Synergistic Chemotherapy Research Articles

ROS-driven supramolecular nanoparticles exhibiting efficient drug delivery for chemo/Chemodynamic combination therapy for Cancer treatment

Drug-based supramolecular self-assembling delivery systems have enhanced the bioavailability of chemotherapeutic drugs and reduced systemic side effects; however, improving the delivery efficiency and responsive release ability of these systems remains challenging. This study focuses primarily on the utilization of per-6-thio-β-cyclodextrin (CD) to link a significant quantity of paclitaxel (PTX) via ROS-sensitive thioketal (TK) linkages (designated as CDTP), thereby allowing efficiently drug release when exposed to high levels of reactive oxygen species (ROS) in the tumor microenvironment. To construct these supramolecular nanoparticles (NPs) with CDTP, we introduced PEGylated ferrocene (Fc) through host-guest interactions. The intracellular hydrogen peroxide (H2O2) is converted into hydroxyl radicals (•OH) through the Fc-catalyzed Fenton reaction. Additionally, the generated Fc+ consumes the antioxidant glutathione (GSH). In both in vivo and in vitro experiments, CDTP@Fc-PEG NPs were absorbed effectively by tumor cells, which increased levels of ROS and decreased levels of GSH, disrupting the redox balance of cancer cells and increasing their sensitivity to chemotherapy. Furthermore, CDTP@Fc-PEG NPs exhibited high tumor accumulation and cytotoxicity without causing significant toxicity to healthy organs. Collectively, our results suggest CDTP@Fc-PEG NPs as a promising supramolecular nano-delivery platform for high drug-loading of PTX and synergistic chemotherapy.

Engineering of smart nanostructured lipid carriers encapsulated in gold nanocomposites and camptothecin for synergistic photothermal and chemotherapy treatment of ovarian cancer

Engineering of smart nanostructured lipid carriers encapsulated in gold nanocomposites and camptothecin for synergistic photothermal and chemotherapy treatment of ovarian cancer

Three-in-One Peptide Prodrug with Targeting, Assembly and Release Properties for Overcoming Bacterium-Induced Drug Resistance and Potentiating Anti-Cancer Immune Response.

The presence of bacteria in tumor results in chemotherapeutic drug resistance and weakens the immune response in colorectal cancer. To overcome bacterium-induced chemotherapeutic drug resistance and potentiate antitumor immunity, herein a novel molecule Biotin-Lys(SA-Cip-OH)-Lys(SA-CPT)-Phe-Phe-Nap (Biotin-Cip-CPT-Nap) is rationally designed containing four functional motifs (i.e., a biotin motif for targeting, Phe-Phe(-Nap) motif for self-assembly, ciprofloxacin derivative (Cip-OH) motif for antibacterial effect, and camptothecin (CPT) motif for chemotherapy). Using the designed molecule, a novel strategy of intracellular enzymatic nanofiber formation and synergistic antibacterium-enhanced chemotherapy and immunotherapy is achieved. Under endocytosis mediated by highly expressed biotin receptor in colorectal cancer cell membrane and the catalysis of highly expressed carboxylesterase in the cytoplasm, this novel molecule can be transformed into Biotin-Nap, which self-assembled into nanofibers. Meanwhile, antibiotic Cip-OH and chemotherapeutic drug CPT are released, overcoming bacterium-induced drug resistance and enhancing the therapeutic efficacy of immunotherapy towards colorectal cancer. This work offers a feasible strategy for the design of novel multifunctional prodrugs to improve the efficiency of colorectal cancer treatment.

Analysis of Anti-Cancer Effects in Grapefruit-based Drug Development: A Narrative Review

Abstract: Cancer remains a significant global health concern, and natural compounds found in fruits and vegetables have shown potential anti-cancer effects. Grapefruit (Citrus paradisi) has gained attention due to its rich phytochemical composition and biological activities, including anti-cancer properties. This narrative review analyzes the literature on grapefruit-based drug development and its potential as an adjunctive or alternative therapeutic strategy for cancer treatment. Grapefruit-derived compounds have been extensively studied for their anti-cancer effects, with preclinical studies showing promising outcomes in inhibiting cancer cell growth and proliferation. Compounds made from grapefruit also have anti-cancer effects. They do this in a number of ways, such as by affecting the cell cycle, apoptosis, angiogenesis, metastasis, and key signalling pathways. Petrified grapefruit compounds have potential synergistic effects with conventional chemotherapy drugs, enhancing cytotoxic effects while reducing adverse side effects. They have shown promising results in overcoming drug resistance, a major obstacle in cancer treatment. However, challenges such as bioavailability, drug interactions, and variability in compound composition remain. Overall, grapefruit-derived compounds possess significant anti-cancer properties and warrant further investigation for clinical application.

GSH-activable heterotrimeric nano-prodrug for precise synergistic therapy of TNBC

Combination chemotherapy is an effective approach for triple-negative breast cancer (TNBC) therapy, especially when drugs are administered at specific optimal ratios. However, at present, strategies involving precise and controllable ratios based on effective loading and release of drugs are unavailable. Herein, we designed and synthesized a glutathione (GSH)--responsive heterotrimeric prodrug and formulated it with an amphiphilic polymer to obtain nanoparticles (DSSC2 NPs) for precise synergistic chemotherapy of TNBC. The heterotrimeric prodrug was prepared using docetaxel (DTX) and curcumin (CUR) at the optimal synergistic ratio of 1: 2. DTX and CUR were covalently conjugated by disulfide linkers. Compared with control NPs, DSSC2 NPs had quantitative/ratiometric drug loading, high drug co-loading capacity, better colloidal stability, and less premature drug leakage. After systemic administration, DSSC2 NPs selectively accumulated in tumor tissues and released the encapsulated drugs triggered by high levels of GSH in cancer cells. In vitro and in vivo experiments validated that DSSC2 NPs released DTX and CUR at the predefined ratio and had a highly synergistic therapeutic effect on tumor suppression in TNBC, which can be attributed to ratiometric drug delivery and synchronous drug activation. Altogether, the heterotrimeric prodrug delivery system developed in this study represents an effective and novel approach for combination chemotherapy.

A Targeted and Responsive Nanoprodrug Delivery System for Synergistic Glioma Chemotherapy.

Doxorubicin (DOX) is widely used as a chemotherapeutic agent for both hematologic and solid tumors and is a reasonable candidate for glioma treatment. However, its effectiveness is hindered by significant toxicity and drug resistance. Moreover, the presence of the blood-brain barrier (BBB) brings a crucial challenge to glioma therapy. In response, a GSH-responsive and actively targeted nanoprodrug delivery system (cRGD/PSDOX-Cur@NPs) are developed. In this system, a disulfide bond-bridged DOX prodrug (PEG-SS-DOX) is designed to release specifically in the high glutathione (GSH) tumor environment, markedly reducing the cardiotoxicity associated with DOX. To further address DOX resistance, curcumin, serving as a P-glycoprotein (P-gp) inhibitor, effectively increased cellular DOX concentration. Consequently, cRGD/PSDOX-Cur@NPs exhibited synergistic anti-tumor effects in vitro. Furthermore, in vivo experiments validated the superior BBB penetration and brain-targeting abilities of cRGD/PSDOX-Cur@NPs, showcasing the remarkable potential for treating both subcutaneous and orthotopic gliomas. This research underscores that this nanoprodrug delivery system presents a novel approach to inhibiting glioma while addressing resistance and systemic toxicity.

A Ferroptosis-Inducing Arsenene-Iridium Nanoplatform for Synergistic Immunotherapy in Pancreatic Cancer.

Due to multidrug resistance and the high risk of recurrence, effective and less toxic alternative pancreatic cancer treatments are urgently needed. Pancreatic cancer cells are highly resistant to apoptosis but sensitive to ferroptosis. In this study, an innovative nanoplatform (AsIr@PDA) was developed by electrostatic adsorption of a cationic iridium complex (IrFN) onto two-dimensional (2D) arsenene nanosheets. This nanoplatform exhibits superior ferroptosis-inducing effects with high drug loading capacity and, importantly, excellent anti-cancer immune activation function, leading to efficient elimination of pancreatic tumors with no observable side effects. Interestingly, AsIr@PDA significantly prevents the recurrence of pancreatic cancer in vivo when compared with a cisplatin-loaded nanoplatform. This designed nanoplatform demonstrated superior therapeutic efficacy by synergistic ferroptosis-induced chemotherapy with immunotherapy via an all-in-one strategy, providing new insights for future pancreatic cancer therapy.

A Novel Activatable Nanoradiosensitizer for Second Near-Infrared Fluorescence Imaging-Guided Safe-Dose Synergetic Chemo-Radiotherapy of Rheumatoid Arthritis.

The precise theranostics of rheumatoid arthritis (RA) remains a formidable challenge in clinical practice. Exploring novel applications of contemporary therapeutic approaches like chemo-radiotherapy is promising as a highly effective strategy for RA. Herein, a novel activatable nanoradiosensitizer-40 (denoted as IRnR-40) is developed, based on encapsulating the clinically approved drugs cisplatin (DDP) and indocyanine green (ICG) within a gelatin shell to achieve second near-infrared fluorescence (NIR-II FL) imaging-guided safe-dose synergetic chemo-radiotherapy. The high concentration of matrix metalloproteinase-9 (MMP-9) in the RA microenvironment plays a pivotal role in triggering the responsive degradation of IRnR-40, leading to the rapid release of functional molecules DDP and ICG. The released ICG serves the dual purpose of illuminating the inflamed joints to facilitate accurate target volume delineation for guiding radiotherapy, as well as acting as a real-time reporter for quantifying the release of DDP to monitor efficacy. Meanwhile, the released DDP achieves highly effective synergistic chemotherapy and radiosensitization for RA via the dual reactive oxygen species (ROS)-mediated mitochondrial apoptotic pathway. To sum up, this activatable nanoradiosensitizer IRnR-40 is believed to be the first attempt to achieve efficient NIR-II FL imaging-guided safe-dose chemo-radiotherapy for RA, which provides a new paradigm for precise theranostics of refractory benign diseases.

PH-Responsive, Self-Assembled Ruthenium Nanodrug: Dual Impact on Lysosomes and DNA for Synergistic Chemotherapy and Immunogenic Cell Death.

Several DNA-damaging antitumor agents, including ruthenium complexes, induce immunogenic cell death (ICD). In this study, an arginyl-glycyl-aspartic acid (RGD) peptide-modified carboline ruthenium complex (KS-Ru) is synthesized as a chemotherapeutic nanodrug and an ICD inducer. The RGD peptide, an integrin ligand, provides tumor-specific targeting and promotes self-assembly of the KS-Ru complex. The pH-responsive self-assembly is assessed through transmission and scanning electron microscopy. Additionally, in vitro cytotoxic activity and anti-metastasis ability are evaluated using MTT and Transwell assays, respectively, along with cellular immunofluorescence staining and imaging flow cytometry. The ability of the complex to inhibit primary tumor formation and lung metastasis in vivo is evaluated using Lewis lung cancer and A549 xenograft models. Furthermore, the tumor immune microenvironment is evaluated using single-cell flow mass cytometry. KS-Ru translocates to the nucleus, causing DNA damage and inducing ICD. Within the lysosomes, KS-Ru self-assembled into nanoflowers, leading to lysosomal swelling and apoptosis. Notably, the as-synthesized pH-dependent ruthenium nanomedicine achieves dual functionality-chemotherapy and immunotherapy. Moreover, the pH-responsive self-assembly of KS-Ru enables simultaneous mechanisms in the lysosome and nucleus, thereby lowering the likelihood of drug resistance. This study provides valuable insight for the design of novel ruthenium-based nanoantitumor drugs.

Sorafenib-Encapsulated Liposomes to Activate Hypoxia-Sensitive Tirapazamine for Synergistic Chemotherapy of Hepatocellular Carcinoma.

Combination therapy with the synergistic effect is an effective way in cancer chemotherapy. Herein, an antiangiogenic sorafenib (SOR) and hypoxia-activated prodrug tirapazamine (TPZ)-coencapsulated liposome (LipTPZ/SOR) is prepared for chemotherapy of hepatocellular carcinoma (HCC). SOR is a multi-target tyrosine kinase inhibitor that can inhibit tumor cell proliferation and angiogenesis. The antiangiogenesis effect of SOR can reduce oxygen supply and aggravate tumor hypoxia, which is able to activate hypoxia-sensitive prodrug TPZ, exhibiting the synergistic antitumor effect. LipTPZ/SOR at different molar ratios of TPZ and SOR can significantly inhibit the proliferation of hepatocellular carcinoma cells. The mole ratio of TPZ and SOR was optimized to 2:1, which exhibited the best synergetic antitumor effect. The synergistic antitumor mechanism of SOR and TPZ was also investigated in vivo. After treated with SOR, the number of vessels was decreased, and the degree of hypoxia was aggravated in tumor tissues. What is more, in the presence of SOR, TPZ could be activated to inhibit tumor growth. The combination of TPZ and SOR exhibited an excellent synergistic antitumor effect. This research not only provides an innovative strategy to aggravate tumor hypoxia to promote TPZ activation but also paints a blueprint about a new nanochemotherapy regimen for the synergistic chemotherapy of HCC, which has excellent biosafety and bright clinical application prospects.

Oxygen-supplying ROS-responsive prodrug for synergistic chemotherapy and photodynamic therapy of colon cancer.

Introduction: The synergistic treatment of chemotherapy and photodynamic therapy (PDT) has remarkable potential in cancer therapy. However, challenges remain, such as unstable chemotherapeutic drug release, suboptimal targeting, and reduced efficacy of PDT under hypoxic conditions commonly found in solid tumors. Methods: To address these issues, we use camptothecin (CPT) and pheophorbide a (Pa) incorporated through the functional thioketal, which serves as the reactive oxygen species (ROS)-responsive trigger, to construct a ROS-responsive prodrug (CPT-TK-Pa). Subsequently, we co-loaded it with a platinum nanozyme (PtNP) in distearylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) to obtain the ROS-responsive prodrug nanoparticle (CPT-TK-Pa/Pt NP). Results and Discussion: Specifically, the incorporated PtNP within CPT-TK-Pa/Pt NP positively catalyzes the conversion of hydrogen peroxide (H2O2) to oxygen, thereby ameliorating the hypoxic state of the tumor. This enhanced oxygen generation could replenish the oxygen that is consumed by Pa during 660nm exposure, enabling controlled CPT release and amplifying the photodynamic response. In vitro investigations reveal the potency of CPT-TK-Pa/Pt NPs in inhibiting colon tumor cells. Given its ROS-responsive release mechanism and enhanced PDT efficacy, CPT-TK-Pa/Pt NP has the potential to be a promising candidate for cancer therapy.

Thiol responsive 6-thioguanine delivery using fluorescent gold nanoconjugate for synergistic oxidative stress amplification and chemotherapy: A combinatorial approach in cancer management

The FDA-approved purine analog 6-thioguanine (6-TG) has shown unsatisfactory therapeutic effects in solid cancers due to poor solubility and bioavailability. In this study, an efficient thiol-based drug delivery platform is developed by conjugating 6-TG to BSA stabilized gold nanocluster (AuNC@BSA-TG) in a facile one-pot synthesis approach by fine-tuning of 6-TG to albumin concentration for maximum drug loading but without compromising the inherent fluorescent properties of gold nanoclusters. AuNC@BSA-TG nanoconjugate has a size of ∼3.3 ± 0.76 nm and exhibits ∼60 % 6-TG conjugation efficiency. The release of 6-TG depends on cellular thiols, with ∼90 % release within 24 h in the presence of 10 mM GSH at pH 7.4, mimicking the cytosol-reducing environment in cancer cells. The nanoconjugate also exhibits synergistic amplification of oxidative stress through GSH depletion and peroxidase mimetic (POD-mimetic) activity. Cytotoxicity analysis reveals an approximately 50 % reduction in IC50 values for AuNC@BSA-TG compared to free 6-TG for HCT116 and A549 cells exhibiting KRAS mutation. Interestingly, KRAS wild-type HEK293T cells showed minimal toxicity to AuNC@BSA-TG under similar conditions. This combinatorial approach subsequently produces overwhelming oxidative stress due to simultaneous intracellular GSH depletion and POD-mimetic activity to generate high ROS levels, which subsequently initiates DNA breakdown and activation of the Caspase 3/7 cascade, leading to apoptotic cell death, thereby potentiating the chemotherapeutic efficacy of 6-TG. Notably, to the best of our knowledge, this is the first attempt to develop a protein-stabilized fluorescent theranostic nanosystem for synergistic oxidative stress amplification and 6-TG-based chemotherapy in treating and managing challenging KRAS-mutated cancers.

Red blood cell membrane-coated functionalized Cu-doped metal organic framework nanoformulations as a biomimetic platform for improved chemo-/chemodynamic/photothermal synergistic therapy

Nanoformulations for combining chemotherapy, chemodynamic therapy, and photothermal therapy have enormous potential in tumor treatment. Coating nanoformulations with cell membranes endows them with homologous cellular mimicry, enabling nanoformulations to acquire new functions and properties, including homologous targeting and long circulation in vivo, and can enhance internalization by homologous cancer cells. Herein, we fused multifunctional biomimetic nanoformulations based on Cu-doped zeolitic imidazolate framework-8 (ZIF-8). Hydroxycamptothecin (HCPT), a clinical anti-tumor drug, was encapsulated into ZIF-8, which was subsequently coated with polydopamine (PDA) and red blood cell membrane. The as-fabricated biomimetic nanoformulations showed an enhanced cell uptake in vitro and the potential to prolong blood circulation in vivo, producing effective synergistic chemotherapy, chemodynamic therapy, and photothermal therapy under the 808 nm laser irradiation. Together, the biomimetic nanoformulations showed a prolonged blood circulation and evasion of immune recognition in vivo to provide a bio-inspired strategy which may have the potential for the multi-synergistic therapy of breast cancer.

Hypoxia and Singlet Oxygen Dual-Responsive Micelles for Photodynamic and Chemotherapy Therapy Featured with Enhanced Cellular Uptake and Triggered Cargo Delivery.

Combination therapy provides better outcomes than a single therapy and becomes an efficient strategy for cancer treatment. In this study, we designed a hypoxia- and singlet oxygen-responsive polymeric micelles which contain azo and nitroimidazole groups for enhanced cellular uptake, repaid cargo release, and codelivery of photosensitizer Ce6 and hypoxia-activated prodrug tirapazamine TPZ (DHM-Ce6@TPZ), which could be used for combining Ce6-mediated photodynamic therapy (PDT) and PDT-activated chemotherapy to enhance the therapy effect of cancer. The hypoxia- and singlet oxygen-responsive polymeric micelles DHM-Ce6@TPZ were prepared by film hydration method. The morphology, physicochemical properties, stimuli responsiveness, in vitro singlet oxygen production, cellular uptake, and cell viability were evaluated. In addition, the in vivo therapeutic effects of the micelles were verified using a tumor xenograft mice model. The resulting dual-responsive micelles not only increased the concentration of intracellular photosensitizer and TPZ, but also facilitated photosensitizer and TPZ release for enhanced integration of photodynamic and chemotherapy therapy. As a photosensitizer, Ce6 induced PDT by generating toxic singlet reactive oxygen species (ROS), resulting in a hypoxic tumor environment to activate the prodrug TPZ to achieve efficient chemotherapy, thereby evoking a synergistic photodynamic and chemotherapy therapeutic effect. The cascade synergistic therapeutic effect of DHM-Ce6@TPZ was effectively evaluated both in vitro and in vivo to inhibit tumor growth in a breast cancer mice model. The designed multifunctional micellar nano platform could be a convenient and powerful vehicle for the efficient co-delivery of photosensitizers and chemical drugs for enhanced synergistic photodynamic and chemotherapy therapeutic effect of cancer.

Metal-polyphenol network coated photothermal nanocarriers for pH-activated drug delivery

The combination of photothermal and chemotherapy is a promising strategy for the synergistic inhibition of tumor cells. By exploiting the tumor microenvironment, chemotherapeutic drugs can target the tumor site, thereby enhancing their efficacy. This study focused on the development of nanodrugs, aiming to harness the synergistic photothermal and chemotherapy capabilities for enhanced anti-tumor effects. The core material was made of copper sulfide (CuS), which possesses photothermal conversion properties, while doxorubicin (DOX) was loaded on mesoporous polydopamine (MPDA). The drug-loaded nanoparticles were then encapsulated in acid-sensitive tannic acid and an Fe complex (TA-Fe). The photothermal conversion properties, drug loading, and release of DOX from CuS-MPDA-DOX@TA-Fe were then investigated. The results showed that DOX had an encapsulation ratio of 82.2 % and a release ratio of 43.49 % in an acidic environment (pH 5.2). In vitro studies showed that CuS-MPDA-DOX@TA-Fe triggered by NIR effectively inhibited tumor cell proliferation and that the tumor cells showed suitable levels of nanoparticle uptake. The results thus show that CuS-MPDA-DOX@TA-Fe nanodrugs could be utilized as a promising therapeutic strategy for cancer treatment with synergistic photothermal/chemotherapeutic anti-tumor effects.

Sorafenib and tetrakis (4-carboxyphenyl) porphyrin assembled nanoparticles for synergistic targeted chemotherapy and sonodynamic therapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is characterized by a high degree of malignancy and mortality. Sorafenib (SOR), a multi-kinase inhibitor, is clinically used in the treatment of HCC. However, SOR suffers from serious side effects and drug resistance. The development of novel therapeutic strategies for HCC therapy is urgently needed. Sonodynamic therapy (SDT) has unique advantages in treating deep tumors due to the merits of deep tissue penetration, low side effects, and the absence of drug resistance. Here, we developed multifunctional nanoparticles (NPs) termed SOR-TCPP@PEG-FA by assembling SOR, tetrakis (4-carboxyphenyl) porphyrin (TCPP), and folic acid (FA)-modified DSPE-PEG. The FA group enhances the tumor targeting capability of these NPs, while TCPP generates ROS under ultrasound (US) irradiation, which are toxic to tumor cells, and SOR with chemotherapeutic effects is released, thus realizing the synergistic SDT and chemotherapy of tumors.

A Multifunctional Liposome for Synergistic Chemotherapy with Ferroptosis Activation of Triple-Negative Breast Cancer.

There is an urgent need to develop efficient treatments for highly invasive triple-negative breast cancer (TNBC) with a high rate of postoperative. Baicalin (BA) has shown inhibitory effects on several tumor cells and could activate ferroptosis in some tumor cells by producing reactive oxygen species (ROS). For overcoming the shortcomings of BA in clinical applications and enhancing the effect of ferroptosis in TNBC, herein, a multifunctional liposome (BA-Fe(III) coordination-polymer-loaded liposome, BA-Fe(III) Lipo) was developed for synergistic chemotherapy of TNBC with ferroptosis activation. Fe(III) released from BA-Fe(III) Lipo could be efficiently reduced to Fe(II) in the presence of high glutathione in tumor microenvironment, which in turn catalyzed the oxidation of unsaturated fats through lipid peroxidation for more ROS production. In addition, BA-Fe(III) Lipo activated tumor cell ferroptosis by down-regulating the enzymatic activity of ferritin heavy chain 1 protein and glutathione peroxidase. This study provided a novel therapeutic strategy for the treatment of TNBC by ingeniously combining chemotherapy with the activation of ferroptosis, which presented potential clinical applications.

Combination of Oridonin and Chlorin e6 with the metal–organic frameworks MIL‐101‐NH2‐AL for tumor chemo‐photodynamic therapy

In this paper, a metal–organic skeleton material MIL‐101‐NH2‐AL was prepared for loading the chemotherapeutic drug Oridonin (Ori) and photosensitizer Chlorin e6 (Ce6). A drug delivery system for synergistic chemotherapy and photodynamic therapy was constructed. At the same time, we evaluated MIL‐101‐NH2‐AL as a drug therapy carrier, including drug loading, cytotoxicity, and safety, verified the photodynamic efficiency of MIL‐101‐NH2‐AL@Ori@Ce6 in vitro, and studied the ability of MIL‐101‐NH2‐AL@Ori@Ce6 cancer cells to produce reactive oxygen species, cell uptake, cytotoxicity, and so on. Experiments have confirmed that MIL‐101‐NH2‐AL, as a nano‐carrier, encapsulated Oridonin and Ce6, the combination of PDT and chemotherapy showed enhanced tumor inhibition and high biosafety. The killing effect on cells was caused by reactive oxygen species produced by photosensitizers and apoptosis of tumor cells induced by Oridonin. The drug delivery system demonstrates enormous potential for synergistic anti‐tumor effects of photodynamic and chemotherapy.

Advances in NIR-Responsive Natural Macromolecular Hydrogel Assembly Drugs for Cancer Treatment.

Cancer is a serious disease with an abnormal proliferation of organ tissues; it is characterized by malignant infiltration and growth that affects human life. Traditional cancer therapies such as resection, radiotherapy and chemotherapy have a low cure rate and often cause irreversible damage to the body. In recent years, since the traditional treatment of cancer is still very far from perfect, researchers have begun to focus on non-invasive near-infrared (NIR)-responsive natural macromolecular hydrogel assembly drugs (NIR-NMHADs). Due to their unique biocompatibility and extremely high drug encapsulation, coupling with the spatiotemporal controllability of NIR, synergistic photothermal therapy (PTT), photothermal therapy (PDT), chemotherapy (CT) and immunotherapy (IT) has created excellent effects and good prospects for cancer treatment. In addition, some emerging bioengineering technologies can also improve the effectiveness of drug delivery systems. This review will discuss the properties of NIR light, the NIR-functional hydrogels commonly used in current research, the cancer therapy corresponding to the materials encapsulated in them and the bioengineering technology that can assist drug delivery systems. The review provides a constructive reference for the optimization of NIR-NMHAD experimental ideas and its application to human body.

Development of Next Generation Antibody-Polymer-Drug Conjugates for Treatment of Multiple Myeloma

Background: Antibody-drug conjugates (ADCs) are an effective class of cancer therapeutics, but current ADCs face stability challenges, resulting in premature payload release and off-target toxicity. To overcome this, we developed a novel strategy using antibody-polymer-based drug conjugates (pADCs). Our pADCs have a number of advantages compared to currently FDA approved ADCs, including: 1) Increased drug payload without altering binding site numbers, ensuring maximum drug loading without affecting antigen and Fc binding; 2) Potential for synergistic immunotherapy and chemotherapy; 3) Improved pharmacokinetics and reduced immunogenicity with modification using water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, providing significant stealth effect; and 4) Enhanced stability under physiological conditions, reducing premature payload release and off-target toxicity. Panobinostat, a pan-HDAC (histone deacetylase) inhibitor, enhances CD38 expression and improves pADC efficiency against MM cells. Our hypothesis is that our pADC system induces strong cytotoxicity, further enhanced by panobinostat-induced CD38 upregulation, leading to more efficient treatment outcomes. Methods:mAbs decorated with cyclooctyne (DBCO) moieties in the hinge region were prepared in two steps: mAbs were reduced with tris(2-carboxyethyl)phosphine (TCEP), then thiol groups were capped with DBCO-PEG4-Mal. Azide-functionalized semitelechelic (ST) polymer-drug conjugates (ST-P-drug-N3) were synthesized via RAFT polymerization. Antibody-polymer-drug conjugates were prepared by CLICK chemistry. MM.1S and RPMI 8226 cell lines (ATCC) were used as the MM cell model. The cell internalization was revealed by confocal imaging. Primary MM cells were collected from the aspirate of eight patients with primary plasma cell leukemia and isolated via Ficoll centrifugation. CD38 upregulation was done by incubating with 10 or 25 nM panobinostat for 24 h and the apoptosis detection employed Annexin V and Propidium Iodide staining followed by flow cytometry analysis. Results: A series of CLICK-able mAbs and semitelechelic polymer-drug conjugates were synthesized. Among them, we firstly prepared Epirubicin (EPI)-based pADCs, such as DARA-P-EPI, ISA-P-EPI and DRO-P-EPI (Fig.1A). Unlike naked mAbs, pADCs can induce EPI concentration-dependent cytotoxicity. Surface calreticulin (CRT) was assessed and demonstrated the induction of EPI-dependent immunogenic cell death on MM.1S cells (Fig.1B). The pADC mechanism of action involves binding to cell surface antigens, internalization via endosomes, and subsequent cleavage of drugs at lysosomes by cathepsin B. This minimizes premature drug release and reduces off-target toxicity (Fig.1C). Ex vivo studies on patient MM cells revealed that pADCs induced significantly higher apoptosis compared to naked mAbs and free EPI, highlighting their efficacy (Fig.1D). CD38-based pADC's efficacy was enhanced by pretreatment with panobinostat (Fig.1F), which increased CD38 expression (Fig.1E). When incubating with NK cells and pADC, the number of target cells decreased significantly indicating the pADC preserve the original mAb ADCC functionality. Notably, co-treatment of RPMI8226 cells with anti-CD38 and GDC0980, a PI3k/mTOR inhibitor, significantly improved cytotoxicity, suggesting DARA's potential for chemo sensitization (Fig.1G). Conclusion: pADC's innovative design offers a high likelihood of successful clinical development and holds significant promise for MM therapy. Moreover, the unique mechanism provides potential to effectively overcome mAb and multiple drug resistance. Its facile nature allows for easy incorporation of multiple types of payloads into the ADC, making its synthesis highly scalable .