocore are wrapped by poly(ß-cyclodextrin) (PCD) as a gatekeeper through host-guest interactions between cyclodextrin units and pyridine groups of pyridine-disulfide bonds that confers pH/redox dual responsiveness, thus constructing stimuli-responsive nanoDDS (DOX@PRMSNs). Meanwhile, PCD's free cyclodextrin is tightly caged by adamantyl (Ad)-terminated daughter modules via host-guest interactions, achieving convenient multifunctionalization of this nanoDDS. DOX@PRMSNs rapidly released DOX in lysosomal pH/redox microenvironment, potently killing drug-resistant cancer cells. Further, three different types of Ad-terminated daughter modules, including two targeting ligands (Ad-PEG-FA and Ad-PEG-LA), a cationic polymer (Ad-PEI), and a fluorescence agent (Ad-FITC), are utilized to functionalize PRMSNs via cyclodextrin-Ad self-assembly, endowing the nanoDDS with cell-targeting capability, gene codelivery property, and imaging function. Thus, this work develops a supramolecular modular self-assembly approach for constructing and multifunctionalizing stimuli-responsive "smart" nanoDDSs.