Self-assembled FeS-based cascade bioreactor with enhanced tumor penetration and synergistic treatments to trigger robust cancer immunotherapy

Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death (ICD) to provoke a robust immune response for metastasis control. Here, a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation, chemodynamic (CDT) and photothermal therapy. Ultrasmall FeS-GOx nanodots were synthesized with glucose oxidase (GOx) as template and induced by paclitaxel (PTX) to form self-assembling FeS-GOx@PTX (FGP) via hydrophobic interaction. After accumulated at tumor sites, FGP disassembles to smaller FeS-GOx for enhanced deep tumor penetration. GOx maintains high enzymatic activity to catalyze glucose with assistant of oxygen to generate hydrogen peroxide (H₂O₂) as starvation therapy. Fenton reaction involving the regenerated H₂O₂ in turn produced more hydroxyl radicals for enhanced CDT. Following near-infrared laser at 808 nm, FGPs displayed pronounced tumor inhibition in vitro and in vivo by the combination therapy. The consequent increased exposure to calreticulin amplified ICD and promoted dendritic cells maturation. In combination with anti-CTLA4 checkpoint blockade, FGP can absolutely eliminate primary tumor and avidly inhibit distant tumors due to the enhanced intratumoral infiltration of cytotoxic T lymphocytes. Our work presents a promising strategy for primary tumor and metastasis inhibition.     

A green approach to dual-drug nanoformulations with targeting and synergistic effects for cancer therapy

Exploration of efficient dual-drug nanohybrids, particularly those with high drug loading, specific targeting property, and long-termed stability, is of highly importance in cancer therapy. A pH-driven coprecipitation was performed in the aqueous phase to obtain a dual-drug nanoformulation, composed of 10-hydroxycamptothecine (HCPT) nanoneedles integrated with an exterior thin layer of the methotrexate (MTX)–chitosan conjugate. The high stability of nanohybrids in water and the targeting property provided by the MTX ingredient function synergistically to the prolonged and sustained drug release property in tumor tissues and the increased cellular uptake. The cytotoxicity test illustrates that dual-drug nanoneedles possess the remarkable killing ability to HeLa cells with the combination index at 0.33?±?0.07. After cellular internalization, the release of both drug ingredients results in an excellent anticancer activity in vivo with the minimized adverse side effects. Design of a green approach to the carrier-free, dual-drug nanoformulations enables to develop emerging drug delivery systems for cancer diagnosis and treatment.     

Enhanced tumor homing of pathogen-mimicking liposomes driven by R848 stimulation: A new platform for synergistic oncology therapy

Although multifarious tumor-targeting modifications of nanoparticulate systems have been attempted in joint efforts by our predecessors, it remains challenging for nanomedicine to traverse physiological barriers involving blood vessels, tissues, and cell barriers to thereafter demonstrate excellent antitumor effects. To further overcome these inherent obstacles, we designed and prepared mycoplasma membrane (MM)-fused liposomes (LPs) with the goal of employing circulating neutrophils with the advantage of inflammatory cytokine-guided autonomous tumor localization to transport nanoparticles. We also utilized in vivo neutrophil activation induced by the liposomal form of the immune activator resiquimod (LPs-R848). Fused LPs preparations retained mycoplasma pathogen characteristics and achieved rapid recognition and endocytosis by activated neutrophils stimulated by LPs-R848. The enhanced neutrophil infiltration in homing of the inflammatory tumor microenvironment allowed more nanoparticles to be delivered into solid tumors. Facilitated by the formation of neutrophil extracellular traps (NETs), podophyllotoxin (POD)-loaded MM-fused LPs (MM-LPs-POD) were concomitantly released from neutrophils and subsequently engulfed by tumor cells during inflammation. MM-LPs-POD displayed superior suppression efficacy of tumor growth and lung metastasis in a 4T1 breast tumor model. Overall, such a strategy of pathogen-mimicking nanoparticles hijacking neutrophils in situ combined with enhanced neutrophil infiltration indeed elevates the potential of chemotherapeutics for tumor targeting therapy.     

An understanding of mitochondria and its role in targeting nanocarriers for diagnosis and treatment of cancer

Nanotechnology has changed the entire paradigm of drug targeting and has shown tremendous potential in the area of cancer therapy due to its specificity. In cancer, several targets have been explored which could be utilized for the better treatment of disease. Mitochondria, the so-called powerhouse of cell, portrays significant role in the survival and death of cells, and has emerged as potential target for cancer therapy. Direct targeting and nanotechnology based approaches can be tailor-made to target mitochondria and thus improve the survival rate of patients suffering from cancer. With this backdrop, in present review, we have reemphasized the role of mitochondria in cancer progression and inhibition, highlighting the different targets that can be explored for targeting of disease. Moreover, we have also summarized different nanoparticulate systems that have been used for treatment of cancer via mitochondrial targeting.     

Bone-seeking nanoplatform co-delivering cisplatin and zoledronate for synergistic therapy of breast cancer bone metastasis and bone resorption

The “vicious cycle” established between tumor growth and osteolysis aggravates the process of breast cancer bone metastasis, leading to life-threatening skeletal-related events that severely reduce survival and quality of life. To effectively interrupt the “vicious cycle”, innovative therapeutic strategies that not only reduce osteolysis but also relieve tumor burden are urgently needed. Herein, a bone-seeking moiety, alendronate (ALN), functionalized coordination polymer nanoparticles (DZ@ALN) co-delivering cisplatin prodrug (DSP) and antiresorptive agent zoledronate (ZOL) via Zn²⁺ crosslinking for combination therapy was reported. The versatile DZ@ALN with a diameter of about 40 nm can cross the fissure in the bone marrow sinus capillaries, and possesses an excellent bone-seeking ability both in vitro and in vivo. Additionally, DZ@ALN could synergistically inhibit the proliferation of cancer cells, suppress the formation of osteoclast-like cells and induce the apoptosis of osteoclasts in vitro. Importantly, it could preferentially accumulate in bone affected site, remarkably inhibit the proliferation of tumor cells, relieving bone pain, and significantly inhibit the activation of osteoclasts, protecting the bone from destruction in vivo, eventually leading to the breakdown of “vicious cycle” without inducing obvious systemic toxicity. This innovative nanoagent combines chemotherapy and osteolysis inhibition, exhibiting an inspiring strategy for effective treatment of bone metastasis.     

恶性瘤病人术前化疗后氧自由基及红细胞改变

目的 了解恶性瘤病人术前化疗后氧自由基变化和红细胞形态及渗透脆性改变。方法 对术前化疗与未化疗各２０例于术前进行过氧化脂质（ＬＰＯ）、黄嘌呤氧化酶（ＸＯ）及超氧物歧化酶（ＳＯＤ）检测，对两组各５例作红细胞透射和扫描电镜观察，对两组各１０例作红细胞渗透脆性试验。结果 化疗组和非化疗组两组病人的ＬＰＯ、ＸＯ均明显高于正常值，而ＳＯＤ则明显低于正常值，化疗组更为突出。两组红细胞透射电镜和扫描电镜观察均见     

紫杉醇联合卡铂化疗治疗卵巢癌的临床观察

目的观察紫杉醇联合卡铂化疗方案治疗卵巢癌的疗效和毒副反应。方法40例卵巢癌患者用“紫杉醇＋卡铂”全身化疗或“紫杉醇＋卡铂”腹腔化疗,观察其疗效及不良反应。结果40例中,CR12例,PR18例,SD6例,PD4例,总有效率75％,主要不良反应为骨髓抑制、脱发、恶心、呕吐,但均可耐受。结论紫杉醇联合卡铂化疗方案治疗卵巢癌有较好疗效,不良反应可耐受。     

Synchronous delivery of oxygen and photosensitizer for alleviation of hypoxia tumor microenvironment and dramatically enhanced photodynamic therapy

Photosensitizer, proper laser irradiation, and oxygen are essential components for effective photodynamic therapy (PDT) in clinical cancer therapy. However, native hypoxic tumoral microenvironment is a major barrier hindering photodynamic reactions in vivo. Thus, we have prepared biocompatible liposomes by loading complexes of oxygen-carrier (hemoglobin, Hb) and photosensitizer (indocyanine green, ICG) for enhanced PDT against hypoxic tumor. Ideal oxygen donor Hb, which is an oxygen-carried protein in red blood cells, makes such liposome which provide stable oxygen supply. ICG, as a photosensitizer, could transfer energy from lasers to oxygen to generate cytotoxic reactive oxygen species (ROS) for treatment. The liposomes loading ICG and Hb (LIH) exhibited efficient tumor homing upon intravenous injection. As revealed by T₂-weighted magnetic resonance imaging and immunohistochemical analysis, the intratumoral hypoxia was greatly alleviated, and the level of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in tumor was obviously down-regulated. A weak PDT efficiency was found in cells incubated in simulated hypoxia condition in vitro, while PDT effect was dramatically enhanced in LIH treated hypoxia cells under near-infrared (NIR) laser, which was mainly attributed to massive generation of ROS with sufficient oxygen supply. ROS trigger oxidative damage of tumors and induce complete suppression of tumor growth and 100% survival rate of mice, which were also in good health condition. Our work highlights a liposome-based nanomedicine that could effectively deliver oxygen to tumor and alleviate tumor hypoxia state, inducing greatly improved efficacy compared to conventional cancer PDT and demonstrates the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome limitations of cancer therapies.     

Blocking drug-induced autophagy with chloroquine in HCT-116 colon cancer cells enhances DC maturation and T cell responses induced by tumor cell lysate

Autophagy is an important mechanism for tumor escape, allowing tumor cells to recover from the damage induced by chemotherapy, radiation therapy, and immunotherapy and contributing to the development of resistance. The pharmacological inhibition of autophagy contributes to increase the efficacy of antineoplastic agents. Exposing tumor cells to low concentrations of select autophagy-inducing antineoplastic agents increases their immunogenicity and enhances their ability to stimulate dendritic cell (DC) maturation. We tested whether the application of an autophagy-inhibiting agent, chloroquine (CQ), in combination with low concentrations of 5-fluorouracil (5-FU) increases the ability of tumor cells to induce DC maturation. DCs sensitized with the lysate of HCT-116 cells previously exposed to such a combination enhanced the DC maturation/activation ability. These matured DCs also increased the allogeneic responsiveness of both CD4+ and CD8+ T cells, which showed a greater proliferative response than those from DCs sensitized with control lysates. The T cells expanded in such cocultures were CD69+ and PD-1- and produced higher levels of IFN-γ and lower levels of IL-10, consistent with the preferential activation of Th1 cells. Cocultures of autologous DCs and lymphocytes improved the generation of cytotoxic T lymphocytes, as assessed by the expression of CD107a, perforin, and granzyme B. The drug combination increased the expression of genes related to the CEACAM family (BECN1, ATGs, MAPLC3B, ULK1, SQSTM1) and tumor suppressors (PCBP1). Furthermore, the decreased expression of genes related to metastasis and tumor progression (BNIP3, BNIP3L, FOSL2, HES1, LAMB3, LOXL2, NDRG1, P4HA1, PIK3R2) was noted. The combination of 5-FU and CQ increases the ability of tumor cells to drive DC maturation and enhances the ability of DCs to stimulate T cell responses.     

多西他赛、顺铂化疗并同步放疗联合综合护理在头颈部鳞癌中的应用效果

目的探讨多西他赛、顺铂化疗并同步放疗联合综合护理在头颈部鳞癌中的应用效果。方法将62例局部晚期头颈部鳞癌患者随机分为对照组（n=31）和观察组（n=31）,两组患者均采用3-DCRT放疗,总剂量为DT60～70Gy／6-7周,对照组放疗结束后静脉滴注多西他赛60mg／m2,d1,顺铂25mg／m2,d1-3,1周期／3周,共2个周期。观察组在3-DCRT放疗的同时静脉滴注多西他赛20mg／m2,d1,顺铂25mg／m2,d1,1次／周,共治疗8周。对照组给予常规护理,观察组给予综合护理干预。结果观察组和对照组的总有效率分别为70．97％和41．94％,差异有统计学意义（P〈0．05）;观察组在胃肠道反应、口腔黏膜反应及皮肤反应等方面的毒副反应较对照组明显减轻（P〈0．05）。结论多西他赛联合顺铂化疗并同步放疗治疗局部晚期头颈部鳞癌的效果较好,综合护理干预措施能减轻胃肠道反应、口腔黏膜反应和皮肤反应。     

曲妥珠单抗联合化疗治疗晚期乳腺癌的观察与护理

目的：观察曲妥珠单抗联合化疗治疗晚期乳腺癌。方法：曲妥珠单抗联合化疗治疗晚期乳腺癌49例,并针对患者心理、并发症等采取护理措施。结果：49例患者顺利完成化疗,总有效率为89.8%,引起了血液系统、消化系统及神经系统等毒副作用,但可耐受。结论：治疗期间重点做到针对患者心理、并发症的观察与护理,能有效控制曲妥珠单抗联合化疗治疗晚期乳腺癌的不良反应,提高疗效。     

Transferrin and octaarginine modified dual-functional liposomes with improved cancer cell targeting and enhanced intracellular delivery for the treatment of ovarian cancer

Off-target effects of drugs severely limit cancer therapy. Targeted nanocarriers are promising to enhance the delivery of therapeutics to tumors. Among many approaches for active tumor-targeting, arginine-rich cell penetrating peptides (AR-CPP) and ligands specific to target over-expressed receptors on cancer-cell surfaces, are popular. Earlier, we showed that the attachment of an AR-CPP octaarginine (R8) to the surface of DOXIL^® (Doxorubicin encapsulated PEGylated liposomes) improved cytoplasmic and nuclear DOX delivery that enhanced the cytotoxic effect in vitro and improved therapeutic efficacy in vivo. Here, we report on DOX-loaded liposomes, surface-modified with, R8 and transferrin (Tf) (Dual DOX-L), to improve targeting of A2780 ovarian carcinoma cells via the over-expressed transferrin receptors (TfRs) with R8-mediated intracellular DOX delivery. Flow cytometry analysis with fluorescently labeled DualL (without DOX) showed two-fold higher cancer-cell association than other treatments after 4?h treatment. Blocking entry pathways of R8 (macropinocytosis) and Tf (receptor-mediated endocytosis, RME) resulted in a decreased cancer-cell association of DualL. Confocal microscopy confirmed involvement of both entry pathways and cytoplasmic liposome accumulation with nuclear DOX delivery for Dual DOX-L. Dual DOX-L exhibited enhanced cytotoxicity in vitro and was most effective in controlling tumor growth in vivo in an A2780 ovarian xenograft model compared to other treatments. A pilot biodistribution study showed improved DOX accumulation in tumors after Dual DOX-L treatment. All results collectively presented a clear advantage of the R8 and Tf combination to elevate the therapeutic potential of DOX-L by exploiting TfR over-expression imparting specificity followed by endosomal escape and intracellular delivery via R8.     

Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages

Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy. However, most reported polymeric systems have sizes above 100 nm, which limits effective extravasation into tumors that are poorly vascularized and have dense stroma. This will, in turn, limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting. In this study, we combined the passive targeting via ultra-small-sized gemcitabine (GEM)-based nanoparticles (NPs) with the active targeting provided by folic acid (FA) conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages (TAMs). We developed an FA-modified prodrug carrier based on GEM (PGEM) to load doxorubicin (DOX), for co-delivery of GEM and DOX to tumors. The co-delivery system showed small particle size of ～10 nm in diameter. The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile. The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor (FR), but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR. Interestingly, in vivo, systemic delivery of FA-PGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model. Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2, which was selectively expressed on TAMs. Thus, targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.     

Thermosensitive magnetic liposomes with doxorubicin cell-penetrating peptides conjugate for enhanced and targeted cancer therapy

To specifically deliver cytotoxic drug to tumor cells and enhance cellular uptake is the key for effective cancer therapy. In this paper, we described a novel drug targeting system, which is designed to combine features of biological (cell-penetrating peptides, CPPs) and physical (magnetic) drug targeting for use in the magnetic hyperthermia-triggered release. A doxorubicin–CPPs conjugate (DOX-CPPs) was loaded into thermosensitive magnetic liposomes (TSMLs) (DOX-CPPs/TSMLs), and in vitro DOX-CPPs thermosensitive release activity, anti-proliferation effect, in vivo targeted delivery as well as in vivo antitumor activity were determined. The results demonstrated that the DOX-CPPs/TSMLs showed good physicochemical properties, effective anti-proliferation effect in MCF-7 cells in vitro. Additionally, in vivo study, DOX-CPPs/TSMLs under AC magnetic field displayed superior in vivo targeted delivery efficacy, antitumor efficacy in an MCF-7 xenograft murine model. In conclusion, the application of DOX-CPPs/TSMLs under AC magnetic field may provide a strategy for the selective and efficient delivery of drug.     

Targeting peptide-decorated biomimetic lipoproteins improve deep penetration and cancer cells accessibility in solid tumor

The limited penetration of nanoparticles and their poor accessibility to cancer cell fractions in tumor remain essential challenges for effective anticancer therapy. Herein, we designed a targeting peptide-decorated biomimetic lipoprotein (termed as BL-RD) to enable their deep penetration and efficient accessibility to cancer cell fractions in a tumor, thereby improving the combinational chemo-photodynamic therapy of triple negative breast cancer. BL-RD was composed of phospholipids, apolipoprotein A1 mimetic peptide (PK22), targeting peptide-conjugated cytotoxic mertansine (RM) and photodynamic agents of DiIC18(5) (DiD). The counterpart biomimetic lipoprotein system without RM (termed as BL-D) was fabricated as control. Both BL-D and BL-RD were nanometer-sized particles with a mean diameter of less than 30 nm and could be efficiently internalized by cancer cells. After intravenous injection, they can be specifically accumulated at tumor sites. When comparing to the counterpart BL-D, BL-RD displayed superior capability to permeate across the tumor mass, extravasate from tumor vasculature to distant regions and efficiently access the cancer cell fractions in a solid tumor, thus producing noticeable depression of the tumor growth. Taken together, BL-RD can be a promising delivery nanoplatform with prominent tumor-penetrating and cancer cells-accessing capability for effective tumor therapy.