Revitalizing Cytokine-Based Cancer Immunotherapy through Advanced Delivery Systems

Cytokines can coordinate robust immune responses, holding great promise as therapeutics against infections, autoimmune diseases, and cancers. In cancer treatment, numerous pro-inflammatory cytokines have displayed promising efficacy in preclinical studies. However, their clinical application is hindered by poor pharmacokinetics, significant toxicity and unsatisfactory anticancer efficacy. Thus, while IFN-α and IL-2 are approved for specific cancer treatments, other cytokines still remain subject of intense investigation. To accelerate the application of cytokines as cancer immunotherapeutics, strategies need to be directed to improve their safety and anticancer performance. In this regard, delivery systems could be used to generate innovative therapies by targeting the cytokines or nucleic acids, such as DNA and mRNA, encoding the cytokines to tumor tissues. This review centers on these innovative delivery strategies for cytokines, summarizing key approaches, such as gene delivery and protein delivery, and critically examining their potential and challenges for clinical translation.     

Hyperbranched Polyglycerol-Induced Porous Silica Nanoparticles as Drug Carriers for Cancer Therapy In Vitro and In Vivo

Mesoporous silica-based nanoparticles are generally accepted as a potential platform for drug loading with a lot of advantages, except for their complex purification procedures and structures that are difficult to decompose. In this work, biocompatible hyperbranched polyglycerol is introduced to synthesize mesoporous silica nanoparticles (MSNs). The materials possess good biocompatibility, controlled release, and biodegradability. They also show passive targeting capability through the enhanced permeability and retention effect and can be excreted from the biological system. The method avoids the needs to employ traditional surfactants and complicated purified procedures, which make these MSNs an efficient delivery system for cancer therapy.     

A Review on Cancer Immunotherapy and Applications of Nanotechnology to Chemoimmunotherapy of Different Cancers

Clinically, different approaches are adopted worldwide for the treatment of cancer, which still ranks second among all causes of death. Immunotherapy for cancer treatment has been the focus of attention in recent years, aiming for an eventual antitumoral effect through the immune system response to cancer cells both prophylactically and therapeutically. The application of nanoparticulate delivery systems for cancer immunotherapy, which is defined as the use of immune system features in cancer treatment, is currently the focus of research. Nanomedicines and nanoparticulate macromolecule delivery for cancer therapy is believed to facilitate selective cytotoxicity based on passive or active targeting to tumors resulting in improved therapeutic efficacy and reduced side effects. Today, with more than 55 different nanomedicines in the market, it is possible to provide more effective cancer diagnosis and treatment by using nanotechnology. Cancer immunotherapy uses the body’s immune system to respond to cancer cells; however, this may lead to increased immune response and immunogenicity. Selectivity and targeting to cancer cells and tumors may lead the way to safer immunotherapy and nanotechnology-based delivery approaches that can help achieve the desired success in cancer treatment.     

Polymeric Micelles in Cancer Immunotherapy

Cancer immunotherapies have generated some miracles in the clinic by orchestrating our immune system to combat cancer cells. However, the safety and efficacy concerns of the systemic delivery of these immunostimulatory agents has limited their application. Nanomedicine-based delivery strategies (e.g., liposomes, polymeric nanoparticles, silico, etc.) play an essential role in improving cancer immunotherapies, either by enhancing the anti-tumor immune response, or reducing their systemic adverse effects. The versatility of working with biocompatible polymers helps these polymeric nanoparticles stand out as a key carrier to improve bioavailability and achieve specific delivery at the site of action. This review provides a summary of the latest advancements in the use of polymeric micelles for cancer immunotherapy, including their application in delivering immunological checkpoint inhibitors, immunostimulatory molecules, engineered T cells, and cancer vaccines.     

季戊四醇-偏苯三酸酐-环氧氯丙烷合成超支化聚合物

以季戊四醇为“中心核”,与1,2,4-偏苯三甲酸酐和环氧氯丙烷反应合成超支化碱溶性聚酯,利用合成聚合物分子外围的羧基与甲基丙烯酸缩水甘油酯反应,在超支化聚合物分子外围引入反应性甲基丙烯酰氧基.研究了树脂组成对感光性和碱溶性的影响.结果表明:通过调整分子外围的羧基及反应性甲基丙烯酰氧基含量,可以获得较好的碱溶性和光固化性能.     

Improving Cancer Immunotherapy Outcomes Using Biomaterials

Immunotherapy has made great strides in improving clinical outcomes in cancer treatment. However, few patients exhibit adequate response rates for key outcome measures and desired long‐term responses, and they often suffer systemic side effects due to the dynamic nature of the immune system. This has motivated a search for alternative strategies to improve unsatisfactory immunotherapeutic outcomes. In recent years, biomaterial‐assisted immunotherapy has shown promise in cancer treatment with improved therapeutic efficacy and reduced side effects. These biomaterials have illuminated fundamental mechanisms underlying the immunoediting process, while greatly improving the efficacy of chimeric antigen receptor (CAR) T‐cell therapy, cancer vaccine therapy, and immune checkpoint blockade therapy. This Minireview discusses recent advances in engineered biomaterials that address limitations associated with conventional cancer immunotherapies.     

功能化修饰的超支化聚缩水甘油醚在药物载体领域的应用

随着纳米医学的发展,具有控制释放药物和生物活性分子、靶向刺激响应生理环境的聚合物纳米载体成为该领域活跃而具潜力的研究方向。超支化聚缩水甘油醚因其特定的三维结构、良好的亲水性、生物相容性和可修饰性而引起生物材料界的广泛关注。而经功能化修饰的超支化聚缩水甘油醚还可自组装成胶束、囊泡等药物载体或共价偶联成大分子前药。本文从超支化聚缩水甘油醚的疏水两亲修饰、环境敏感性功能化和超分子组装体改性三方面综述了功能化修饰的超支化聚缩水甘油醚在药物载体领域的研究进展。并系统归纳了超支化聚缩水甘油醚两亲功能化、环境敏感功能化的分子设计策略。另外,对基于环糊精主客体作用的超支化超分子聚缩水甘油醚共聚物的组装行为进行了简述。     

超支化有机硅基聚合物

超支化有机硅基聚合物(HBOSP)是一类新型功能性半有机半无机聚合物,在催化剂载体、陶瓷前驱体、发光材料和耐热材料等领域都有非常广阔的应用前景.本文概述了近10年来利用ABx、A2-Bx或A2-B'Bx-1以及Bf-ABx型单体制备新型结构HBOSP的进展,以及对这类聚合物的分子量及其分布和支化度调控的研究进展;着重总结了近年来针对该类聚合物的端基功能化改性及其应用情况,并在此基础上展望了该类聚合物的研究趋势.     

Hyperbranched Polymers by Type II Photoinitiated Self‐Condensing Vinyl Polymerization

Type II photoinitiated self‐condensing vinyl polymerization for the preparation of hyperbranched polymers is explored using 2‐hydroxyethyl methacrylate (HEMA) or 2‐(dimethylamino)ethyl methacrylate (DMAEMA), and methyl methacrylate as hydrogen donating inimers and comonomer, respectively, in the presence of benzophenone and camphorquinone under UV and visible light. Upon irradiation at the corresponding wavelength, the excited photoinitiator abstracts hydrogen from HEMA or DMAEMA leading to the formation of initiating radicals. Depending on the concentration of inimers, type of the photoinitiator, and irradiation time, hyperbranched polymers with different branching densities and cross‐linked polymers are formed.

     

Hyperbranched copolymer micelles as delivery vehicles of doxorubicin in breast cancer cells

Four types of drug nanoparticles (NPs) based on amphiphilic hyperbranched block copolymers were developed for the delivery of the chemotherapeutic doxorubicin (DOX) to breast cancer cells. These carriers have their hydrophobic interior layer composed of the hyperbranched aliphatic polyester, Boltorn^® H30 or Boltorn^® H40, that are polymers of poly 2,2‐bis (methylol) propionic acid (bis‐MPA), while the outer hydrophilic shell was composed of about 5 poly(ethylene glycol) (PEG) segments of 5 or 10 kDa molecular weight. A chemotherapeutic drug DOX, was further encapsulated in the interior of these polymer micelles and was shown to exhibit a controlled release profile. Dynamic light scattering and transmission electron microscopy analysis confirmed that the NPs were uniformly sized with a mean hydrodynamic diameter around 110 nm. DOX‐loaded H30‐PEG10k NPs exhibited controlled release over longer periods of time and greater cytotoxicity compared with the other materials developed against our tested breast cancer cell lines. Additionally, flow cytometry and confocal scanning laser microscopy studies indicated that the cancer cells could internalize the DOX‐loaded H30‐PEG10k NPs, which contributed to the sustained drug release, and induced more apoptosis than free DOX did. These findings indicate that the H30‐PEG10k NPs may offer a very promising approach for delivering drugs to cancer cells. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Entanglement Transition in Hyperbranched Polyether‐Polyols

Are hyperbranched polymers capable of forming entanglements? This is the central issue of this contribution. Hyperbranched polyglycerol (hbPG) samples with different molecular weights (600–106 000 g · mol⁻¹), narrow polydispersities (1.2–1.8) and high degrees of branching (≈0.6) were prepared by anionic ring‐opening polymerization. The viscoelastic properties of these polymers with respect to molecular architecture and molar mass were investigated. At low molecular weights “classical” scaling behavior between zero shear viscosity and molecular weight can be observed, whereas between 3 000 and 10 000 g · mol⁻¹ a plateau‐like area is found. The results indicate entanglement dynamics when exceeding a critical molar mass ( ≈ 20 000 g · mol⁻¹) due to entangled hyperbranched polyglycerols.

     

Two Routes for Immobilization of a Hyperbranched OH-Terminated Polyester on a Silicon Surface

Summary: Stable thin films of a hyperbranched aromatic-aliphatic OH-terminated polyester (POH) were prepared on silicon substrates. We report on grafting-to processes using macromolecular (PGMA) and bifunctional low-molecular weight coupling agents (BOX). An appropriate annealing procedure was developed for the covalent immobilization. The HBP films were characterized with spectroscopic ellipsometry, drop shape analysis (DSA), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and electrokinetic measurements. The immobilized films have an uniform surface morphology and are slightly hydrophilic (θ_a = 79°). The grafting process did not influence the chemical composition and the surface properties, which is important for the further application as functional layers in aqueous media.     

Hyperbranched copolyfluorene from a 2,4,7‐trifunctional fluorene monomer

A new hyperbranched ( P1 ) and linear copolyfluorene ( P2 ) were prepared from 2,4,7‐trifunctional (branching) and 2,7‐bifunctional fluorene monomer, respectively, by the Wittig reaction, followed with end‐capping by aromatic oxadiazole groups, to study the effect of hyperbranch structure. The weight‐average molecular weights (M_w) of P1 and P2 , determined by gel permeation chromatography using polystyrene as standard, were 33,000 and 25,700, respectively. The polymers were readily soluble in common organic solvents and exhibited good thermal stability (T_d > 400 °C). Optical properties, both in solution and film state, were investigated using absorption and photoluminescence (PL) spectra. In film state, the absorption and PL spectra peaked at 401–425 nm and 480–495 nm, respectively. The P1 showed energy funnel effect and enhanced fluorescence efficiency owing to hyperbranched structure and terminal oxadiazole groups. The HOMO and LUMO levels of P1 ( P2) , estimated from cyclic voltammograms, are ?5.34 (?5.25) eV and ?2.94 (?2.94) eV, respectively. Two‐layer polymer light‐emitting diodes devices (ITO/PEDOT/ P1 /Ca/Al) exhibited maximal luminance and luminous efficiency of 3630 cd/m² and 0.78 cd/A, respectively, which are superior to its linear counterpart P2 (598 cd/m², 0.11 cd/A). © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5541–5551, 2007     

Hyperbranched polyalkenylsilanes by hydrosilylation with platinum catalysts. I. Polymerization

Hyperbranched polycarbosilanes were synthesized by hydrosilylation addition of methyldivinylsilane, methyldiallylsilane, triallylsilane, and methyldiundecenylsilane. Molecular mass distributions of the hyperbranched polymers were investigated upon systematic variation of the reaction conditions. The formation of hyperbranched polycarbosilanes depended strongly on the reaction conditions and the monomer structure. Although cyclization reactions impeded the build up of molecular weight, crosslinking due to rearrangement reactions caused the formation of multimodal molecular weight distributions and gelation. Crosslinking could be avoided by the appropriate choice of the reaction conditions. In the case of methyldiundecenylsilane, where the distance between the double bond and silicon atom essentially was enlarged, high molecular weight polymers with remarkably narrow molecular weight distributions were obtained; the molecular mass could be controlled by subsequent addition of further monomer. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 741–751, 2000     

Activation of Stimulation of Interferon Genes (STING) Signal and Cancer Immunotherapy

Stimulator of interferon gene (STING), an intracellular receptor in the endoplasmic reticulum, could induce the production of cytokines such as type I interferon (IFN) by activating the cGAS-STING signal pathway. In recent years, activation of STING has shown great potential to enhance anti-tumor immunity and reshape the tumor microenvironment, which is expected to be used in tumor immunotherapy. A number of STING agonists have demonstrated promising biological activity and showed excellent synergistic anti-tumor effects in combination with other cancer therapies in preclinical studies and some clinical trials. The combination of STING agonists and ICI also showed a potent effect in improving anti-tumor immunity. In this review, we introduce the cGAS-STING signaling pathway and its effect in tumor immunity and discuss the recent strategies of activation of the STING signaling pathway and its research progress in tumor immunotherapy.     

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.     

Nanocomposites of Size‐Tunable ZnO‐Nanoparticles and Amphiphilic Hyperbranched Polymers

Highly dispersed ZnO nanoparticles with variable particle sizes were successfully prepared within an amphiphilic hyperbranched polyetherpolyol matrix via decomposition of an organometallic precursor in the presence of air leading to stable nanocomposites. The high degree of stabilization during and after the synthesis by the polymer permits control over the nanoparticle size and therefore, due to the quantum‐size‐effect, the particle properties. Furthermore, these polymer‐inorganic nanocomposites can easily be dispersed in apolar solvents to yield highly transparent, stable solutions.

     

Hyperbranched Polymers in Cationic UV Curing

Summary: A wide range of hyperbranched polymers (HBP) was synthesized and investigated as additives in cationic photopolymerization of epoxy systems. The HBP were inserted into the polymeric network either by a copolymerization or through a chain transfer reaction involving the phenolic hydroxyl groups. By varying the type and concentration of HBP a modification of the bulk properties of photocured films was induced. An increase of toughness properties together with a flexibilization was obtained without affecting the processability and the viscosity of the photocurable mixture. In the presence of fluorine-containing HBP, a surface modification was induced.     

Hyperbranched luminescent polyfluorenes containing aromatic triazole branching units

Using a new aromatic 1,2,4‐triazole branching monomer (4.8–13.3 mol %), three hyperbranched polyfluorenes ( P2 – P4 ) were synthesized by the Suzuki coupling reaction to investigate the structural effect on optoelectronic properties. Poly(9,9‐dihexylfluorene) ( P1 ) was also prepared for comparative investigation. Their weight‐average molecular weights and polydispersity indices are in the range of 1.16 × 10⁴ to 5.9 × 10⁴ and 1.49–2.25, respectively. Optical properties, both in solution and film state, were investigated using absorption and photoluminescence (PL) spectra. In film state, the absorption and PL spectra peaked at 377–392 and 424–425 nm, respectively, blue‐shift with increasing triazole concentration. Furthermore, a linear relationship between 1/λ_max,abs and 1/(1 ? n_triazole) is correlated (n: molar fraction), indicating a smooth decrease in conjugation length by incorporation of the branch unit. The P4 containing 13.3 mol % triazole reveals stable blue emission even at 150 °C (in air). The HOMO and LUMO levels of P2 – P4 , estimated from cyclic voltammograms, are ?5.69, ?5.73, ?5.78 eV and ?2.63, ?2.64, ?2.63 eV, respectively. The maximal brightness (current efficiency) of the electroluminescent devices (ITO/PEDOT:PSS/ P2 – P4 /Ca/Al) improves from 828 cd/m² (0.19 cd/A) to 2054 cd/m² (0.46 cd/A) with increasing triazole concentration. The results suggest that incorporation of aromatic 1,2,4‐triazole branch units is an effective way to improve annealing stability and EL performance of polyfluorenes. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 4465–4476, 2007     

The Microbiome and Its Implications in Cancer Immunotherapy

Cancer is responsible for ~18 million deaths globally each year, representing a major cause of death. Several types of therapy strategies such as radiotherapy, chemotherapy and more recently immunotherapy, have been implemented in treating various types of cancer. Microbes have recently been found to be both directly and indirectly involved in cancer progression and regulation, and studies have provided novel and clear insights into the microbiome-mediated emergence of cancers. Scientists around the globe are striving hard to identify and characterize these microbes and the underlying mechanisms by which they promote or suppress various kinds of cancer. Microbes may influence immunotherapy by blocking various cell cycle checkpoints and the production of certain metabolites. Hence, there is an urgent need to better understand the role of these microbes in the promotion and suppression of cancer. The identification of microbes may help in the development of future diagnostic tools to cure cancers possibly associated with the microbiome. This review mainly focuses on various microbes and their association with different types of cancer, responses to immunotherapeutic modulation, physiological responses, and prebiotic and postbiotic effects.