Lipase‐Triggered Water‐Responsive “Pandora's Box” for Cancer Therapy: Toward Induced Neighboring Effect and Enhanced Drug Penetration

Insufficient drug release as well as poor drug penetration are major obstacles for effective nanoparticles (NPs)‐based cancer therapy. Herein, the high aqueous instability of amorphous calcium carbonate (ACC) is employed to construct doxorubicin (DOX) preloaded and monostearin (MS) coated “Pandora's box” (MS/ACC–DOX) NPs for lipase‐triggered water‐responsive drug release in lipase‐overexpressed tumor tissue to induce a neighboring effect and enhance drug penetration. MS as a solid lipid can prevent potential drug leakage of ACC–DOX NPs during the circulatory process, while it can be readily be disintegrated in lipase‐overexpressed SKOV3 cells to expose the ACC–DOX core. The high aqueous instability of ACC will lead to burst release of the encapsulated DOX to induce apoptosis and cytotoxicity to kill the tumor cells. The liberated NPs from the dead or dying cells continue to respond to the ubiquitous aqueous environment to sufficiently release DOX once unpacked, like the “Pandora's box”, leading to severe cytotoxicity to neighboring cells (neighboring effect). Moreover, the continuously released free DOX molecules can readily diffused through the tumor extracellular matrix to enhance drug penetration to deep tumor tissue. Both effects contribute to achieve elevated antitumor benefits.     

Dual pH/ROS‐Responsive Nanoplatform with Deep Tumor Penetration and Self‐Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA‐NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active‐targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self‐amplified drug release for effective drug delivery. The RLPA‐NPs are constructed by encapsulation of a pH‐sensitive polymer octadecylamine‐poly(aspartate‐1‐(3‐aminopropyl) imidazole) (OA‐P(Asp‐API)) and a ROS‐generation agent, β‐Lapachone (Lap), in micelles assembled by the tumor‐penetration peptide internalizing RGD (iRGD)‐modified ROS‐responsive paclitaxel (PTX)‐prodrug. iRGD could promote RLPA‐NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor‐mediated endocytosis, OA‐P(Asp‐API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA‐NPs escape from the endosome through the “proton sponge effect”. At the same time, the RLPA‐NPs micelle disassembles, releasing Lap and PTX‐prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA‐NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA‐NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.     

A pH-switched mesoporous nanoreactor for synergetic therapy

Zinc oxide nanoparticles (ZnO NPs),as a new type of pH-sensitive drug carrier,have received much attention.ZnO NPs are stable at physiological pH,but can dissolve quickly in the acidic tumor environment (pH ＜ 6) to generate cytotoxic zinc ions and reactive oxygen species (ROS).However,the protein corona usually causes the non-specific degradation of ZnO NPs,which has limited their application considerably.Herein,a new type of pH-sensitive nanoreactor (ZnO-DOX@F-mSiO2-FA),aimed at reducing the non-specific degradation of ZnO NPs,is presented.In the acidic tumor environment (pH ＜ 6),it can release cytotoxic zinc ions,ROS,and anticancer drugs to kill cancer cells effectively.In addition,the fluorescence emitted from fluorescein isothiocyanate (FITC)-labeled mesoporous silica (F-mSiO2) and doxorubicin (DOX) can be used to monitor the release behavior of the anticancer drug.This report provides a new method to avoid the non-specific degradation of ZnO NPs,resulting in synergetic therapy by taking advantage of ZnO NPs-induced oxidative stress and targeted drug release.     

Programmed Nanococktail for Intracellular Cascade Reaction Regulating Self‐Synergistic Tumor Targeting Therapy

In this work, a ZnO based nanococktail with programmed functions is designed and synthesized for self‐synergistic tumor targeting therapy. The nanococktail can actively target tumors via specific interaction of hyaluronic acid (HA) with CD44 receptors and respond to HAase‐rich tumor microenvironment to induce intracellular cascade reaction for controlled therapy. The exposed cell‐penetrating peptide (R8) potentiates the cellular uptake of therapeutic nanoparticles into targeted tumor cells. Then ZnO cocktail will readily degrade in acidic endo/lysosomes and induce the production of desired reactive oxygen species (ROS) in situ. The destructive ROS not only leads to serious cell damage but also triggers the on‐demand drug release for precise chemotherapy, thus achieving enhanced antitumor efficiency synergistically. After tail vein injection of ZnO cocktail, a favorable tumor apoptosis rate (71.2 ± 8.2%) is detected, which is significantly superior to that of free drug, doxorubicin (12.9 ± 5.2%). Both in vitro and in vivo studies demonstrate that the tailor‐made ZnO cocktail with favorable biocompatibility, promising tumor specificity, and self‐synergistically therapeutic capacity opens new avenues for cancer therapy.     

Amino Acid Metabolism Abnormity and Microenvironment Variation Mediated Targeting and Controlled Glioma Chemotherapy

Energy metabolism abnormity is one of the most significant hallmarks of cancer. As a result, large amino acid transporter 1 (LAT1) is remarkably overexpressed in both blood‐brain‐barrier and glioma tumor cells, leading a rapid and sufficient substrate transportation. 3CDIT and 4CDIT are originally synthesized by modifying the existing most potent LAT1 substrate. 3CDIT is selected as its higher glioma‐targeting ability. Since the microenvironment variation in tumor cells is another important feature of cancer, a great disparity in adenosine‐5′‐triphosphate (ATP) and glutathione (GSH) levels between extracellular and intracellular milieu can provide good possibilities for dual‐responsive drug release in tumor cells. Doxorubicin (DOX) is successfully intercalated into the ATP aptamer DNA scaffolds, compressed by GSH‐responsive polymer pOEI, and modified with 3CDIT to obtain 3CDIT‐targeting pOEI/DOX/ATP aptamer nanoparticles (NPs). Enhanced NP accumulation and rapid GSH & ATP dual‐responsive DOX release in glioma are demonstrated both in vitro and in vivo. More efficient therapeutic effects are shown with 3CDIT‐targeting pOEI/DOX/ATP aptamer NPs than free DOX and no systemic toxicity is observed. Therefore, glioma‐targeting delivery and GSH & ATP dual‐responsive release guarantee an adequate DOX accumulation within tumor cells and ensure a safe and efficient chemotherapy for glioma.     

PD‐1 Blockade for Improving the Antitumor Efficiency of Polymer–Doxorubicin Nanoprodrug

Chemotherapy is well recognized to induce immune responses during some chemotherapeutic drugs‐mediated tumor eradication. Here, a strategy involving blocking programmed cell death protein 1 (PD‐1) to enhance the chemotherapeutic effect of a doxorubicin nanoprodrug HA‐Psi‐DOX is proposed and the synergetic mechanism between them is further studied. The nanoprodrugs are fabricated by conjugating doxorubicin (DOX) to an anionic polymer hyaluronic acid (HA) via a tumor overexpressed matrix metalloproteinase sensitive peptide (CPLGLAGG) for tumor targeting and enzyme‐activated drug release. Once accumulated at the tumor site, the nanoprodrug can be activated to release antitumor drug by tumor overexpressed MMP‐2. It is found that HA‐Psi‐DOX nanoparticles can kill tumor cells effectively and initiate an antitumor immune response, leading to the upregulation of interferon‐γ. This cytokine promotes the expression of programmed cell death protein‐ligand 1 (PD‐L1) on tumor cells, which will cause immunosuppression after interacting with PD‐1 on the surface of lymphocytes. The results suggest that the therapeutic efficiency of HA‐Psi‐DOX nanoparticles is significantly improved when combined with checkpoint inhibitors anti‐PD‐1 antibody (α‐PD1) due to the neutralization of immunosuppression by blocking the interaction between PD‐L1 and PD‐1. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between conventional tumor therapies and immunotherapy.     

Double‐Targeting Explosible Nanofirework for Tumor Ignition to Guide Tumor‐Depth Photothermal Therapy

This study reports a double‐targeting “nanofirework” for tumor‐ignited imaging to guide effective tumor‐depth photothermal therapy (PTT). Typically, ≈30 nm upconversion nanoparticles (UCNP) are enveloped with a hybrid corona composed of ≈4 nm CuS tethered hyaluronic acid (CuS‐HA). The HA corona provides active tumor‐targeted functionality together with excellent stability and improved biocompatibility. The dimension of UCNP@CuS‐HA is specifically set within the optimal size window for passive tumor‐targeting effect, demonstrating significant contributions to both the in vivo prolonged circulation duration and the enhanced size‐dependent tumor accumulation compared with ultrasmall CuS nanoparticles. The tumors featuring hyaluronidase (HAase) overexpression could induce the escape of CuS away from UCNP@CuS‐HA due to HAase‐catalyzed HA degradation, in turn activating the recovery of initially CuS‐quenched luminescence of UCNP and also driving the tumor‐depth infiltration of ultrasmall CuS for effective PTT. This in vivo transition has proven to be highly dependent on tumor occurrence like a tumor‐ignited explosible firework. Together with the double‐targeting functionality, the pathology‐selective tumor ignition permits precise tumor detection and imaging‐guided spatiotemporal control over PTT operation, leading to complete tumor ablation under near infrared (NIR) irradiation. This study offers a new paradigm of utilizing pathological characteristics to design nanotheranostics for precise detection and personalized therapy of tumors.     

Combretastatin A4 Nanodrug‐Induced MMP9 Amplification Boosts Tumor‐Selective Release of Doxorubicin Prodrug

Tumor‐associated enzyme‐activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the paucity of tumor‐associated enzymes which are essential for prodrug activation usually limits the antitumor potency. A cooperative strategy that utilizes combretastatin A4 nanodrug (CA4‐NPs) and matrix metalloproteinase 9 (MMP9)‐activated doxorubicin prodrug (MMP9‐DOX‐NPs) is developed. CA4 is a typical vascular disrupting agent that can selectively disrupt immature tumor blood vessels and exacerbate the tumor hypoxia state. After treatment with CA4‐NPs, MMP9 expression can be significantly enhanced by 5.6‐fold in treated tumors, which further boosts tumor‐selective active drug release of MMP9‐DOX‐NPs by 3.7‐fold in an orthotopic 4T1 mammary adenocarcinoma mouse model. The sequential delivery of CA4‐NPs and MMP9‐DOX‐NPs exhibits enhanced antitumor efficacy with reduced systemic toxicity compared with the noncooperative controls.     

Redox and pH Dual Responsive Polymer Based Nanoparticles for In Vivo Drug Delivery

Responsive nanomaterials have emerged as promising candidates as drug delivery vehicles in order to address biomedical diseases such as cancer. In this work, polymer‐based responsive nanoparticles prepared by a supramolecular approach are loaded with doxorubicin (DOX) for the cancer therapy. The nanoparticles contain disulfide bonds within the polymer network, allowing the release of the DOX payload in a reducing environment within the endoplasm of cancer cells. In addition, the loaded drug can also be released under acidic environment. In vitro anticancer studies using redox and pH dual responsive nanoparticles show excellent performance in inducing cell death and apoptosis. Zebrafish larvae treated with DOX‐loaded nanoparticles exhibit an improved viability as compared with the cases treated with free DOX by the end of a 3 d treatment. Confocal imaging is utilized to provide the daily assessment of tumor size on zebrafish larva models treated with DOX‐loaded nanoparticles, presenting sustainable reduction of tumor. This work demonstrates the development of functional nanoparticles with dual responsive properties for both in vitro and in vivo drug delivery in the cancer therapy.     

Hyaluronidase-triggered anticancer drug and siRNA delivery from cascaded targeting nanoparticles for drug-resistant breast cancer therapy

Drug resistance renders standard chemotherapy ineffective in the treatment of connective tissue growth factor (CTGF)-overexpressing breast cancer.By co-embedding the breast tumor cell-penetrating peptide (PEGA-pVEC) and hyaluronic add (HA) as a targeting media,novel cascaded targeting nanoparticles (HACT NPs) were created on a rattle mesoporous silica (rmSiO2) scaffold for the pinpoint delivery of siRNAs along with an anticancer drug,aiming at overcoming the drug resistance of CTGF-overexpressing breast cancer in vivo.The targeting nanoparticles selectively accumulated in the vasculature under the guidance of the PEGA-pVEC peptide,cascaded by receptor-mediated endocytosis with the aid of another targeting agent,HA,presenting a greater in vivo tumor targeting ability than single targeting ligand vectors.In addition,an HA shell prevented the leakage of therapeutic drugs during the cargo transport process,until the hyaluronidase (HAase)-triggered degradation upon lysosomes entering,guaranteeing a controllable drug release inside the target cells.When the protective shell disintegrates,the released siRNA took charge to silence the gene associated with drug resistance,CTGF,thus facilitating doxorubicin-induced apoptosis.The cascaded targeting media (PEGA-pVEC and HA) advances precision-guided therapy in vivo,while the encapsulation of siRNAs into a chemotherapy drug delivery system provides an effident strategy for the treatment of drug resistance cancers.     

Cyclo(RGD)‐Decorated Reduction‐Responsive Nanogels Mediate Targeted Chemotherapy of Integrin Overexpressing Human Glioblastoma In Vivo

Cyclo(Arg‐Gly‐Asp) peptide (cRGD) decorated disulfide (SS) containing poly(vinyl alcohol) nanogels (cRGD‐SS‐NGs) with an average diameter of 142 nm prepared by inverse nanoprecipitation, “click” reaction, and cRGD conjugation are developed for targeted treatment of integrin overexpressing human glioblastoma in vivo. Doxorubicin (DOX) release from cRGD‐SS‐NGs is highly inhibited under physiological conditions, while accelerated at endosomal pH and in response to cytoplasmic concentration of glutathione. Confocal microscopy shows that cRGD‐SS‐NGs facilitate the cellular uptake and intracellular DOX release in α_vβ₃ integrin overexpressing human glioblastoma U87‐MG cells. DOX‐loaded cRGD‐SS‐NGs present much better killing activity toward U87‐MG cells than that for nontargeted nanogels determined by MTT assay. The in vivo imaging and biodistribution studies reveal that DOX‐loaded cRGD‐SS‐NGs have a much better tumor targetability toward human U87‐MG glioblastoma xenograft in nude mice. Also the tumor growth is effectively inhibited by treatment with DOX‐loaded cRGD‐SS‐NGs, while continuous tumor growth is observed for mice treated with nondecorated nanogels as well as free DOX. Furthermore, the treatment with DOX‐loaded cRGD‐SS‐NGs has much fewer side effects, rendering these nanogels as a new platform for cancer chemotherapy in vivo.     

TPGS‐Functionalized Polydopamine‐Modified Mesoporous Silica as Drug Nanocarriers for Enhanced Lung Cancer Chemotherapy against Multidrug Resistance

A nanocarrier system of d ‐a‐tocopheryl polyethylene glycol 1000 succinate (TPGS)‐functionalized polydopamine‐coated mesoporous silica nanoparticles (NPs) is developed for sustainable and pH‐responsive delivery of doxorubicin (DOX) as a model drug for the treatment of drug‐resistant nonsmall cell lung cancer. Such nanoparticles are of desired particle size, drug loading, and drug release profile. The surface morphology, surface charge, and surface chemical properties are also successfully characterized by a series of techniques such as transmission electron microscopy (TEM), X‐ray photoelectron spectroscopy (XPS), Brunauer‐Emmett‐Teller (BET) method, thermal gravimetric analysis (TGA), dynamic light scattering (DLS), and Fourier transform infrared spectroscopy (FTIR). The normal A549 cells and drug‐resistant A549 cells are employed to access the cytotoxicity and cellular uptake of the NPs. The therapeutic effects of TPGS‐conjugated nanoparticles are evaluated in vitro and in vivo. Compared with free DOX and DOX‐loaded NPs without TPGS ligand modification, MSNs‐DOX@PDA‐TPGS exhibits outstanding capacity to overcome multidrug resistance and shows better in vivo therapeutic efficacy. This splendid drug delivery platform can also be sued to deliver other hydrophilic and hydrophobic drugs.     

Sequentially Responsive Shell‐Stacked Nanoparticles for Deep Penetration into Solid Tumors

Nanomedicine to overcome both systemic and tumor tissue barriers ideally should have a transformable size and surface, maintaining a certain size and negative surface charge for prolonged circulation, while reducing to a smaller size and switching to a positive surface charge for efficient penetration to and retention in the interstitial space throughout the tumor tissue. However, the design of such size and charge dual‐transformable nanomedicine is rarely reported. Here, the design of a shell‐stacked nanoparticle (SNP) is reported, which can undergo remarkable size reduction from about 145 to 40 nm, and surface charge reversal from ?7.4 to 8.2 mV at acidic tumor tissue, for enhanced tumor penetration and uptake by cells in deep tumor tissue. The disulfide‐cross‐linked core maintains the stability of the particle and prevents undesired premature drug release until the shedding of the shell, which accelerates the cleavage of more exposed disulfide bond sand intracellular drug release. SNP penetrates about 1 mm into xenografted A549 lung carcinoma, which is about four times penetration depth of the nontransformable one. The doxorubicin (DOX)‐loaded SNP (SNP/DOX) shows significant antitumor efficacy and nearly eradicates the tumor, substantiating the importance of the design of size and charge dual‐transformable nanomedicine.     

A Size-Changeable Collagenase-Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

The complex tumor microenvironment constitutes a variety of barriers to prevent nanoparticles (NPs) delivery and results in extremely low accumulation of nanomedicines in solid tumors. Here, a newly developed size-changeable collagenase-modified polymer micelle is employed to enhance the penetration and retention of nanomedicine in deep tumor tissue. The TCPPB micelle is first formed by self-assembly of maleimide-terminated poly(ethylene glycol)-block-poly(β-amino ester) (MAL-PEG-PBAE) and succinic anhydride-modified cisplatin-conjugated poly(ε-caprolactone)-block-poly(ethylene oxide)-triphenylphosphonium (CDDP-PCL-PEO-TPP). Next, Col-TCPPB NPs are prepared through a “click” chemical combination of thiolated collagenase and maleimide groups on TCPPB micelle. Finally, biocompatible chondroitin sulfate (CS) is coated to obtain CS/Col-TCPPB NPs for avoiding collagenase inactivation in blood circulation. In tumor acidic microenvironment, the hydrophobic PBAE segments of the resultant micelles become hydrophilic, leading to a dissociation and subsequent dissolution of partial collagenase-containing components (Col-PEG-PBAE) from NPs. The dissolved Col-PEG-PBAE promotes the digestion of collagen fibers in tumor tissue like a scavenger, which enhances the NPs penetration. Simultaneously, the increased hydrophilicity of residual Col-PEG-PBAE in the micellar matrix causes an expansion of the NPs, resulting in an enhanced intratumoral retention. In tumor cells, the NPs target to release the cisplatin drugs into mitochondria, achieving an excellent anticancer efficacy.     

Responsive Assembly of Upconversion Nanoparticles for pH‐Activated and Near‐Infrared‐Triggered Photodynamic Therapy of Deep Tumors

Upconversion nanoparticle (UCNP)‐mediated photodynamic therapy has shown great effectiveness in increasing the tissue‐penetration depth of light to combat deep‐seated tumors. However, the inevitable phototoxicity to normal tissues resulting from the lack of tumor selectivity remains as a major challenge. Here, the development of tumor‐pH‐sensitive photodynamic nanoagents (PPNs) comprised of self‐assembled photosensitizers grafted pH‐responsive polymeric ligands and UCNPs is reported. Under neutral pH conditions, photosensitizers aggregated in the PPNs are self‐quenched; however, upon entry into a tumor microenvironment with lower pH, the PPNs not only exhibit enhanced tumor‐cell internalization due to charge reversal but also are further disassembled into well‐dispersed nanoparticles in the endo/lysosomes of tumor cells, enabling the efficient activation of photosensitizers. The results demonstrate the attractive properties of both UCNP‐mediated deep‐tissue penetration of light and high therapeutic selectivity in vitro and in vivo.     

Gadolinium Metallofullerene‐Based Activatable Contrast Agent for Tumor Signal Amplification and Monitoring of Drug Release

Activatable imaging probes are promising to achieve increased signal‐to‐noise ratio for accurate tumor diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is a noninvasive imaging technique with excellent anatomic spatial resolution and unlimited tissue penetration depth. However, most of the activatable MRI contrast agents suffer from metal ion‐associated potential long‐term toxicity, which may limit their bioapplications and clinical translation. Herein, an activatable MRI agent with efficient MRI performance and high safety is developed for drug (doxorubicin) loading and tumor signal amplification. The agent is based on pH‐responsive polymer and gadolinium metallofullerene (GMF). This GMF‐based contrast agent shows high relaxivity and low risk of gadolinium ion release. At physiological pH, both GMF and drug molecules are encapsulated into the hydrophobic core of nanoparticles formed by the pH‐responsive polymer and shielded from the aqueous environment, resulting in relatively low longitudinal relativity and slow drug release. However, in acidic tumor microenvironment, the hydrophobic‐to‐hydrophilic conversion of the pH‐responsive polymer leads to amplified MR signal and rapid drug release simultaneously. These results suggest that the prepared activatable MRI contrast agent holds great promise for tumor detection and monitoring of drug release.     

pH值响应性透明质酸纳米粒的制备及作为阿霉素载体的研究

通过化学交联法合成组氨酸修饰透明质酸耦合物(His-HA),制备载阿霉素纳米粒,分析其pH值响应性和抗肿瘤特征.研究显示,随着pH值的降低(7.4～5.5),纳米粒的粒径增大(230～780nm),zeta电位升高,载药纳米粒的体外释放量增加.细胞毒性实验显示粒径＜300nm的载药纳米粒具更高的毒性.细胞摄入实验表明,阿霉素通过受体介导的胞吞和载药纳米粒的胞外释放两种途径被细胞摄入.以上研究显示组氨酸修饰透明质酸纳米粒具有显著的pH值响应性,具备作为阿霉素药物载体的应用前景.     

Thermoplasmonic‐Triggered Release of Loads from DNA‐Modified Hydrogel Microcapsules Functionalized with Au Nanoparticles or Au Nanorods

Microcapsules consisting of hydrogel shells cross‐linked by glucosamine–boronate ester complexes and duplex nucleic acids, loaded with dyes or drugs and functionalized with Au nanoparticles (Au NPs) or Au nanorods (Au NRs), are developed. Irradiation of Au NPs or Au NRs results in the thermoplasmonic heating of the microcapsules, and the dissociation of the nucleic acid cross‐linkers. The separation of duplex nucleic acid cross‐linkers leads to low‐stiffness hydrogel shells, allowing the release of loads. Switching off the light‐induced plasmonic heating results in the regeneration of stiff hydrogel shells protecting the microcapsules, leading to the blockage of release processes. The thermoplasmonic release of tetramethylrhodamine‐dextran, Texas Red‐dextran, doxorubicin‐dextran (DOX‐D), or camptothecin‐carboxymethylcellulose (CPT‐CMC) from the microcapsules is introduced. By loading the microcapsules with two different drugs (DOX‐D and CPT‐CMC), the light‐controlled dose release is demonstrated. Cellular experiments show efficient permeation of Au NPs/DOX‐D or Au NRs/DOX‐D microcapsules into MDA‐MB‐231 cancer cells and inefficient uptake by MCF‐10A epithelial breast cells. Cytotoxicity experiments reveal selective thermoplasmon‐induced cytotoxicity of the microcapsules toward MDA‐MB‐231 cancer cells as compared to MCF‐10A cells. Also, selective cytotoxicity towards MDA‐MB‐231 cancer cells upon irradiation of the Au NPs‐ and Au NRs‐functionalized microcapsules at λ = 532 or 910 nm is demonstrated.     

荔枝状CaCO3@HA/Fe3O4磁性介孔多级微球的制备

为了克服常规的生物陶瓷微球缺乏靶向功能的缺点, 本研究制备了内核为CaCO₃, 外壳为磁性可调控羟基磷灰石(HA)的新型荔枝状多孔微球。结果表明: 抗肿瘤药物阿霉素(DOX)能有效地负载于磁性HA微球上, 并具备磁性靶向功能。此外, HA外壳具有良好的生物相容性和pH响应特性, 可在模拟酸性肿瘤细胞环境中控制DOX的释放, 有效杀死肿瘤细胞, 并在模拟正常细胞培养环境中减少对正常细胞的毒副作用。这种新型的微球材料具有超顺磁性能, 且微结构可控, 是一种智能化药物控释微球载体, 可以灵敏地释放DOX, 从而有效地实现抗肿瘤活性。     

A Probiotic Spore‐Based Oral Autonomous Nanoparticles Generator for Cancer Therapy

Spores, the dormant life forms of probiotics, can germinate to metabolically active vegetative cells with the disintegration of their hydrophobic protein coat in the intestinal microenvironment, which provides the possibility for the formation of nanoparticles (NPs) in vivo. Inspired by the natural physiological process of spores, herein, an oral autonomous NPs generator is developed to overcome the spatially variable gastrointestinal tract environment and multibiological barriers. Spores modified with deoxycholic acid (DA) and loaded with chemotherapeutic drugs (doxorubicin and sorafenib, DOX/SOR) serve as an autonomous production line of NPs, which can efficaciously protect the drugs passing through the rugged environment of the stomach and furthermore can be transported to the intestinal environment and colonized rapidly. Subsequently, the DOX/SOR/Spore‐DA NPs are produced by the autonomous NPs generator in the intestinal regions based on the disintegrated hydrophobic protein and the hydrophilic DA, and they can efficiently penetrate the epithelial cells via the bile acid pathway, increasing basolateral drug release. In vitro and in vivo studies confirm that this biological nanogenerator can autonomously produce substantial NPs in the intestine, providing a promising strategy for cancer therapy.