Nanoparticle‐Mediated Immunogenic Cell Death Enables and Potentiates Cancer Immunotherapy

Cancer immunotherapies that train or stimulate the inherent immunological systems to recognize, attack, and eradicate tumor cells with minimal damage to healthy cells have demonstrated promising clinical responses in recent years. However, most of these immunotherapeutic strategies only benefit a small subset of patients and cause systemic autoimmune side effects in some patients. Immunogenic cell death (ICD)‐inducing modalities not only directly kill cancer cells but also induce antitumor immune responses against a broad spectrum of solid tumors. Such strategies for generating vaccine‐like functions could be used to stimulate a “cold” tumor microenvironment to become an immunogenic, “hot” tumor microenvironment, working in synergy with immunotherapies to increase patient response rates and lead to successful treatment outcomes. This Minireview will focus on nanoparticle‐based treatment modalities that can induce and enhance ICD to potentiate cancer immunotherapy.     

高分子材料调控肿瘤免疫微环境的研究进展

随着肿瘤免疫疗法在临床应用取得巨大突破,通过抗肿瘤免疫反应提高抗肿瘤疗效的治疗方式受到了广泛的关注.然而,肿瘤组织存在复杂的免疫抑制性微环境,严重限制了部分免疫疗法的效果.长期以来,高分子材料作为重要的药物递送载体受到广泛关注,但是其在调控肿瘤免疫微环境的功能及应用方面尚未引起足够的重视.在本文中,我们一方面介绍了肿瘤组织形成免疫抑制性微环境的成因,如肿瘤组织存在多种免疫抑制性细胞,如调节性T细胞(Tregs)、髓系来源抑制性细胞(MDSCs)和肿瘤相关巨噬细胞(TAMs)等,以及免疫细胞、肿瘤细胞等分泌的大量细胞因子、趋化因子、代谢产物等.另一方面,重点介绍了近年来高分子材料作为载体递送免疫调节分子或发挥自身免疫调节功能,调控或逆转免疫抑制性微环境的策略和典型代表,证明了高分子材料在调控肿瘤免疫微环境,改善肿瘤治疗效果方面的巨大潜力.     

Surface-modulated and thermoresponsive polyphosphoesternanoparticles for enhanced intracellular drug delivery

The chemical structure of end groups influenced the phase transition temperature of thermoresponsive polymers. We demonstrated a strategy for the preparation of the pH/thermo-responsive polymeric nanoparticles via subtle modification of end groups of thermoresponsive polymer segments with a carboxyl group and revealed its potential application for enhanced intracellular drug delivery. By developing a polymeric nanoparticle composed of poly(aliphatic ester) as the inner core and thermoresponsive polyphosphoester as the outer shell, we showed that end groups of thermoresponsive polyphosphoester segments modified by carboxyl groups exhibited a pH/thermo-responsive behavior due to the hydrophilic to hydrophobic transitions of the end groups in response to the pH. Moreover, by encapsulating doxorubicin into the hydrophobic core of such pH/thermo-responsive polymer nanoparticles, their intracellular delivery and cytotoxicity to wild-type and drug-resistant tumor cells were significantly enhanced through the phase-transition-dependent drug release that was triggered by endosomal/lysosomal pH. This novel strategy and the multi-responsive polymer nanoparticles achieved by the subtle chain-terminal modification of thermoresponsive polymers provide a smart platform for biomedical applications.     

Advances in Biomimetic Nanoparticles for Targeted Cancer Therapy and Diagnosis

Biomimetic nanoparticles have recently emerged as a novel drug delivery platform to improve drug biocompatibility and specificity at the desired disease site, especially the tumour microenvironment. Conventional nanoparticles often encounter rapid clearance by the immune system and have poor drug-targeting effects. The rapid development of nanotechnology provides an opportunity to integrate different types of biomaterials onto the surface of nanoparticles, which enables them to mimic the natural biological features and functions of the cells. This mimicry strategy favours the escape of biomimetic nanoparticles from clearance by the immune system and reduces potential toxic side effects. Despite the rapid development in this field, not much has progressed to the clinical stage. Thus, there is an urgent need to develop biomimetic-based nanomedicine to produce a highly specific and effective drug delivery system, especially for malignant tumours, which can be used for clinical purposes. Here, the recent developments for various types of biomimetic nanoparticles are discussed, along with their applications for cancer imaging and treatments.     

Advances in Targeting Drug Biological Carriers for Enhancing Tumor Therapy Efficacy

Chemotherapy drugs continue to be the main component of oncology treatment research and have been proven to be the main treatment modality in tumor therapy. However, the poor delivery efficiency of cancer therapeutic drugs and their potential off-target toxicity significantly limit their effectiveness and extensive application. The recent integration of biological carriers and functional agents is expected to camouflage synthetic biomimetic nanoparticles for targeted delivery. The promising candidates, including but not limited to red blood cells and their membranes, platelets, tumor cell membrane, bacteria, immune cell membrane, and hybrid membrane are typical representatives of biological carriers because of their excellent biocompatibility and biodegradability. Biological carriers are widely used to deliver chemotherapy drugs to improve the effectiveness of drug delivery and therapeutic efficacy in vivo, and tremendous progress is made in this field. This review summarizes recent developments in biological vectors as targeted drug delivery systems based on microenvironmental stimuli-responsive release, thus highlighting the potential applications of target drug biological carriers. The review also discusses the possibility of clinical translation, as well as the exploitation trend of these target drug biological carriers.     

Synthesis of mesoporous silica nanoparticles and nanorods: Application to doxorubicin delivery

The synthesis and application of mesoporous silica nanoparticles (MSN) and mesoporous silica nanorods (MSNR) for drug delivery were described. MSN or MSNR were obtained by adjusting the amount of added cosolvent to the sol-gel solution. Therefore, the addition of ethanol (EtOH) has contributed to the control of the particle shape and to the structure of the mesoporosity. MSN and MSNR particles were then loaded with doxorubicin and incubated with MCF-7 breast cancer cells. MSN and MSNR particles were efficient in killing cancer cells but their behavior in drug delivery was altered on account of the difference in their morphology. MSN showed a burst release of doxorubicin in cells whereas MSNR showed a sustained delivery of the anti-cancer drug.     

用于基因传输及磁共振显像的聚乙烯亚胺-g-聚己内酯共聚物的合成与表征

采用可生物降解的聚己内酯改性聚乙烯亚胺,得到两亲性的接枝共聚物(PEI-g-PCL).该共聚物通过溶剂挥发法在水中自组装形成纳米粒子,其内部负载有超顺磁性四氧化三铁纳米粒子(SPIO)及质粒DNA(pDNA).研究表明,PEI-g-PCL聚合物自组装形成的颗粒为胶束状,无论是否负载SPIO纳米粒子都可以有效地负载pDNA,并对293细胞具有较高的转染效率.此类载体有望在基因转染的过程中利用磁共振手段进行实时、无创观测.     

A new class of silica cross-linked micellar core-shell nanoparticles

Micellar nanoparticles made of surfactants and polymers have attracted wide attention in the materials and biomedical community for controlled drug delivery, molecular imaging, and sensing; however, their long-term stability remains a topic of intense study. Here we report a new class of robust, ultrafine silica core-shell nanoparticles formed from silica cross-linked, individual block copolymer micelles. Compared with pure polymeric micelles, the main advantage of the new core-shell nanoparticles is that they have significantly improved stability and do not break down during dilution. We also studied the drug loading and release properties of the silica cross-linked micellar particles, and we found that the new core-shell nanoparticles have a slower release rate which allows the entrapped molecules to be slowly released over a much longer period of time under the same experimental conditions. A range of functional groups can be easily incorporated through co-condensation with the silica matrix. The potential to deliver hydrophobic agents into cancer cells has been demonstrated. Because of their unique structures and properties, these novel core-shell nanoparticles could potentially provide a new nanomedicine platform for imaging, detection, and treatment, as well as novel colloidal particles and building blocks for mutlifunctional materials.     

Chitosan-based nanoparticles for in vivo delivery of interfering agents including siRNA

The potential of siRNA to knock down expression of genes has been identified as an exciting strategy for specific treatments of disease-associated genes. However, their clinical development is pended to the achievement of their effective intracellular delivery in the target cells in vivo. So far, this was a bottleneck for fast development of siRNA in clinics because of their high enzymatic susceptibility in biological media and their poor intracellular uptake. The realization of therapeutic potential of the RNA interference approach strongly depended on the rational design of safe and effective carriers. This review considers carriers made of chitosan-based nanoparticles. It reports the methods of synthesis and the interactions of siRNA with chitosan which is at the basis of the association, stability and delivery to cells of siRNA with these carriers. Results of evaluations of the interference activity produced in vitro and in vivo by the interfering molecule delivered with chitosan-based nanoparticle carriers are discussed. As pointed out from different examples, the remarkable efficacy of the chitosan-based nanoparticles to deliver active interfering agents in vivo and to achieve a successful systemic delivery including by oral administration are very encouraging. Although we are still in the early stage of developments, it can be expected that results reported so far paved the road to stimulate further developments and strengthen their clinical application perspectives.     

Stability of Self-Assembled Polymeric Micelles in Serum

The stability of polymeric nanoparticles in serum is critical to their use in drug delivery where dilution after intravenous injection often results in nanoparticle disassembly and drug unloading; however, few investigate this in biologically relevant media. To gain greater insight into nanoparticle stability in blood, the stability of self-assembled polymeric micelles of poly(d,l-lactide-co-2-methyl-2-carboxytrimethylene carbonate)-g-poly(ethylene glycol), P(LA-co-TMCC)-g-PEG, were tested in both serum and individual serum protein solutions. By encapsulating F?rster resonance energy transfer pairs and following their release by fluorescence, these micelles demonstrated excellent thermodynamic and kinetic stability in the presence of serum. Further analyses by fast protein liquid chromatography and dynamic light scattering confirmed these data. Moreover, these micelles are compatible with red blood cells, as shown by a hemolysis assay. The stability and compatibility demonstrated in blood suggest that these micelles may be stable in vivo, which is critical for intravenous drug delivery applications. This comprehensive approach to understanding micelle stability and compatibility is broadly applicable.     

Engineering Polymer Hydrogel Nanoparticles for Lymph Node‐Targeted Delivery

The induction of antigen‐specific adaptive immunity exclusively occurs in lymphoid organs. As a consequence, the efficacy by which vaccines reach these tissues strongly affects the efficacy of the vaccine. Here, we report the design of polymer hydrogel nanoparticles that efficiently target multiple immune cell subsets in the draining lymph nodes. Nanoparticles are fabricated by infiltrating mesoporous silica particles (ca. 200 nm) with poly(methacrylic acid) followed by disulfide‐based crosslinking and template removal. PEGylation of these nanoparticles does not affect their cellular association in vitro, but dramatically improves their lymphatic drainage in vivo. The functional relevance of these observations is further illustrated by the increased priming of antigen‐specific T cells. Our findings highlight the potential of engineered hydrogel nanoparticles for the lymphatic delivery of antigens and immune‐modulating compounds.     

Biodegradable polymeric nanoparticles based on amphiphilic principle: construction and application in drug delivery

The use of nanotechnology in drug-delivery systems (DDS) is attractive for advanced diagnosis and treatment of cancer diseases. Biodegradable polymeric nanoparticles, for example, have promising applications as advanced drug carriers in cancer treatment. In this review, we discuss the development of drug-delivery systems based on an amphiphilic principle mainly conducted by our group for anti-cancer drug delivery. We first briefly address the synthetic chemistry for amphiphilic biodegradable polymers. In the second part, we summarize progress in the application of self-assembled polymer micelles using amphiphilic biodegradable copolymers as anti-tumor drug carriers.     

Tumor cell surface modification with immuno-amplified nanoparticles to enhance cancer immunotherapy

The process of cancer immunogenic cell death (ICD) provides adjuvanticity and antigenicity from dying tumor cells, thereby stimulating host immune system and promoting antitumor immunity. However, due to the immune evasion of tumor cells and the immunosuppressive tumor microenvironment formed in the process of cancer progression, it is far from satisfactory in the efficacy of the cancer treatments based on ICD. Herein, we report an immuno-amplified nanoparticle (IANP) that can modify mannose onto the tumor cell surface while delivering ICD-inducing drug doxorubicin (DOX) into the tumor cytoplasm. IANP consists of a DOX-loaded polymer core encapsulated within a mannose modified, fusogenic liposome. After reaching tumor cells, IANP achieved to transfer the mannose groups onto the surface of tumor cells through membrane fusion, and simultaneously transport the polymer core into tumor cells for DOX delivery. With this unique ability, IANP triggered the ICD of tumor cells and facilitated the activation of dendritic cells (DCs) via the mannose-C-type lectin receptors (CLRs) interaction, leading to the enhanced immunogenic effects of chemotherapy-induced tumor cell death. As a result, intratumoral injection of IANP achieved to trigger ICD of tumor cells and enhance the anti-tumor immune responses, thereby suppressing the tumor growth effectively. This work demonstrated a potential strategy towards the development of novel ICD-based cancer immunotherapies.     

Polyethylenimine-based polyplex nanoparticles and features of their behavior in cells and tissues

The design of efficient systems for the targeted delivery of nucleic acids into cells is a rapidly developing area of polymer chemistry, molecular biology, and medicine. Complexes between DNA or RNA polyanions and various polycations, which are usually called polyplexes, hold promise as such delivery systems. Polyethylenimines (PEIs) and their derivatives are often used in research for the preparation of such complexes with plasmid DNA, oligonucleotides, and small RNA. Polyplex nanoparticles are employed for the delivery of genetic material into cells in culture and for the development of methods for the treatment of genetic and cancer diseases. The properties of polyplexes depend on the size, dispersity, and hydrophilicity of the used PEI or its derivatives and the ratio of polymers in the complex, which are responsible for the size, surface charge, and hydrophilicity of the resulting nanoparticles. The efficiency of polyplexes is determined by their ability to interact with components of biological systems on the surface and inside the cells, as well as with the blood vascular walls and the extracellular matrix during systemic in vivo use.     

Surface Modification of Functional Nanoparticles for Controlled Drug Delivery

Abstract

Surface‐modified nanoparticles have received much attention as drug carriers. Natural and synthetic polymers are used as the materials to prepare nanoparticles and the properties of these nanoparticles originate with these polymeric materials. In particular, these nanoparticles are modified for specific objectives. The surface characteristics of (shell) nanoparticles are more important than those of the core, because the shell layer directly contacts body fluids and organs. Generally, the nanoparticles are coated with hydrophilic polymer to give long circulation and/or are conjugated with functional ligands or proteins for site‐specific delivery. In this review, the preparative methods and the applications of surface modification of polymeric functionalized nanoparticles for long‐circulation, site‐specific delivery, and oral delivery are discussed.     

Proton-sponge coated quantum dots for siRNA delivery and intracellular imaging

We report the rational design of multifunctional nanoparticles for short-interfering RNA (siRNA) delivery and imaging based on the use of semiconductor quantum dots (QDs) and proton-absorbing polymeric coatings (proton sponges). With a balanced composition of tertiary amine and carboxylic acid groups, these nanoparticles are specifically designed to address longstanding barriers in siRNA delivery such as cellular penetration, endosomal release, carrier unpacking, and intracellular transport. The results demonstrate dramatic improvement in gene silencing efficiency by 10-20-fold and simultaneous reduction in cellular toxicity by 5-6-fold, when compared directly with existing transfection agents for MDA-MB-231 cells. The QD-siRNA nanoparticles are also dual-modality optical and electron-microscopy probes, allowing real-time tracking and ultrastructural localization of QDs during delivery and transfection. These new insights and capabilities represent a major step toward nanoparticle engineering for imaging and therapeutic applications.     

Smart polymeric materials: emerging biochemical applications

Smart polymeric materials respond with a considerable change in their properties to small changes in their environment. Environmental stimuli include temperature, pH, chemicals, and light. "Smart" stimuli-sensitive materials can be either synthetic or natural. This review discusses the application of smart materials as tools to solve biological problems such as bioseparation, drug delivery, biosensor design, tissue engineering, protein folding, and microfluidics. The goal for these endeavors is to mimic the "smartness" of biological systems and ultimately moderate complex systems such as immune responses at desired levels. The versatility and untapped potential of smart polymeric materials makes them one of the most exciting interfaces of chemistry and biology.     

Photodynamic characterization and in vitro application of methylene blue-containing nanoparticle platforms

This article presents the development and characterization of nanoparticles loaded with methylene blue (MB), which are designed to be administered to tumor cells externally and deliver singlet oxygen (1O2) for photodynamic therapy (PDT), i.e. cell kill via oxidative stress to the membrane. We demonstrated the encapsulation of MB, a photosensitizer (PS), in three types of sub-200 nm nanoparticles, composed of polyacrylamide, sol-gel silica and organically modified silicate (ORMOSIL), respectively. Induced by light irradiation, the entrapped MB generated 1O2, and the produced 1O2 was measured quantitatively with anthracene-9,10-dipropionic acid, disodium salt, to compare the effects of different matrices on 1O2 delivery. Among these three different kinds of nanoparticles, the polyacrylamide nanoparticles showed the most efficient delivery of 1O2, but its loading of MB was low. In contrast, the sol-gel nanoparticles had the best MB loading but the least efficient 1O2 delivery. In addition to investigating the matrix effects, a preliminary in vitro PDT study using the MB-loaded polyacrylamide nanoparticles was conducted on rat C6 glioma tumor cells with positive photodynamic results. The encapsulation of MB in nanoparticles should diminish the interaction of this PS with the biological milieu, thus facilitating its systemic administration. Furthermore, the concept of the drug-delivering nanoparticles has been extended to a new type of dynamic nanoplatform (DNP) that only delivers 1O2. This DNP could also be used as a targeted multifunctional platform for combined diagnostics and therapy of cancer.     

Design of polymeric nanoparticles for biomedical delivery applications

Polymeric nanoparticles-based therapeutics show great promise in the treatment of a wide range of diseases, due to the flexibility in which their structures can be modified, with intricate definition over their compositions, structures and properties. Advances in polymerization chemistries and the application of reactive, efficient and orthogonal chemical modification reactions have enabled the engineering of multifunctional polymeric nanoparticles with precise control over the architectures of the individual polymer components, to direct their assembly and subsequent transformations into nanoparticles of selective overall shapes, sizes, internal morphologies, external surface charges and functionalizations. In addition, incorporation of certain functionalities can modulate the responsiveness of these nanostructures to specific stimuli through the use of remote activation. Furthermore, they can be equipped with smart components to allow their delivery beyond certain biological barriers, such as skin, mucus, blood, extracellular matrix, cellular and subcellular organelles. This tutorial review highlights the importance of well-defined chemistries, with detailed ties to specific biological hurdles and opportunities, in the design of nanostructures for various biomedical delivery applications.     

Current Status and Trends in Nucleic Acids for Cancer Therapy: A Focus on Polysaccharide-Based Nanomedicines

The efficacious delivery of therapeutic nucleic acids to cancer still remains an open issue. Through the years, several strategies are developed for the encapsulation of genetic molecules exploiting different materials, such as viral vectors, lipid nanoparticles (LNPs), and polymeric nanoparticles (NPs). Indeed, the rapid approval by regulatory authorities and the wide use of LNPs complexing the mRNA coding for the spark protein for COVID-19 vaccination paved the way for the initiation of several clinical trials exploiting lipid nanoparticles for cancer therapy. Nevertheless, polymers still represent a valuable alternative to lipid-based formulations, due to the low cost and the chemical flexibility that allows for the conjugation of targeting ligands. This review will analyze the status of the ongoing clinical trials for cancer therapy, including vaccination and immunotherapy approaches, exploiting polymeric materials. Among those nanosized carriers, sugar-based backbones are an interesting category. A cyclodextrin-based carrier (CALAA-01) is the first polymeric material to enter a clinical trial complexed with siRNA for cancer therapy, and chitosan is one of the most characterized non-viral vectors able to complex genetic material. Finally, the recent advances in the use of sugar-based polymers (oligo- and polysaccharides) for the complexation of nucleic acids in advanced preclinical stage will be discussed.