Complete rejection of large established breast cancer by local immunochemotherapy with T cell activation against neoantigens.

Cancer immunotherapies, including immune checkpoint blockage and adoptive transfer of CAR-T cells, have achieved historical successes for many kinds of malignancy. However, a minority of patients survive long term over 5 years without relapse, perhaps owing to tumor heterogeneity and potent immunosuppression in the tumor microenvironment. Here, using an established mouse tumor model of triple-negative 4T1 breast cancer, we show that local immunochemotherapy triggers powerful local and systemic antitumor immunity. Paraneoplastic injection of CpG, α-OX40, and anthracycline completely eliminated both local and distant large established 4T1 breast cancer without obvious relapse. Analysis of the immune cells at tumor tissues, draining lymph nodes, and spleens revealed that the local treatment increased the infiltration of CD4+ and CD8+ T cells in all three tissues and inhibited the accumulation of myeloid-derived suppressor cells in the spleen in a delayed response. Most importantly, this treatment triggered systemic T cell response against 4T1 tumors and some of their neoantigen epitopes as detected by IFN-γ ELISpot and intracellular cytokine assays in splenocytes. Furthermore, T cells showed specific cytotoxic activity against 4T1 tumor cells in vitro. In general, this local immunochemotherapy provides a new approach to target highly diverse neoantigens in various types of cancers without complicated and expensive antigen identification via next-generation sequencing.

A reconstituted thermosensitive hydrogel system based on paclitaxel-loaded amphiphilic copolymer nanoparticles and antitumor efficacy.

Combination delivery systems composed of injectable hydrogels and drug-incorporated nanoparticles are urgently in regional cancer chemotherapy to facilitate efficient delivery of chemotherapeutic agents, enhance antitumor efficiency, and decrease side effects. Here, we developed a novel thermosensitive amphiphilic triblock copolymer consisting of methoxy poly(ethylene glycol), poly(octadecanedioic anhydride), and d,l-lactic acid oligomer (PEOALA), built a combination system of thermosensitive injectable hydrogel PTX/PEOALAGel based on paclitaxel (PTX)-loaded PEOALA nanoparticles (NPs). PTX/PEOALAGel could be stored as freeze-dried powders of paclitaxel-loaded PEOALA NPs, which could be easily redispersed into the water at ambient temperature, and form a hydrogel at the injected site in vivo. The in vitro cytotoxicity of PTX/PEOALAGel showed no obvious cytotoxicity in comparison with Taxol® against MCF-7 and HeLa cells. However, the in vivo antitumor activity showed that a single intratumoral injection of the PTX/PEOALAGel formulation was more effective than four intravenous (i.v.) injections of Taxol® at a total dosage of 20 mg/kg in inhibiting the growth of MCF-7 tumor-bearing Balb/c mice, and the inhibition could be sustained for more than 17 d. The pharmacokinetic study demonstrated that the intratumoral injection of PTX/PEOALAGel could greatly decrease the systemic exposure of PTX, as confirmed by the rather low plasma concentration, and prolonged circulation time and enhanced tumor PTX accumulation, implying fewer off-target side effects. In summary, the PTX/PEOALAGel combination local delivery system could enhance tumor inhibition effect and tumor accumulation of PTX, and lower the systemic exposure. So, the reconstituted PTX/PEOALAGel system could potentially be a useful vehicle for regional cancer chemotherapy.

Solitary breast cancer metastasis to pelvic bone treated with a unique method of surgery combined with local doxorubicin administration.

Treatment of bone metastasis is a major challenge for current and future orthopedic and oncology specialists. For the treatment of single metastases, there is a continuing search for effective local treatments that do not affect the whole patient. The current report describes the case of single breast cancer metastasis to the pelvic bone in a 50-year-old woman treated surgically by bone osteotomy combined with local doxorubicin application. The presence of cancer cells was confirmed by histopathological examination. After 6 months, the same defect was operated on again and a successful therapeutic result was confirmed by negative tumor pathology tests. The bone defect caused by osteotomy was reconstructed with allogenic bone grafts that healed completely over 14 months. To the best of our knowledge, this report is the first to combine the removal bone metastasis with direct local cytostatic drug administration without the use of a specific carrier, followed by successful bone reconstruction 6 months later using bone allografts. Thus, single bone metastasis may be successfully treated with resection and local cytostatic administration, enabling bone reconstruction in the postoperative period. The potential benefits of such treatments must be evaluated by considering the potential risks involved, including necrosis of surrounding soft tissues and general reactions to the chemotherapy. No data has been available until now regarding the risk of cancer disease generalization being influenced by such treatments, but patient quality of life can be improved significantly by the successful removal of a solitary bone metastasis. The present case report supports the continuation of research on improving local cytostatic drug administration during the treatment of bone metastasis.

Injectable, Adhesive Albumin Nanoparticle-Incorporated Hydrogel for Sustained Localized Drug Delivery and Efficient Tumor Treatment.

Injectable hydrogels are receiving increasing attention as local depots for sustained anticancer drug delivery. However, most current hydrogel-based carriers lack tissue-adhesive ability, a property that is important for the immobilization of drug-loaded systems at tumor sites to increase local drug concentration. In this study, we developed a paclitaxel (PTX)-loaded injectable hydrogel with firm tissue adhesion for localized tumor therapy. PTX-loaded bovine serum albumin (BSA) nanoparticles (PTX@BN) were prepared, and the drug-loaded hydrogel was then fabricated by cross-linking PTX@BN with o-phthalaldehyde (OPA)-terminated 4-armed poly(ethylene glycol) (4aPEG-OPA) via a condensation reaction between OPA and the amines in BSA. The hydrogel showed firm adhesion to various organs and tumor tissues ex vivo due to the condensation reaction of unreacted OPA groups and amines in the tissues. The PTX-loaded nanocomposite hydrogels sustained PTX release over 30 days following the Korsmeyer-Peppas model and exhibited notable inhibition activities against mouse C26 colon and 4T1 breast cancer cells in vitro. Following peritumoral injection into mice with C26 or 4T1 tumors, the PTX@BN-loaded hydrogel significantly enhanced the antitumor efficacy and prolonged animal survival time compared to free PTX solutions with low systemic toxicity. Therefore, the adhesive, PTX-loaded nanocomposite hydrogels have the potential for efficient localized tumor therapy.

Biodegradable Local Chemotherapy Platform with Prolonged and Controlled Release of Doxorubicin for the Prevention of Local Tumor Recurrence.

Local recurrence after surgical and therapeutic treatment remains a significant clinical problem in oncology. Recurrence may be due to imperfections in existing therapies, particularly chemotherapy. To improve antitumor activity and prevent local cancer recurrence while keeping toxicity at acceptable levels, we have developed and demonstrated a biodegradable local chemotherapy platform that provides controlled and prolonged drug release. The platform consists of a polycaprolactone (PCL) substrate, which provides the structural integrity of the platform and the predominant unidirectional drug release, and a thin multilayer coating (∼200 nm) containing doxorubicin (DOX). The coating is an electrostatic complex obtained by the layer-by-layer (LbL) assembly and consists of natural polyelectrolytes [poly-γ-glutamic acid (γ-PGA) and chitosan (CS) or poly-l-lysine (PLL)]. To improve the release stability, an ionic conjugate of DOX and γ-PGA was prepared and incorporated into the multilayer coating. By varying the structure of the coating by adding empty (without DOX) bilayers, we were able to control the kinetics of drug release. The resulting platforms contained equal numbers of empty bilayers and DOX-loaded bilayers (15 + 15 or 30 + 30 bilayers) with a maximum loading of 566 ng/cm2. The platforms demonstrated prolonged and fairly uniform drug release for more than 5 months while retaining antitumor activity in vitro on ovarian cancer cells (SKOV-3). The empty platforms (without DOX) showed good cytocompatibility and no cytotoxicity to human fibroblasts and SKOV-3 cells. This study presents the development of a local chemotherapy platform consisting of a PCL-based substrate which provides structural stability and a biodegradable polyelectrolyte layered coating which combines layers containing a polyanion ionic complex with DOX with empty bilayers to ensure prolonged and controlled drug release. Our results may provide a basis for improving the efficacy of chemotherapy using drug delivery systems.

Local administration of shikonin improved the overall survival in orthotopic murine glioblastoma models with temozolomide resistance.

BACKGROUND: Glioblastoma is a type of intracranial malignancy. Shikonin, a Chinese traditional medicine, has been shown to have anti-tumor efficacy toward human glioblastoma cells in vitro. However, shikonin cannot easily cross the blood-brain barrier. To address this issue, we evaluated the anti-tumor effects of direct intracranial infusion of shikonin in in vivo orthotopic syngeneic murine glioblastoma models using C57BL/6 mice. MATERIALS AND METHODS: The cytotoxic effects of shikonin against murine glioblastoma cells, SB28 and CT-2A, were reported resistance to temozolomide, were evaluated using an allophycocyanin-conjugated annexin V and propidium iodide assay with flow cytometry. Impedance-based real-time cell analysis (RTCA) was used to analyze the inhibitory effects of shikonin on growth and proliferation. To evaluate the anti-tumor activity of shikonin in vivo, we used orthotopic syngeneic murine glioblastoma models with SB28 and CT-2A cells. RESULTS: In flow cytometry-based cytotoxic assays, shikonin induced apoptosis. RTCA indicated that shikonin decreased the cell index of murine glioblastoma cells, SB28 and CT-2A, in a dose-dependent manner (p < 0.0001 for both cell lines), while temozolomide did not (p = 0.91 and 0.82, respectively). In murine glioblastoma models, SB28 and CT-2A, direct intracranial infusion of shikonin, as a local chemotherapy, improved the overall survival of mice in a dose-dependent manner compared with control groups (p < 0.0001 and p = 0.02, respectively). While temozolomide did not (p = 0.48 and 0.52, respectively). CONCLUSIONS: The direct intracranial infusion of shikonin has potential as a local therapy for patients with glioblastoma.

Tumor Microenvironment Activated Photoacoustic-Fluorescence Bimodal Nanoprobe for Precise Chemo-immunotherapy and Immune Response Tracing of Glioblastoma.

Synergistic therapy strategy and prognostic monitoring of glioblastoma's immune response to treatment are crucial to optimize patient care and advance clinical outcomes. However, current systemic temozolomide (TMZ) chemotherapy and imaging methods for in vivo tracing of immune responses are inadequate. Herein, we report an all-in-one theranostic nanoprobe (PEG/αCD25-Cy7/TMZ) for precise chemotherapy and real-time immune response tracing of glioblastoma by photoacoustic-fluorescence imaging. The nanoprobe was loaded with TMZ and targeted regulatory T lymphocyte optical dye αCD25-Cy7 encapsulated by glutathione-responsive DSPE-SS-PEG2000. The results showed that the targeted efficiency of the nanoprobe to regulatory T lymphocytes is up to 92.3%. The activation of PEG/αCD25-Cy7/TMZ by glutathione enhanced the precise delivery of TMZ to the tumor microenvironment for local chemotherapy and monitored glioblastoma's boundary by photoacoustic-fluorescence imaging. Immunotherapy with indoleamine 2,3-dioxygenase inhibitors after chemotherapy could promote immunological responses and reduce regulatory T lymphocyte infiltration, which could improve the survival rate. Photoacoustic imaging has in real-time and noninvasively depicted the dynamic process of immune response on a micrometer scale, showing that the infiltration of regulatory T lymphocytes after chemotherapy was up-regulated and would down-regulate after IDO inhibitor treatment. This all-in-one theranostic strategy is a promising method for precisely delivering TMZ and long-term dynamically tracing regulatory T lymphocytes to evaluate the immune response in situ for accurate tumor chemo-immunotherapy.

Self-Cross-Linked Chitosan/Albumin-Bound Nanoparticle Hydrogel for Inhibition of Postsurgery Malignant Glioma Recurrence.

The development of chemoimmunotherapy with reduced systemic toxicity using local formulations is an effective strategy for combating tumor recurrence. Herein, we reported a localized hydrogel system for antitumor chemoimmunotherapy, formed by doxorubicin (DXR)-loaded bovine serum albumin (BSA) nanoparticles self-cross-linked with natural polysaccharide chitosan (CS). The drug-loaded hydrogel (DXR-CBGel) with antiswelling performance and prolonged drug-release profile was combined with antiprogrammed cell death protein 1 (aPD-1) as an in situ vaccine for treating glioblastoma multiforme (GBM) lesions. The antiswelling hydrogel system shows excellent biosafety for volume-sensitive GBM lesions. Both the albumin-bound formulation and the in situ gelation design facilitate the local retention and sustained release of DXR to generate long-term chemoimmunotherapy with reduced systemic toxicity. The chemotherapy-induced immunogenic cell death of DXR with the assistance of immunotherapeutic CS can trigger tumor-specific immune responses, which are further amplified by an immune checkpoint blockade to effectively inhibit cancer recurrence. The strategy of combining albumin-bound drug formulation and biocompatible polymer-based hydrogel for localized chemoimmunotherapy shows great potential against postsurgery glioblastoma recurrence.

A Review of the Release Profiles and Efficacies of Chemotherapy Drug-Loaded Electrospun Membranes.

Electrospun fibrous membranes loaded with chemotherapy drugs have been broadly studied, many of which have had promising data demonstrating therapeutic effects on cancer cell inhibition, tumor size reduction, the life extension of tumor-bearing animals, and more. Nevertheless, their drug release profiles are difficult to predict since their degradation pattern varies with crystalline polymers. In addition, there is room for improving their release performances, optimizing the release patterns, and achieving better therapeutic outcomes. In this review, the key factors affecting electrospun membrane drug release profiles have been systematically reviewed. Case studies of the release profiles of typical chemotherapy drugs are carried out to determine the preferred polymer choices and techniques to achieve the expected prolonged or enhanced release profiles. The therapeutic effects of these electrospun, chemo-drug-loaded membranes are also discussed. This review aims to assist in the design of future drug-loaded electrospun materials to achieve preferred release profiles with enhanced therapeutic efficacies.

5-Fluorouracil crystal-incorporated, pH-responsive, and release-modulating PLGA/Eudragit FS hybrid microparticles for local colorectal cancer-targeted chemotherapy.

5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent for colorectal cancer (CRC) owing to its potent anticancer effects. However, severe systemic side effects and poor drug accumulation in the CRC tissues limit its efficacy. This study aimed to develop 5-FU crystal-incorporated, pH-responsive, and release-modulating poly(d,l-lactide-co-glycolide)/Eudragit FS hybrid microparticles (5FU-EPMPs) for the local CRC-targeted chemotherapy. Approximately 150 µm 5FU-EPMPs were fabricated via the S/O/W emulsion solvent evaporation method, with 7.93 ± 0.24% and 87.23 ± 2.64% 5-FU loading and encapsulation efficiencies, respectively. Drug release profiles in a simulated pH environment of the gastrointestinal tract revealed that premature 5-FU release in the stomach and small intestine was prevented, thereby minimizing systemic 5-FU absorption. After reaching the colon, 5-FU was continuously released for >15 h, allowing long-term exposure of CRC tissues to sufficient 5-FU concentrations. Furthermore, in a CRC mouse model, the 5FU-EPMPs showed potent inhibition of tumor growth without signs of systemic toxicity. Thus, the 5FU-EPMPs represent a promising drug delivery system for local CRC-targeted chemotherapy.

Long-acting therapeutic delivery systems for the treatment of gliomas.

Despite the emergence of cutting-edge therapeutic strategies and tremendous progress in research, a complete cure of glioma remains elusive. The heterogenous nature of tumor, immunosuppressive state and presence of blood brain barrier are few of the major obstacles in this regard. Long-acting depot formulations such as injectables and implantables are gaining attention for drug delivery to brain owing to their ease in administration and ability to elute drug locally for extended durations in a controlled manner with minimal toxicity. Hybrid matrices fabricated by incorporating nanoparticulates within such systems help to enhance pharmaceutical advantages. Utilization of long-acting depots as monotherapy or in conjunction with existing strategies rendered significant survival benefits in many preclinical studies and some clinical trials. The discovery of novel targets, immunotherapeutic strategies and alternative drug administration routes are now coupled with several long-acting systems with an ultimate aim to enhance patient survival and prevent glioma recurrences.

Comparison of Image-Guided Iodine-125 Seed Interstitial Brachytherapy and Local Chemotherapy Perfusion in Treatment of Advanced Pancreatic Cancer.

OBJECTIVE: To compare the efficacy and safety of iodine-125 seed interstitial brachytherapy and local chemotherapy perfusion in treatment of advanced pancreatic cancer. METHODS: The present open prospective randomized control study included a total of 165 cases of advanced pancreatic cancer patients who were admitted in our hospital during December 2016 to April 2019. All patients were randomized into two groups with 84 cases in iodine-125 group and 81 cases in chemotherapy perfusion group. Basic clinical characteristics and demographic data were collected. The main outcome was the tumor efficiency. The pain condition was measured by visual analogue scale (VAS) and the Karnofsky score was also measured at different time points, before the treatment, 1 d, 7 d, 14 d, 1 mon, 2 mon and 3 mon after treatment. Serum levels of CEA, CA19-9 and CA50 were measured by immunochemiluminescence. The overall survival was analyzed by K-M curve. RESULTS: The ratio of partial remission patients was significantly higher, and the ratio of stable disease (SD)+progressive disease patients was also remarkably lower in iodine-125 group than the chemotherapy perfusion group. The mean VAS scores decreased markedly after treatment and were significantly lower and the mean Karnofsky scores were remarkably higher in iodine-125 group than the chemotherapy perfusion group. The levels of CA19-9 and CA50 were remarkably lower in iodine-125 group, however no significant difference was found for CEA. The survival analysis by K-M curve showed the iodine-125 patients had longer overall survival time than the chemotherapy perfusion group. No infection, pancreatic fistula, biliary fistula, intestinal fistula, gastrointestinal obstruction or radiation enteritis was found in both groups. CONCLUSION: Iodine-125 seed interstitial brachytherapy could achieve better efficacy with no increased side complications than chemotherapy perfusion in advanced pancreatic cancer.

Biodegradable gellan gum hydrogels loaded with paclitaxel for HER2+ breast cancer local therapy.

Hydrogels loaded with chemotherapeutics are promising tools for local tumor treatment. In this work, redox-responsive implantable hydrogels based on gellan gum were prepared as paclitaxel carriers for HER2-positive breast cancer therapy. To achieve different degrees of chemical crosslinking, hydrogels were synthesized in both acetate buffer and phosphate buffer and crosslinked with different concentrations of l-cysteine. It was shown that both, the type of buffer and the l-cysteine concentration used, conditioned the dynamic modulus, equilibrium swelling rate, porosity, and thermal stability of the hydrogels. Then, the biocompatibility of the hydrogels with the most suitable porosity for drug delivery applications was assessed. Once confirmed, these hydrogels were loaded with paclitaxel:ß-cyclodextrin inclusion complexes, and they showed a glutathione-responsive controlled release of the taxane. Moreover, when tested in vitro, paclitaxel-loaded hydrogels exhibited great antitumor activity. Thus, they could act as excellent local tailored carriers of paclitaxel for future, post-surgical treatment of HER2-overexpressing breast tumors.

A Local and Low-Dose Chemotherapy/Autophagy-Enhancing Regimen Treatment Markedly Inhibited the Growth of Established Solid Tumors Through a Systemic Antitumor Immune Response.

Chemotherapy is one of the main options for the treatment of a variety of malignant tumors. However, the severe side effects resulting from the killing of normal proliferating cells limit the application of cancer-targeting chemotherapeutic drugs. To improve the efficacy of classic systemic chemotherapy, the local delivery of high-dose chemotherapeutic drugs was developed as a method to enhance local drug concentrations and minimize systemic toxicity. Studies have demonstrated that chemotherapy is often accompanied by cancer-associated immunogenic cell death (ICD) and that autophagy is involved in the induction of ICD. To improve the efficacy of local cancer chemotherapy, we hypothesized that the local delivery of chemotherapeutic plus autophagy-enhancing agents would enhance the promotive effects of ICD on the antitumor immune response. Here, we report that a low-dose chemotherapy/autophagy enhancing regimen (CAER) not only resulted in the increased death of B16F10 and 4T1 tumor cells, but also induced higher levels of autophagy in vitro. Importantly, the local delivery of the CARE drugs significantly inhibited tumor growth in B16F10 and 4T1 tumor-bearing mice. Systemic antitumor T-cell immunity was observed in vivo, including neoantigen-specific T-cell responses. Furthermore, bioinformatic analysis of human breast cancer and melanoma tissues showed that autophagy-associated gene expression was upregulated in tumor samples. Increased autophagy and immune cell infiltration in tumor tissues were positively correlated with good prognosis of tumor patients. This work highlights a new approach to improve the effects of local chemotherapy and enhance systemic antitumor immunity.

Bone cement as a local chemotherapeutic drug delivery carrier in orthopedic oncology: A review.

Metastatic bone lesions are common among patients with advanced cancers. While chemotherapy and radiotherapy may be prescribed immediately after diagnosis, the majority of severe metastatic bone lesions are treated by reconstructive surgery, which, in some cases, is followed by postoperative radiotherapy or chemotherapy. However, despite recent advancements in orthopedic surgery, patients undergoing reconstruction still have the risk of developing severe complications such as tumor recurrence and reconstruction failure. This has led to the introduction and evaluation of poly (methyl methacrylate) and inorganic bone cements as local carriers for chemotherapeutic drugs (usually, antineoplastic drugs (ANPDs)). The present work is a critical review of the literature on the potential use of these cements in orthopedic oncology. While several studies have demonstrated the benefits of providing high local drug concentrations while minimizing systemic side effects, only six studies have been conducted to assess the local toxic effect of these drug-loaded cements and they all reported negative effects on healthy bone structure. These findings do not close the door on chemotherapeutic bone cements; rather, they should assist in materials selection when designing future materials for the treatment of metastatic bone disease.

Practical strategy to construct anti-osteosarcoma bone substitutes by loading cisplatin into 3D-printed titanium alloy implants using a thermosensitive hydrogel.

Surgical resection and perioperative adjuvant chemotherapy-based therapies have improved the prognosis of patients with osteosarcoma; however, intraoperative bone defects, local tumour recurrence, and chemotherapy-induced adverse effects still affect the quality of life of patients. Emerging 3D-printed titanium alloy (Ti6Al4V) implants have advantages over traditional implants in bone repair, including lower elastic modulus, lower stiffness, better bone conduction, more bone in-growth, stronger mechanical interlocking, and lager drug-loading capacity by their inherent porous structure. Here, cisplatin, a clinical first-line anti-osteosarcoma drug, was loaded into Ti6Al4V implants, within a PLGA-PEG-PLGA thermo-sensitive hydrogel, to construct bone substitutes with both anti-osteosarcoma and bone-repair functions. The optimal concentrations of cisplatin (0.8 and 1.6 mg/mL) were first determined in vitro. Thereafter, the anti-tumour effect and biosafety of the cisplatin/hydrogel-loaded implants, as well as their bone-repair potential were evaluated in vivo in tumour-bearing mouse, and bone defect rabbit models, respectively. The loading of cisplatin reduced tumour volume by more than two-thirds (from 641.1 to 201.4 mm3) with negligible organ damage, achieving better anti-tumour effects while avoiding the adverse effects of systemic cisplatin delivery. Although bone repair was hindered by cisplatin loading at 4 weeks, no difference was observed at 8 weeks in the context of implants with versus without cisplatin, indicating acceptable long-term stability of all implants (with 8.48%-10.04% bone in-growth and 16.94%-20.53% osseointegration). Overall, cisplatin/hydrogel-loaded 3D-printed Ti6Al4V implants are safe and effective for treating osteosarcoma-caused bone defects, and should be considered for clinical use.

Survival Benefit of Radiofrequency Ablation with Intratumoral Cisplatin Administration in a Rabbit VX2 Lung Tumor Model.

PURPOSE: This study evaluated the survival benefit of a combination therapy with radiofrequency ablation (RFA) and intratumoral cisplatin (ITC) administration for lung tumors by using a rabbit VX2 tumor model. MATERIALS AND METHODS: Experiments were approved by the institutional animal care committee. VX2 tumor suspension was injected into the lungs of Japanese white rabbits under CT guidance to create a lung tumor model. Thirty-two rabbits bearing a transplanted VX2 lung tumor were randomly assigned to four groups of eight: control (untreated); RFA alone; ITC alone; and RFA with ITC. All treatments were performed one week after tumor transplantation. Kaplan-Meier survival curves were compared by the log-rank test. RESULTS: The median survival time was 24.5 days (range 17-33 days) in the control group, 40 days (30-80 days) in the RFA alone group, 31.0 days (24-80 days) in the ITC alone group, and not reached (53-80 days) in the RFA with ITC group. The median survival was significantly longer with the RFA/ITC combination compared to the control group (P < 0.001), RFA alone (P = 0.034), and ITC alone (P = 0.004). The survival time after RFA alone was also significantly longer than that of the control group (P < 0.001). There was no significant difference in tumor size or the rate of pneumothorax between each group. CONCLUSION: RFA prolonged the survival of rabbits with lung VX2 tumors when combined with ITC.

Management of lymph node metastasis via local chemotherapy can prevent distant metastasis and improve survival in mice.

Management of lymph node metastasis (LNM) by conventional modalities such as radiotherapy and systemic chemotherapy exhibit limited LNM selectivity and therefore can cause off-target adverse events. While development of LNM-specific drug delivery systems has tremendous potential to provide a safer treatment modality and improve cancer treatment, precise assessment of therapeutic efficacy and implications has been challenging due to lack of a suitable preclinical model. Here, we established an experimental LNM model in mice by directly seeding cancer cells into a lymph node (LN), which developed spontaneous LNM-borne distant metastasis (DM) in the absence of a primary tumor. In the model, early, but not late, management of LNM before thereof tumor cells systemically disseminated could confer significant survival benefit, which suggests that time to LNM management is critical. Systematic comparative assessment of various local drug delivery systems revealed that a micellar formulation could achieve highly LNM-specific delivery of a chemotherapeutic agent, which was superior to systemic chemotherapy, effective at a very low dose, and safe. This study suggests not only that the experimental LNM model provides a useful preclinical model to study LNM management and its therapeutic implications but also that micelles are a promising drug delivery system for LNM management via local administration.

Ocular surface complications of local anticancer drugs for treatment of ocular tumors.

Local chemotherapy is increasingly used, either in combination with surgery or as monotherapy, for management of ocular tumors. Yet many of the local chemotherapeutic agents used for ocular tumors are cytotoxic drugs that are frequently associated with toxicities in normal ocular tissues. Understanding and managing these side effects are important because they affect treatment tolerability, outcome and quality of vision. Herein, we review local anticancer drugs administered for the treatment of ocular tumors, with an emphasis on their toxicities to the ocular surface, adnexa and lacrimal drainage system. We provide the underlying mechanisms and management strategies for the ocular side effects. Recent innovations in anticancer immunotherapy and ocular drug delivery systems also are discussed as new potential therapeutic modalities for alleviation of side effects.

Feasibility and efficacy evaluation of metallic biliary stents eluting gemcitabine and cisplatin for extrahepatic cholangiocarcinoma.

BACKGROUND: Effective endoscopic management is fundamental for the treatment of extrahepatic cholangiocarcinoma (ECC). However, current biliary stents that are widely used in clinical practice showed no antitumor effect. Drug-eluting stents (DESs) may achieve a combination of local chemotherapy and biliary drainage to prolong stent patency and improve prognosis. AIM: To develop novel DESs coated with gemcitabine (GEM) and cisplatin (CIS)-coloaded nanofilms that can maintain the continuous and long-term release of antitumor agents in the bile duct to inhibit tumor growth and reduce systemic toxicity. METHODS: Stents coated with different drug-eluting components were prepared by the mixed electrospinning method, with poly-L-lactide-caprolactone (PLCL) as the drug-loaded nanofiber membrane and GEM and/or CIS as the antitumor agents. Four different DESs were manufactured with four drug-loading ratios (5%, 10%, 15%, and 20%), including bare-loaded (PLCL-0), single-drug-loaded (PLCL-GEM and PLCL-CIS), and dual-drug-loaded (PLCL-GC) stents. The drug release property, antitumor activity, and biocompatibility were evaluated in vitro and in vivo to confirm the feasibility and efficacy of this novel DES for ECC. RESULTS: The in vitro drug release study showed the stable, continuous release of both GEM and CIS, which was sustained for over 30 d without an obvious initial burst, and a higher drug-loaded content induced a lower release rate. The drug-loading ratio of 10% was used for further experiments due to its ideal inhibitory efficiency and relatively low toxicity. All drug-loaded nanofilms effectively inhibited the growth of EGI-1 cells in vitro and the tumor xenografts of nude mice in vivo; in addition, the dual-loaded nanofilm (PLCL-GC) had a significantly better effect than the single-drug-loaded nanofilms (P < 0.05). No significant differences in the serological analysis (P > 0.05) or histopathological changes were observed between the single-loaded and drug-loaded nanofilms after stent placement in the normal porcine biliary tract. CONCLUSION: This novel PLCL-GEM and CIS-eluting stent maintains continuous, stable drug release locally and inhibits tumor growth effectively in vitro and in vivo. It can also be used safely in normal porcine bile ducts. We anticipate that it might be considered an alternative strategy for the palliative therapy of ECC patients.