Tailored core‒shell dual metal–organic frameworks as a versatile nanomotor for effective synergistic antitumor therapy

Malignant tumor has become an urgent threat to global public healthcare. Because of the heterogeneity of tumor, single therapy presents great limitations while synergistic therapy is arousing much attention, which shows desperate need of intelligent carrier for co-delivery. A core‒shell dual metal–organic frameworks (MOFs) system was delicately designed in this study, which not only possessed the unique properties of both materials, but also provided two individual specific functional zones for co-drug delivery. Photosensitizer indocyanine green (ICG) and chemotherapeutic agent doxorubicin (DOX) were stepwisely encapsulated into the nanopores of MIL-88 core and ZIF-8 shell to construct a synergistic photothermal/photodynamic/chemotherapy nanoplatform. Except for efficient drug delivery, the MIL-88 could be functioned as a nanomotor to convert the excessive hydrogen peroxide at tumor microenvironment into adequate oxygen for photodynamic therapy. The DOX release from MIL-88-ICG@ZIF-8-DOX nanoparticles was triggered at tumor acidic microenvironment and further accelerated by near-infrared (NIR) light irradiation. The in vivo antitumor study showed superior synergistic antitumor effect by concentrating the nanoparticles into dissolving microneedles as compared to intravenous and intratumoral injection of nanoparticles, with a significantly higher inhibition rate. It is anticipated that the multi-model synergistic system based on dual-MOFs was promising for further biomedical application.     

Dual Responsive Hybrid Nanoparticle for Tumor Chemotherapy Combined with Photothermal Therapy

With the deepening of tumor targeting research, the application of intelligent responsive drug carriers in the field of controlled drug release has become more and more extensive, and multiple responsive nano drug carriers have attracted greater attention. In this paper, nanoparticles with gold nanorods (GNR) as the core, mesoporous silica (mSiO₂) doped with hydroxyapatite (HAP) as the inorganic hybrid shell and physically loaded with doxorubicin hydrochloride (DOX·HCl) are prepared (DOX/GNR/mSiO₂/HAP, DNPs). DNPs nanoparticles have a typical core-shell structure. The gold nanorods as the core have extremely high light-to-heat conversion efficiency. Under the irradiation of near-infrared light, light can be converted into heat. The inorganic hybrid shell is a drug reservoir. The excellent photothermal response of gold nanorods combined with the excellent pH response of hydroxyapatite can obtain slow and sustained release of chemotherapeutic drugs. In vivo and in vitro anti-tumor cell activity study show that the DNPs in the laser showed stronger cytotoxicity than the other groups. Compared to chemotherapy and phototherapy alone, DNPs selectively accumulate in the tumor through the enhanced penetration and retention (EPR) effects. and have the unified function of hyperthermia and chemotherapy, and have significant inhibitory effect on tumor growth. Therefore, this study provides a new idea for the study of the combination of multiple therapeutic methods in the treatment of cancer.     

Mussel-inspired polydopamine coated mesoporous silica nanoparticles as pH-sensitive nanocarriers for controlled release

A novel pH-sensitive controlled release system is proposed by using mussel-inspired polydopamine (PDA) coated mesoporous silica nanoparticles (MSNs) as nanocarriers. MSNs with a large pore diameter are synthesized by using 1,3,5-trimethylbenzene as a pore-expanding agent and are modified with a PDA coating by virtue of oxidative self-polymerization of dopamine in neutral pH. PDA coated MSNs are characterized by FTIR, TEM, N₂ adsorption and XPS techniques. The PDA coating can work as pH-sensitive gatekeepers to control the release of drug molecules from MSNs in response to the pH-stimulus. Doxorubicin (DOX, an anticancer drug) can be released in the acid media and blocked in the neutral media.     

基于钙离子驱动的药物负载构建光响应性介孔硅纳米粒的研究

目的 提高介孔硅纳米粒(mesoporous silicon nanoparticles，MSNs)中药物负载量，并使其具备光响应性等功能。方法 本研究采用模板法制备氨基化的介孔硅纳米粒(MSN-NH₂)，并通过钙离子负载的MSNs(MSN-Ca)诱导化疗药物阿霉素(Doxorubicin，Dox)及光热治疗药物Cypate、二氢卟吩e6(Ce6)的高效负载，制得光响应性载单药或多药的MSNs，并对其理化性质及释药特性进行研究。结果 钙离子可有效负载于MSNs内，并可以诱导Dox、Cypate、Ce6在MSNs孔道内的高效负载，其载药量可分别达到(28.5±1.4)%，(36.8±1.5)%，(36.6±1.7)%；MSN-Ca还可以实现Dox、Cypate、Ce6中的2种或3种药物共同负载。负载Cypate的MSNs具有良好的光热升温效果。载Dox的MSNs具有酸性pH响应性释放Dox的特点。785 nm激光照射可明显增强MSN-Ca-Dox/Cypate的Dox释放，具有光响应性释药的特点。结论 钙离子驱动的药物负载策略在多功能MSNs的构建及其抗肿瘤协同治疗研究中具有重要作用。     

多功能介孔二氧化硅纳米粒在肿瘤治疗中的研究进展

介孔二氧化硅纳米粒由于较高的物理化学稳定性、易于官能化、低毒性以及对许多不同类型治疗剂的巨大负载能力,涉及了化学药物治疗、光热治疗、光动力治疗以及联合治疗,在肿瘤治疗方面受到极大的关注和广泛的研究探索。本文介绍了近年来基于介孔二氧化硅纳米粒作为载体在肿瘤治疗方面的一些研究报道,这些智能化的多功能性已经促使介孔二氧化硅纳米粒成为将来用于临床的非常有前途的药物纳米载体。     

Multifunctional liposome for photoacoustic/ultrasound imaging-guided chemo/photothermal retinoblastoma therapy

Retinoblastoma (RB) is a malignant intraocular neoplasm that occurs in children. Diagnosis and therapy are frequently delayed, often leading to metastasis, which necessitates effective imaging and treatment. In recent years, the use of nanoplatforms allowing both imaging and targeted treatment has attracted much attention. Herein, we report a novel nanoplatform folate-receptor (FR) targeted laser-activatable liposome termed FA-DOX-ICG-PFP@Lip, which is loaded with doxorubicin (DOX)/indocyanine green (ICG) and liquid perfluoropentane (PFP) for photoacoustic/ultrasound (PA/US) dual-modal imaging-guided chemo/photothermal RB therapy. The dual-modal imaging capability, photothermal conversion under laser irradiation, biocompatibility, and antitumor ability of these liposomes were appraised. The multifunctional liposome showed a good tumor targeting ability and was efficacious as a dual-modality contrast agent both in vivo and in vitro. When laser-irradiated, the liposome converted light energy to heat. This action caused immediate destruction of tumor cells, while simultaneously initiating PFP phase transformation to release DOX, resulting in both photothermal and chemotherapeutic antitumor effects. Notably, the FA-DOX-ICG-PFP@Lip showed good biocompatibility and no systemic toxicity was observed after laser irradiation in RB tumor-bearing mice. Hence, the FA-DOX-ICG-PFP@Lip shows great promise for dual-modal imaging-guided chemo/photothermal therapy, and may have significant value for diagnosing and treating RB.     

Targeted peptide-modified oxidized mesoporous carbon nanospheres for chemo-thermo combined therapy of ovarian cancer in vitro

Ovarian cancer remains one of serious hazards to human health due to many drawbacks of existing available treatment options. In this study, a multifunctional chemo-thermo combined therapy nanoplatform (OMCNPID) was successfully prepared, which is composed of I₆P₈ peptide as a targeting moiety to interleukin-6 receptors (IL-6Rs), oxidized mesoporous carbon nanospheres (OMCN) as a near infrared (NIR)-triggered drug carrier and doxorubicin (DOX) as a chemotherapeutic drug and fluorescent agent. The synthesized multifunctional nanoplatform displayed high storage capacity for drugs and excellent photothermal properties. Besides, DOX was rapidly released from OMCNPID at the condition of low pH and NIR laser irradiation due to the dissociation of DOX from graphitic cores of OMCN. In vitro experimental results verified that OMCNPID could be markedly taken up by SKOV-3 monolayer cells and tumor spheroids, and revealed a remarkable synergistic chemo-photothermal effect against ovarian cancer. All the results demonstrated that OMCNPID is a pH/NIR dual-stimulus responsive nanoplatform and can achieve efficient chemo-thermo combined therapy.     

一氧化氮供体和阿霉素的共递送系统用于逆转肿瘤低氧耐药研究

目的构建一种一氧化氮供体和阿霉素的共递送系统,以逆转肿瘤低氧耐药。方法利用酰胺反应合成一氧化氮供体单硝酸异山梨酯(IM)修饰的透明质酸(HA-IM),再通过硫化学作用将其嫁接于二硫化钼(MoS₂)纳米片,制备出载体二硫化钼-单硝酸异山梨酯修饰的透明质酸(MoS₂-HA-IM),考察此载体的理化特性。通过疏水作用装载抗癌药阿霉素(DOX),构建一氧化氮供体和抗癌药物的共递送系统,并在细胞水平上考察此系统的抗肿瘤效果。结果二硫化钼-单硝酸异山梨酯修饰的透明质酸-阿霉素(MoS₂-HA-IM-DOX)可通过透明质酸受体介导的内吞作用有效地将装载的单硝酸异山梨酯和阿霉素输送到肿瘤细胞内,且在肿瘤弱酸性内环境和近红外光照射的双重刺激下迅速将药物释放出来,提高胞内游离药物的浓度。同时,装载的单硝酸异山梨酯能够逆转肿瘤细胞的低氧耐受性,进一步增强二硫化钼-单硝酸异山梨酯修饰的透明质酸-阿霉素的化疗效果,再联合基于二硫化钼材料产生的光热,共使肿瘤细胞的生长抑制率高达93.6%,明显高于其他组。结论二硫化钼-单硝酸异山梨酯修饰的透明质酸-阿霉素能够靶向输送一氧化氮供体和抗癌药物至肿瘤细胞内,双重响应控制药物释放,逆转肿瘤低氧耐药,最大限度地提高化疗效果,结合光热治疗,显示出优异的抗肿瘤效果。     

Photosensitizer-assembled PEGylated graphene-copper sulfide nanohybrids as a synergistic near-infrared phototherapeutic agent

Objectives: Stimulative nanostructures play a crucial role in developing the smart nanomedicine for high therapeutic efficacy with minimum adverse effects. Herein, a near-infrared (NIR) light-responsive nanohybrids p-nanographene oxide (GO)-copper sulfide (CuS)/indocyanine green (ICG) comprised of GO, CuS nanoparticles and photosensitizer ICG was fabricated to couple the photothermal property of CuS and photodynamic effect of ICG in one system in order to achieve the synergistic phototherapy.

Methods: pGO-CuS/ICG was constructed by self-assembling ICG on pGO-CuS nanostructure. Its physicochemical, photothermal and photodynamic properties were studied by spectroscopic methods. The in vitro cellular uptake, cytotoxicity, the single/combined photothermal therapeutic (PTT) and photodynamic therapeutic (PDT) effects were investigated with biological techniques.

Results: pGO-CuS/ICG exhibited high efficacy of photothermal conversation and singlet oxygen generation under NIR laser excitation. It entered into the target cancer cells probably via passive transmembrane pathway and exerted obvious PTT and PDT effect against the tumor cells upon irradiation with the respective 940 and 808 nm lasers. In particular, the tremendous synergistic efficacy of PDT and PTT had been demonstrated by tuning the NIR laser combined irradiation.

Conclusions: This study promises the future applications of pGO-CuS/ICG as a NIR light activable theranostic nanodrug for deep-seated cancer noninvasive phototherapy.     

Aptamer Tethered Bio-Responsive Mesoporous Silica Nanoparticles for Efficient Targeted Delivery of Paclitaxel to Treat Ovarian Cancer Cells

Ovarian cancer is the leading cause of cancer deaths in female patients. The current therapeutics in ovarian cancer are limited and inefficient in curing the disease. To tackle this, we have synthesized tetrasulfide derivative of silica doped, biodegradable, glutathione-responsive targeted mesoporous silica nanoparticles modified with heterobifunctional polyethylene glycol as a linker and mucin-1 aptamer for triggered paclitaxel delivery to the ovarian cancer cells. Degradable mesoporous silica nanoparticles were synthesized by a modified sol-gel method with tetraethyl orthosilicate and Bis (triethoxysilylpropyl) tetrasulfide. The degradable mesoporous silica nanoparticles were characterized by dynamic light scattering, Fourier-transform infrared spectroscopy, Scanning electron microscopy and Transmission electron microscopy. The degradable mesoporous silica nanoparticles had good paclitaxel encapsulation efficiency and glutathione-responsive paclitaxel release ability. The glutathione utilization assay and visual destruction observed within 10 days in transmission electron microscopy images confirmed the degradation of the mesoporous silica nanoparticles in the tumor cell environment. The targeted degradable mesoporous silica nanoparticles were efficiently taken up by ovarian cancer cell lines OVACAR-3 and PA-1. The cytotoxicity of bare mesoporous silica nanoparticles evaluated on NIH-3T3 cell line showed good biocompatibility (>90% cell viability). Significant toxicity on OVACAR-3 (IC₅₀ 25.66 nM) and PA-1 (IC₅₀ 42.93 nM) cell lines was observed when treated with paclitaxel-loaded targeted degradable mesoporous silica nanoparticles. Results of this study demonstrated that mucin-1 targeted, glutathione-responsive mesoporous silica nanoparticles loaded with paclitaxel had a significant antitumor effect on ovarian cancer cells. All these findings demonstrated that developed nano-formulation could be suitable for ovarian cancer treatment.     

Trimodal synergistic antitumor drug delivery system based on graphene oxide

A multifunctional antitumor drug delivery system was synthesized based on graphene oxide (GO) for near-infrared (NIR) light controlling chemotherapeutic/photothermal (PTT) /photodynamic (PDT) trimodal synergistic therapy. The system named ICG-Wed-GO was formed by co-loading wedelolactone (Wed) and indocyanine green (ICG) on the surface of GO through π–π stacking interaction. Under NIR laser irradiation, ICG-Wed-GO could effectively absorb and transform optical energy to heat, generate reactive oxygen species (ROS) to ablating and damage tumor cells. The temperature of ICG-Wed-GO solution reached up to 79.4?°C in 10?min with NIR irradiation. In in vitro and in vivo study, ICG-Wed-GO showed excellent antitumor effect. After 14-day treatment of ICG-Wed-GO with NIR laser irradiation, the tumor disappeared completely on tumor-bearing mice. The low biotoxicity of ICG-Wed-GO was also proved. The system achieved the synergistic trimodal chemotherapeutic/photothermal/photodynamic treatment and demonstrated excellent antitumor effect, which is expected to have a greater potential for cancer therapy.     

Real-time SERS monitoring anticancer drug release along with SERS/MR imaging for pH-sensitive chemo-phototherapy

In situ and real-time monitoring of responsive drug release is critical for the assessment of pharmacodynamics in chemotherapy. In this study, a novel pH-responsive nanosystem is proposed for real-time monitoring of drug release and chemo-phototherapy by surface-enhanced Raman spectroscopy (SERS). The Fe₃O₄@Au@Ag nanoparticles (NPs) deposited graphene oxide (GO) nanocomposites with a high SERS activity and stability are synthesized and labeled with a Raman reporter 4-mercaptophenylboronic acid (4-MPBA) to form SERS probes (GO-Fe₃O₄@Au@Ag-MPBA). Furthermore, doxorubicin (DOX) is attached to SERS probes through a pH-responsive linker boronic ester (GO-Fe₃O₄@Au@Ag-MPBA-DOX), accompanying the 4-MPBA signal change in SERS. After the entry into tumor, the breakage of boronic ester in the acidic environment gives rise to the release of DOX and the recovery of 4-MPBA SERS signal. Thus, the DOX dynamic release can be monitored by the real-time changes of 4-MPBA SERS spectra. Additionally, the strong T₂ magnetic resonance (MR) signal and NIR photothermal transduction efficiency of the nanocomposites make it available for MR imaging and photothermal therapy (PTT). Altogether, this GO-Fe₃O₄@Au@Ag-MPBA-DOX can simultaneously fulfill the synergistic combination of cancer cell targeting, pH-sensitive drug release, SERS-traceable detection and MR imaging, endowing it great potential for SERS/MR imaging-guided efficient chemo-phototherapy on cancer treatment.     

Targeted delivery of doxorubicin by CSA-binding nanoparticles for choriocarcinoma treatment

Gestational trophoblastic neoplasia (GTN) can result from the over-proliferation of trophoblasts. Treatment of choriocarcinoma, the most aggressive GTN, currently requires high doses of systemic chemotherapeutic agents, which result in indiscriminate drug distribution and severe toxicity. To overcome these disadvantages and enhance the chemotherapeutic efficacy, chondroitin sulfate A (CSA)-binding nanoparticles were developed for the targeted delivery of doxorubicin (DOX) to choriocarcinoma cells using a synthetic CSA-binding peptide (CSA-BP), derived from malarial protein, which specifically binds to the CSA exclusively expressed in the placental trophoblast. CSA-BP-conjugated nanoparticles rapidly bonded to choriocarcinoma (JEG3) cells and were efficiently internalized into the lysosomes. Moreover, CSA-BP modification significantly increased the anti-cancer activity of the DOX-loaded nanoparticles in vitro. Intravenous injections of CSA-BP-conjugated nanoparticles loaded with indocyanine green (CSA-INPs) were rapidly localized to the tumor. The CSA-targeted nanoparticles loaded with DOX (CSA-DNPs) strongly inhibited primary tumor growth and, more importantly, significantly suppressed metastasis in vivo. Collectively, our results highlight the potential of the CSA-BP-decorated nanoparticles as an alternative targeted delivery system of chemotherapeutic agents for treating choriocarcinoma and for developing new GTN therapies based on drug targeting.     

Fucoidan-based dual-targeting mesoporous polydopamine for enhanced MRI-guided chemo-photothermal therapy of HCC via P-selectin-mediated drug delivery

The development of novel theranostic agents with outstanding diagnostic and therapeutic performances is still strongly desired in the treatment of hepatocellular carcinoma(HCC). Here, a fucoidan-modified mesoporous polydopamine nanoparticle dual-loaded with gadolinium iron and doxorubicin(FMPDA/Gd³⁺/DOX) was prepared as an effective theranostic agent for magnetic resonance imaging(MRI)-guided chemo-photothermal therapy of HCC. It was found that FMPDA/Gd³⁺/DOX had a high pho...     

Visual targeted therapy of hepatic cancer using homing peptide modified calcium phosphate nanoparticles loading doxorubicin guided by T1 weighted MRI

Effective treatment and real-time monitoring of hepatic cancer are essential. A multifunctional calcium phosphate nanoparticles loading chemotherapeutic agent doxorubicin and magnetic resonance imaging contrast agent diethylenetriaminepentaacetic acid gadolinium (A54-CaP/Gd-DTPA/DOX) was developed for visual targeted therapy of hepatic cancer via T1-weighted MRI in real-time. A54-CaP/Gd-DTPA/DOX exhibited a higher longitudinal relaxivity (6.02?mM^?1?s^?1) than commercial MR contrast agent Gd-DTPA (3.3765?mM^?1?s^?1). The DOX release from the nanoparticles exhibited a pH dependent behavior. The cellular uptake results showed that the internalization of A54-CaP/Gd-DTPA/DOX into BEL-7402 cells was1.9-fold faster than that of HepG2 cells via A54 binding. In vivo experiments presented that A54-CaP/Gd-DTPA/DOX had higher distribution and longer retention time in tumor tissue than CaP/Gd-DTPA/DOX and free DOX, and also displayed great antitumor efficacy (95.38% tumor inhibition rate) and lower toxicity. Furthermore, the Gd-DTPA entrapped in the nanoparticles could provide T1-weighted MRI for real-time monitoring the progress of tumor treatment.     

A comparison of mesoporous silica nanoparticles and mesoporous organosilica nanoparticles as drug vehicles for cancer therapy

Mesoporous silica nanoparticles (MSNs) are promising drug carriers for use in cancer treatment owing to their excellent biocompatibility and drug‐loading capacity. However, MSN's incomplete drug release and toxic bioaccumulation phenomena limit their clinical application. Recently, researchers have presented redox responsive mesoporous organosilica nanoparticles containing disulfide (S–S) bridges (ss‐MONs). These nanoparticles retained their ability to undergo structural degradation and increased their local release activity when exposed to reducing agents. Disulfide‐based mesoporous organosilica nanoparticles offer researchers a better option for loading chemotherapeutic drugs due to their effective biodegradability through the reduction of glutathione. Although the potential of ss‐MONs in cancer theranostics has been studied, few researchers have systematically compared ss‐MONs with MSNs with regard to endocytosis, drug release, cytotoxicity, and therapeutic effect. In this work, ss‐MONs and MSNs with equal morphology and size were designed and used to payload doxorubicin hydrochloride (DOX) for liver cancer chemotherapy. The ss‐MONs showed considerable degradability in the presence of glutathione and performed comparably to MSNs on biocompatibility measures, including cytotoxicity and endocytosis, as well as in drug‐loading capacity. Notably, DOX‐loaded ss‐MONs exhibited higher intracellular drug release in cancer cells and better anticancer effects in comparison with DOX‐loaded MSNs. Hence, the ss‐MONs may be more desirable carriers for a highly efficient and safe treatment of cancer.     

Evaluation of doxorubicin-loaded pH-sensitive polymeric micelle release from tumor blood vessels and anticancer efficacy using a dorsal skin-fold window chamber model

Aim： To evaluation the doxorubicin （DOX）-loaded pH-sensitive polymeric micelle release from tumor blood vessels into tumor interstitium using an animal vessel visibility model, the so-called dorsal skin-fold window chamber model.
Methods： DOX-loaded pH-sensitive polyHis-b-PEG micelles and DOX-loaded pH-insensitive PLLA-b-PEG micelles were prepared. The uptake of the micelles by MDA-MB-231 breast cancer cells in vitro and in vivo was examined using flow cytometry. The pharmacokinetic parameters of the micelles were determined in SD rats after intravenous injection of a DOX dose （6 mg/kg）. The release of the micelles from tumor vasculature and the antitumor efficacy were evaluated in MDA-MB-231 breast cancer xenografted in nude mice using a dorsal skin-fold window chamber.
Results： The effective elimination half-life t1/2 of the pH-sensitive, pH-insensitive polymeric micelles and DOX-PBS in rats were 11.3 h, 9.4 h, and 2.1 h, respectively. Intravital microscopy in MDA-MB-231 breast cancer xenografted in nude mice showed that the pH-sensitive polymeric micelles rapidly extravasated from the tumor blood vessels, and DOX carried by the pH-sensitive micelles was preferentially released at the tumor site as compared to the pH-insensitive polymeric micelles. Furthermore, the pH-sensitive polymeric micelles exhibited significant greater efficacy in inhibition of tumor growth in the nude mice.
Conclusion： When DOX is loaded into pH-sensitive polymeric micelles, the acidity in tumor interstitium causes the destabilization of the micelles and triggers drug release, resulting in high local concentrations within the tumor, thus more effectively inhibiting the tumor growth in vivo.     

A Multi-Functional Tumor Theranostic Nanoplatform for MRI Guided Photothermal-Chemotherapy

Purpose

To develop a multi-functional theranostic nanoplatform with increased tumor retention, improving antitumor efficacy and decreased side effects of chemotherapy drugs.

Methods

GO@Gd nanocomposites was synthesized via decorating gadolinium (Gd) nanoparticles (GdNP) onto graphene oxide (GO), and then functionalized by polyethylene glycol (PEG2000), folic acid (FA), a widely used tumor targeting molecule, was linked to GO@Gd-PEG, finally, doxorubicin (DOX) was loaded onto GO@Gd-PEG-FA and obtained a tumor-targeting drug delivery system (GO@Gd-PEG-FA/DOX). GO@Gd-PEG-FA/DOX was characterized and explored its theranostic applications both in a cultured MCF-7 cells and tumor-bearing mice.

Results

GO@Gd-PEG-FA/DOX could efficiently cross the cell membranes, lead to more apoptosis and afford higher antitumor efficacy without obvious toxic effects to normal organs owing to its prolonged blood circulation and 7.6-fold higher DOX uptake of tumor than DOX. Besides, GO@Gd-PEG-FA/DOX also served as a powerful photothermal therapy (PTT) agent for thermal ablation of tumor and a strong T1-weighted contrast agent for tumor MRI diagnosis. The multi-functional nanoplatform also could selectively kill cancer cells in highly localized regions via the excellent tumor-targeting and MRI guided PTT abilities.

Conclusions

GO@Gd-PEG-FA/DOX exhibited excellent photothermal-chemotherapeutic efficacy, tumor-targeting property and tumor diagnostic ability.

     

Chemo-photothermal immunotherapy for eradication of orthotopic tumors and inhibition of metastasis by intratumoral injection of polydopamine versatile hydrogels

Cancer remains one of the leading causes of death globally and metastasis always leads to treatment failure. Here, we develop a versatile hydrogel loading photothermal agents, chemotherapeutics, and immune-adjuvants to eradicate orthotopic tumors and inhibit metastasis by combinational therapy. Hydrogel networks were synthesized via the thiol-Michael addition of polydopamine (PDA) with thiolated hyaluronic acid. PDA acted as a cross-linking agent and endowed the hydrogel with excellent photothermal property. Meanwhile, a chemotherapeutic agent, doxorubicin (DOX), was loaded in the hydrogel via π?π stacking with PDA and an immune-adjuvant, CpG-ODN, was loaded via electrostatic interaction. The release of DOX from the hydrogel was initially slow but accelerated due to near infrared light irradiation. The hydrogels showed remarkably synergistic effect against 4T1 cancer cells and stimulated plenty of cytokines secreting from RAW264.7 cells. Moreover, the hydrogels eradicated orthotopic murine breast cancer xenografts and strongly inhibited metastasis after intratumoral injection and light irradiation. The high anticancer efficiency of this chemo-photothermal immunotherapy resulted from the strong synergistic effect of the versatile hydrogels, including the evoked host immune response. The combinational strategy of chemo-photothermal immunotherapy is promising for highly effective treatment of breast cancer.     

Nanoparticles with rough surface improve the therapeutic effect of photothermal immunotherapy against melanoma

Photothermal therapy has been intensively investigated for treating cancer in recent years. However, the long-term therapeutic outcome remains unsatisfying due to the frequently occurred metastasis and recurrence. To address this challenge, immunotherapy has been combined with photothermal therapy to activate anti-tumor immunity and relieve the immunosuppressive microenvironment within tumor sites. Here, we engineered silica-based core?shell nanoparticles (JQ-1@PSNs-R), in which silica cores were coated with the photothermal agent polydopamine, and a bromodomain-containing protein 4 (BRD4) inhibitor JQ-1 was loaded in the polydopamine layer to combine photothermal and immune therapy for tumor elimination. Importantly, to improve the therapeutic effect, we increased the surface roughness of the nanoparticles by hydrofluoric acid (HF) etching during the fabrication process, and found that the internalization of JQ-1@PSNs-R was significantly improved, leading to a strengthened photothermal killing effect as well as the increased intracellular delivery of JQ-1. In the animal studies, the multifunctional nanoparticles with rough surfaces effectively eradicated melanoma via photothermal therapy, successfully activated tumor-specific immune responses against residual tumor cells, and further prevented tumor metastasis and recurrence. Our results indicated that JQ-1@PSNs-R could serve as an innovative and effective strategy for combined cancer therapy.