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BACKGROUND: There are few available studies that compare the feasibility, efficacy, and safety of robotic pelvic lateral lymph node dissection compared to laparoscopic pelvic lateral lymph node dissection (LPLND) in advanced rectal cancer. This meta-analysis aims to compare perioperative outcomes between robotic and LPLND. METHODS: We performed a systemic literature review of PubMed, Embase, and Web of Science databases. Perioperative parameters were extracted and pooled for analysis. This meta-analysis provided an analysis of heterogeneity and prediction intervals. RESULTS: Five studies were included: 567 patients divided between 266 robotic and 301 LPLND. Overall operation time was longer in the robotic group than laparoscopic group (difference in means = 67.11, 95% CI [30.80, 103.42], p < 0.001) but the difference in the pelvic lateral lymph dissection time was not statistically significant (difference in means = - 1.212, 95% CI [ - 11.594, 9.171], p = 0.819). There were fewer overall complications in the robotic than in the laparoscopic group (OR = 1.589, 95% CI [1.009, 2.503], p = 0.046), especially with respect to urinary retention (OR = 2.23, 95% CI [1.277, 3.894], p = 0.005). More pelvic lateral lymph nodes were harvested by robotic surgery than by laparoscopy (differences in means = - 1.992, 95% CI [ - 2.421, 1.563], p < 0.001). CONCLUSIONS: In this meta-analysis, robotic pelvic lateral lymph node dissection was associated with more pelvic lateral lymph nodes harvested and lower overall complications, especially urinary retention when compared to LPLND. Further studies are needed to reinforce these findings.
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Laparoscopia , Excisão de Linfonodo , Pelve , Neoplasias Retais , Procedimentos Cirúrgicos Robóticos , Humanos , Excisão de Linfonodo/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Laparoscopia/métodos , Neoplasias Retais/cirurgia , Neoplasias Retais/patologia , Duração da Cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
INTRODUCTION: No universal consensus exists on the management of intraperitoneal anastomosis leakage after colonic surgery. The aim of the study was to evaluate the outcomes of laparoscopic reintervention without stoma creation for intraperitoneal leaks after colonic surgery. MATERIAL AND METHODS: Single tertiary center study conducted from January 2010 to December 2020. 54 patients with intraperitoneal leakage were divided into 2 groups according to whether they received a stoma (n = 37) or not (n = 17) during laparoscopic reintervention. Short term outcome was analyzed. RESULTS: Patients in the no stoma group had lower American Society of Anesthesiologists (ASA) score (P = .009), lower Acute Physiology And Chronic Health Evaluation II (APACHE II) score (5 vs. 10; P < .001) compared with the stoma group. Intensive care unit admission (43.2% vs. 5.8%; P = .006) and major complications (35.1% vs. 5.8%; P = .015) occurred more in the stoma group compared to the no stoma group. After multivariate logistic regression analysis, initial surgical procedure (P = .001) and APACHE II score (P = .039) were significant predictors of no stoma. The APACHE II score(P = .035) was an independent predictor of major complications. Finally, Receiver Operating Characteristic curve analysis showed that the cutoff value of APACHE II score for no stoma was 7.5. CONCLUSIONS: In our study, APACHE II score was an independent predictor of stoma formation and the cutoff value of APACHE II score for no stoma was 7.5. Our results need to be confirmed by larger and randomized studies. In particular, a specific APACHE II threshold to omit a stoma in this setting remains to be determined.
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Laparoscopia , Estomas Cirúrgicos , Humanos , Fístula Anastomótica/cirurgia , Fístula Anastomótica/etiologia , Colo/cirurgia , Laparoscopia/efeitos adversos , Prognóstico , Estudos Retrospectivos , Curva ROC , Estomas Cirúrgicos/efeitos adversosRESUMO
INTRODUCTION: Natural orifice specimen extraction is the next step in minimally invasive colorectal surgery but can be technically challenging, with additional risks, especially for oncologic surgery. For several key reasons, sigmoid volvulus is well suited for natural orifice specimen extraction surgery. We describe our method and experience with double-stapled anastomosis transrectal natural orifice specimen extraction for sigmoid volvulus. TECHNIQUE: Using 3- or 4-port laparoscopy, the mesentery is separated from the long sigmoid loop. After the distal bowel is tied off and washed out, the rectum is completely transected and the proximal bowel delivered transrectally through a wound protector. Proximal transection is performed externally, and the circular stapler anvil is set before the bowel is returned into the abdominal cavity. The rectum stump is closed with an endoscopic linear stapler, and a circular-stapled anastomosis is performed. RESULTS: After successful endoscopic decompression, 6 patients underwent elective laparoscopic sigmoidectomy with natural orifice specimen extraction for volvulus at China Medical University Hospital from 2015 to 2020. The median operative time was 179 minutes (range, 151-236 min). No intraoperative complications were encountered. The median postoperative length of stay was 4 days (range, 2-9 d). One patient experienced postoperative small-bowel ileus resulting in readmission. The median follow-up duration was 12 months (range, 2-49 mo). One recurrence of volvulus was recorded 27 months postsurgery. CONCLUSION: Uncomplicated sigmoid volvulus can be treated effectively with sigmoidectomy and natural orifice specimen extraction. Surgeons who attempt this procedure should be well versed with conventional laparoscopy but do not necessarily need to be experienced with natural orifice specimen extraction for successful surgery.
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Colectomia/métodos , Colo Sigmoide/cirurgia , Volvo Intestinal/cirurgia , Laparoscopia/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Descompressão Cirúrgica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sigmoidoscopia , Manejo de Espécimes/métodos , Cirurgia Endoscópica Transanal/métodos , Adulto JovemRESUMO
Background: To compare tumor margins and surgical outcomes between transanal minimally invasive surgery (TAMIS) and endoscopic submucosal dissection (ESD) for large or malignant rectal adenomatous polyps. Methods: Single institution retrospective analysis of patients who underwent TAMIS or ESD surgery. Results: In total, 30 consecutive patients with similar demographics who underwent either TAMIS (n = 19) or ESD (n = 11) were included. The median (interquartile range, IQR) tumor distances from the anal verge for TAMIS and ESD were 5 cm (3.5-8) and 3 cm (2-4.25) (P = 0.016). Four in TAMIS and two in ESD occupied more than half of the circumference of the bowel lumen. Five (four in situ and one stage 1) in TAMIS and two (one in situ and one stage 1) in ESD were malignant. The median specimen length, width, and height were 3.2 cm, 2.6 cm, and 1.0 cm and 3.5 cm, 2.0 cm, and 0.3 cm for TAMIS and ESD, respectively. There were no statistically significant differences in tumor circumference, malignant ratios, or specimen sizes. Resection margins were involved in two of the ESD, while none of the TAMIS were involved (P = 0.041). The median (IQR) operative time was 72 (62-89) minutes and 120 (90-180) minutes for TAMIS and ESD (P = 0.005). The median (IQR) follow-up time was 3.3 (0.3-11.7) and 0.9 (0.3-15.4) months for TAMIS and ESD. There were no morbidities, no mortalities, or local recurrences among the two groups. Conclusions: Both TAMIS and ESD were found to be feasible and safe in community hospital practice. Operative time was shorter, and there were no involved margins in TAMIS (versus ESD).
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The infiltration of cytotoxic T lymphocytes promises to suppress the most irresistible metastatic tumor for immunotherapy, yet immune privilege and low immunogenic responses in these aggressive clusters often restrict lymphocyte recruitment. Here, an in situ adherent porous organic nanosponge (APON) doubles as organ selection agent and antigen captor to overcome immune privilege is developed. With selective organ targeting, the geometric effect of APON composed of disc catechol-functionalized covalent organic framework (COF) boosts the drug delivery to lung metastases. Along with a self-cascaded immune therapy, the therapeutic agents promote tumor release of damage-associated molecular patterns (DAMPs), and then, in situ deposition of gels to capture these antigens. Furthermore, APON with catechol analogs functions as a reservoir of antigens and delivers autologous DAMPs to detain dendritic cells, resulting in a sustained enhancement of immunity. This disc sponges (APON) at lung metastasis as antigen reservoirs and immune modulators effectively suppress the tumor in 60 days and enhanced the survival rate.
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Neoplasias Pulmonares , Humanos , Porosidade , Linfócitos T Citotóxicos , Imunoterapia , Antígenos de Neoplasias , Células Dendríticas , CatecóisRESUMO
KRAS mutation in tumor tissue is a well-known predictor of resistance to the treatment of anti-EGFR antibodies in metastatic colorectal cancers (mCRC). However, the prognostic value of low-frequency plasma circulating tumor DNA (ctDNA) KRAS mutation in predicting treatment resistance in pretreated mCRC patients remains controversial. This study retrospectively reviewed the clinical course, including response to anti-EGFR and anti-VEGF therapies, and changes in serum tumor marker levels along with image studies in mCRC patients with <1.5% KRAS mutations detected in plasma ctDNA by next-generation sequencing (NGS) at a single center in Taiwan. We identified six pretreated mCRC patients with low-frequency KRAS G12V/G12D/G12S/G13D mutations (variant allele frequency 0.26~1.23%) in plasma ctDNA. Co-occurring low-frequency ctDNA mutations in APC, TP53, MAP2K1, KEAP1, or CTNNB1 were also detected. Although all six patients had treatment adjustments within one month after the ctDNA genetic test, image-evident tumor progression was noted in all patients within a median of 4 months afterwards. Re-challenge therapy with a combination of anti-EGFR, anti-VEGF, and FOLFIRI chemotherapy was found to be ineffective in a patient with 0.38% KRAS G12D mutation in baseline ctDNA. Our study suggests that the detection of low-frequency KRAS mutations in ctDNA could be used as a predictor of treatment response in mCRC patients.
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In this study, a plasmon-semiconductor nanotheranostic system comprising Au nanostars/graphene quantum dots (AuS/QD) hybrid nanoparticles loaded with BNN6 and surface modified with PEG-pyrene was developed for the photo-triggered hyperthermia effect and NO production as the dual modality treatment against orthotopic triple-negative breast cancer. The structure and morphology of the hybrid nanodevice was characterized and the NIR-II induced thermal response and NO production was determined. The hybrid nanodevice has shown enhanced plasmonic energy transfer from localized surface plasmonic resonance of Au nanostars to QD semiconductor that activates the BNN6 species loaded on QD surfaces, leading to the effective NO production and the gas therapy in addition to the photothermal response. The increased accumulation of the NIR-II-responsive hybrid nanotheranostic in tumor via the enhanced permeation and retention effects was confirmed by both in vivo fluorescence and photoacoustic imaging. The prominent therapeutic efficacy of the photothermal/NO combination therapy from the BNN6-loaded AuS@QD nanodevice with the NIR-II laser irradiation at 1064 nm against 4T1 breast cancer was observed both in vitro and in vivo. The NO therapy for the cancer treatment was evidenced with the increased cellular nitrosative and oxidative stress, nitration of tyrosine residues of mitochondrial proteins, vessel eradication and cell apoptosis. The efficacy of the photothermal treatment was corroborated directly by severe tissue thermal ablation and tumor growth inhibition. The NIR-II triggered thermal/NO combination therapy along with the photoacoustic imaging-guided therapeutic accumulation in tumor shows prominent effect to fully inhibit tumor growth and validates the promising strategy developed in this study.
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Hipertermia Induzida , Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Terapia Combinada , Humanos , Hipertermia Induzida/métodos , Nanopartículas/química , Neoplasias/terapia , Fototerapia/métodosRESUMO
One of the major criticisms of laparoscopic colectomy is the requirement of an additional mini laparotomy to remove the resected specimen. This may be associated with postoperative pain and wound complications. Therefore, the use of a natural orifice as a delivery route for the specimen extraction without a laparotomy incision can subsequently reduce the risk of wound complications. In this video, we demonstrate the natural orifice specimen extraction procedure with a side-to-end single-stapling colorectal anastomosis.
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The combination therapy, as an emerging strategy for improved clinical efficacy of cancer therapy, may not achieve effective response owing to the lack of highly selective and efficient tumor targeting. Herein, a dual stimuli-guided chemo/magnetothermal combination therapy system based upon histamine dodecyl carbamate (HDC)-coated doxorubicin (DOX)/magnetite-loaded solid lipid nanoparticles (SLNs) was developed for enhanced anticancer effects. Taking advantage of the dual pHe-induced electrostatic and magnetic guidance, the in vitro cellular uptake of these functionalized SLNs by TRAMP-C1 cancer cells was highly enhanced, leading to remarkably increased anticancer ability. With the highly selective delivery of the therapeutics toward tumor via the dual stimuli-mediated guidance, the effective growth inhibition of tumors with the small initial size (ca 50 mm3) by only chemotherapy was observed whereas the combination therapy was essentially required to fully inhibit the growth of large tumors (200 mm3). The IHC staining of tumor tissue sections with the combination therapy against large tumors showed the appreciable increase of tumor cell apoptosis and reduction of tumor angiogenesis. The results suggest that the dual stimuli-guided combination therapy system developed herein be prominent in fully inhibiting tumor growth even with the solid tumors of large size at the onset of the treatment.
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Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Terapia Combinada , Doxorrubicina , Sistemas de Liberação de Medicamentos , Lipídeos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/tratamento farmacológicoRESUMO
Peritoneal carcinomatosis colorectal cancer (pcCRC) is one of the most challenging cases in clinical treatment due to its aggressive characteristics and diagnostic limitations, impeding the therapeutic efficacy of chemotherapy. In this study, a poly(lactic-co-glycolic acid) nanoparticle (NP)-based drug delivery system capable of encapsulating the chemodrug SN38 and enhancing drug accumulation in metastatic tumors was developed for the treatment of pcCRC. The SN38-loaded NPs with a diameter of ca. 160 nm were decorated with N-acetyl histidine-modified d-α-tocopheryl polyethylene glycol succinate (TPGS) and folate-TPGS on their surfaces for enhancing drug accumulation through surface charge conversion in a mildly acidic tumor microenvironment and further allowing the NPs to selectively target the folate receptor-overexpressed colon cancer cells. This hierarchically targeted drug delivery strategy improved not only the highly enhanced cellular uptake of drug-loaded NPs, but also the prominent anticancer effect against CT26 cancer cells in vitro. In vivo studies demonstrated the sound tumor inhibition of the SN38-loaded NPs in terms of large reductions in both tumor size and nodule number and prolongation of the survival time of pcCRC-bearing mice, indicating their high therapeutic potential for the practical treatment of pcCRC.
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Antineoplásicos , Neoplasias do Colo , Neoplasias Colorretais , Nanopartículas , Neoplasias Peritoneais , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Camundongos , Neoplasias Peritoneais/tratamento farmacológico , Polietilenoglicóis , Microambiente TumoralRESUMO
Soluble amyloid-ß oligomers (oAß42)-induced neuronal death and inflammation response has been recognized as one of the major causes of Alzheimer's disease (AD). In this work, a novel strategy adopting silica-coated iron oxide stir bar (MSB)-based AD therapy system via magnetic stirring-induced capture of oAß42 into magnetic plaques (mpAß42) and activation of microglia on cellular plaque clearance was developed. With oAß42 being effectively converted into mpAß42, the neurotoxicity toward neuronal cells was thus greatly reduced. In addition to the good preservation of neurite outgrowth through the diminished uptake of oAß42, neurons treated with oAß42 under magnetic stirring also exhibited comparable neuron-specific protein expression to those in the absence of oAß42. The phagocytic uptake of mpAß42 by microglia was enhanced significantly as compared to the counterpart of oAß42, and the M1 polarization of microglia often occurring after the uptake of oAß42 restricted to an appreciable extent. As a result, the inflammation induced by pro-inflammatory cytokines was greatly alleviated.
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At present, natural orifice specimen extraction surgery (NOSES) has attracted more and more attention worldwide, because of its great advantages including minimal cutaneous trauma and post-operative pain, fast post-operative recovery, short hospital stay, and positive psychological impact. However, NOSES for the treatment of gastric cancer (GC) is still in its infancy, and there is great potential to improve its theoretical system and clinical practice. Especially, several key points including oncological outcomes, bacteriological concerns, indication selection, and standardized surgical procedures are raised with this innovative technique. Therefore, it is necessary to achieve an international consensus to regulate the implementation of GC-NOSES, which is of great significance for healthy and orderly development of NOSES worldwide.
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Although oral formulations of anticancer chemotherapies are clinically available, the therapeutic action relies mostly on drug absorption, being inevitably accompanied with systemic side effects. It is thus desirable to develop oral therapy systems for the local treatment of colon cancers featured with highly selective delivery to cancer cells and minimized systemic drug absorption. The present study demonstrates the effective accumulation and cell uptake of the doxorubicin and superparamagnetic iron oxide nanoparticles-loaded solid lipid nanoparticle (SLN) delivery system for chemo/magnetothermal combination therapy at tumors by hierarchical targeting of folate (FA) and dextran coated on SLN surfaces in a sequential layer-by-layer manner. Both the in vitro and in vivo characterizations strongly confirmed that the dextran shells on SLN surfaces not only retarded the cellular transport of the FA-coated SLNs by the proton-coupled FA transporter on brush border membranes in small intestine, but also enhanced the particle residence in colon by specific association with dextranase. The enzymatic degradation and removal of dextran coating led to the exposure of the FA residues, thereby further facilitating the cellular-level targeting and uptake of the SLNs by the receptor-mediated endocytosis. The evaluation of the in vivo antitumor efficacy of the hierarchically targetable SLN therapy system by oral administration showed the effective inhibition of primary colon tumors and peritoneal metastasis in terms of the ascites volume and tumor nodule number and size, along with the absence of systemic side effects.
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Antibióticos Antineoplásicos/uso terapêutico , Neoplasias do Colo/terapia , Doxorrubicina/uso terapêutico , Nanopartículas/uso terapêutico , Polissacarídeos/uso terapêutico , Animais , Antibióticos Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Ácido Fólico/química , Ácido Fólico/uso terapêutico , Hipertermia Induzida/métodos , Lipídeos/química , Lipídeos/uso terapêutico , Camundongos , Nanopartículas/química , Polissacarídeos/químicaRESUMO
In recent years, natural orifice specimen extraction surgery (NOSES) in the treatment of colorectal cancer has attracted widespread attention. The potential benefits of NOSES including reduction in postoperative pain and wound complications, less use of postoperative analgesic, faster recovery of bowel function, shorter length of hospital stay, better cosmetic and psychological effect have been described in colorectal surgery. Despite significant decrease in surgical trauma of NOSES have been observed, the potential pitfalls of this technique have been demonstrated. Particularly, several issues including bacteriological concerns, oncological outcomes and patient selection are raised with this new technique. Therefore, it is urgent and necessary to reach a consensus as an industry guideline to standardize the implementation of NOSES in colorectal surgery. After three rounds of discussion by all members of the International Alliance of NOSES, the consensus is finally completed, which is also of great significance to the long-term progress of NOSES worldwide.
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BACKGROUND/AIMS: The employment of laparoscopy in the treatment of locally advanced colorectal cancer is still questioned by many surgeons, mainly due to the fear of spreading tumors by the laparoscopic procedure. However, it is still unknown whether laparoscopy is actually associated with increased tumor dissemination, especially for those with tumor invasion through the serosa. The main purpose of this study is to investigate the effect of pneumoperitoneum on the intra-abdominal tumor growth and spreading of colon cancer cells by an animal study of murine model. METHODOLOGY: Under anesthesia, 10(6) tumor cells (CT26) were inoculated into the lower abdominal cavity of BALB/c mice by a mini-laparotomy. The mice were randomized to undergo pneumoperitoneum with CO2 (n=10), helium (n=10), or to act as controls (n=10). Pneumoperitoneum was established over 20 min at a pressure of 10cm H2O. The distribution pattern and the weight of peritoneal tumor growth of each mouse were recorded and analyzed at 15 days after surgery. RESULTS: The mean ratios of the tumor mass over the total body weight of the mice were 0.77+/-1.13% (control group), 4.30+/-0.86% (CO2 pneumoperitoneum), and 2.17+/-0.88% (helium pneumoperi-toneum). The mean tumor weight ratio (3.23+/-1.38%) of the pneumoperitoneal group was 4 times larger than that of the control group (p<0.001). Regarding the use of different insufflation gases over tumor growth, CO2 accelerates tumor growth more significantly than helium (p<0.001). Intraabdominal distribution (p=0.047) and diaphragm spreading (p<0.001) were significantly greater in the pneumoperitoneum group than the control group. CONCLUSIONS: The results of this animal study imply that presence of a pneumoperitoneum enhances the implantation and growth of free intraperitoneal malignant colon cancer cells in this in vivo mouse model. The results of the current study suggest that insufflation during pneumoperitoneum may play an important role in the development of peritoneal dissemination when there are free tumor cells in the intra-abdominal cavity, and the effect of using CO2 might be greater than that of using helium.
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Dióxido de Carbono , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Hélio , Inoculação de Neoplasia , Neoplasias Peritoneais/patologia , Pneumoperitônio Artificial , Animais , Divisão Celular/fisiologia , Linhagem Celular Tumoral , Diafragma/patologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de NeoplasiasRESUMO
Therapeutic efficacy of glioblastoma multiforme (GBM) is often severely limited by poor penetration of therapeutics through blood-brain barrier (BBB) into brain tissues and lack of tumor targeting. In this regard, a functionalized upconversion nanoparticle (UCNP)-based delivery system which can target brain tumor and convert deep tissue-penetrating near-infrared (NIR) light into visible light for precise phototherapies on brain tumor was developed in this work. Methods: The UCNP-based phototherapy delivery system was acquired by assembly of oleic acid-coated UCNPs with angiopep-2/cholesterol-conjugated poly(ethylene glycol) and the hydrophobic photosensitizers. The hybrid nanoparticles (ANG-IMNPs) were characterized by DLS, TEM, UV/vis and fluorescence spectrophotometer. Cellular uptake was examined by laser scanning confocal microscopy and flow cytometry. The PDT/PTT effect of ANG-IMNPs was evaluated using MTT assay. Tumor accumulation of NPs was determined by a non-invasive in vivo imaging system (IVIS). The in vivo anti-glioma effect of ANG-IMNPs was evaluated by immunohistochemical (IHC) examination of tumor tissues and Kaplan-Meier survival analysis. Results: In vitro data demonstrated enhanced uptake of ANG-IMNPs by murine astrocytoma cells (ALTS1C1) and pronounced cytotoxicity by combined NIR-triggered PDT and PTT. In consistence with the increased penetration of ANG-IMNPs through endothelial monolayer in vitro, the NPs have also shown significantly enhanced accumulation at brain tumor by IVIS. The IHC tissue examination confirmed prominent apoptotic and necrotic effects on tumor cells in mice receiving targeted dual photo-based therapies, which also led to enhanced median survival (24 days) as compared to the NP treatment without angiopep-2 (14 days). Conclusion: In vitro and in vivo data strongly indicate that the ANG-IMNPs were capable of selectively delivering dual photosensitizers to brain astrocytoma tumors for effective PDT/PTT in conjugation with a substantially improved median survival. The therapeutic efficacy of ANG-IMNPs demonstrated in this study suggests their potential in overcoming BBB and establishing an effective treatment against GBM.
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Neoplasias Encefálicas/terapia , Sistemas de Liberação de Medicamentos , Glioblastoma/terapia , Hipertermia Induzida , Nanopartículas/uso terapêutico , Fotoquimioterapia , Fototerapia , Animais , Barreira Hematoencefálica/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Difusão Dinâmica da Luz , Glioblastoma/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/ultraestrutura , Oligopeptídeos/química , Peptídeos Cíclicos , Somatostatina/análogos & derivados , Somatostatina/química , Temperatura , Distribuição TecidualRESUMO
BACKGROUND & AIMS: Interstitial cells of Cajal (ICC) closely associate with nerves and smooth muscles to modulate gut motility. In the ICC microenvironment, although the circulating hormones/factors have been shown to influence ICC activities, the association between ICC and microvessels in the gut wall has not been described. We applied three-dimensional (3D) vascular histology with c-kit staining to identify the perivascular ICC and characterize their morphologic and population features in the human colon wall. METHODS: Full-thickness colons were obtained from colectomies performed for colorectal cancer. We targeted the colon wall away from the tumor site. Confocal microscopy with optical clearing (use of immersion solution to reduce scattering in optical imaging) was performed to simultaneously reveal the ICC and vascular networks in space. 3D image rendering and projection were digitally conducted to illustrate the ICC-vessel contact patterns. RESULTS: Perivascular ICC were identified in the submucosal border, myenteric plexus, and circular and longitudinal muscles via high-definition 3D microscopy. Through in-depth image projection, we specified two contact patterns-the intimate cell body-to-vessel contact (type I, 18% of ICC in circular muscle) and the long-distance process-to-vessel contact (type II, 16%)-to classify perivascular ICC. Particularly, type I perivascular ICC were detected with elevated c-kit staining levels and were routinely found in clusters, making them readily distinguishable from other ICC in the network. CONCLUSIONS: We propose a new subclass of ICC that closely associates with microvessels in the human colon. Our finding suggests a functional relationship between these mural ICC and microvessels based on the morphologic proximity.
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In this study, a novel pH-responsive cholesterol-PEG adduct-coated solid lipid nanoparticles (C-PEG-SLNs) carrying doxorubicin (DOX) capable of overcoming multidrug resistance (MDR) breast cancer cells is presented. The DOX-loaded SLNs have a mean hydrodynamic diameter of ~100 nm and a low polydispersity index (under 0.20) with a high drug-loading efficiency ranging from 80.8% to 90.6%. The in vitro drug release profiles show that the DOX-loaded SLNs exhibit a pH-controlled drug release behavior with the maximum and minimum unloading percentages of 63.4% at pH 4.7 and 25.2% at pH 7.4, respectively. The DOX-loaded C-PEG-SLNs displayed a superior ability in inhibiting the proliferation of MCF-7/MDR cells. At a DOX concentration of 80 µM, the cell viabilities treated with C-PEG-SLNs were approximately one-third of the group treated with free DOX. The inhibition activity of C-PEG-SLNs could be attributed to the transport of C-PEG to cell membrane, leading to the change of the composition of the cell membrane and thus the inhibition of permeability glycoprotein activity. This hypothesis is supported by the confocal images showing the accumulation of DOX in the nuclei of cancer cells and the localization of C-PEG on the cell membranes. The results of in vivo study further demonstrated that the DOX delivered by the SLNs accumulates predominantly in tumor via enhanced permeability and retention effect, the enhanced passive tumor accumulation due to the loose intercellular junctions of endothelial cells lining inside blood vessels at tumor site, and the lack of lymphatic drainage. The growth of MCF-7/MDR xenografted tumor on Balb/c nude mice was inhibited to ~400 mm(3) in volume as compared with the free DOX treatment group, 1,140 mm(3), and the group treated with 1,2 distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] solid lipid nanoparticles, 820 mm(3). Analysis of the body weight of nude mice and the histology of organs and tumor after the administration of DOX-loaded SLNs show that the SLNs have no observable side effects. These results indicate that the C-PEG-SLN is a promising platform for the delivery of therapeutic agents for MDR cancer chemotherapy.
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Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Resistencia a Medicamentos Antineoplásicos , Lipídeos/farmacologia , Nanopartículas/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Lipídeos/química , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoglicóis/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Photodynamic therapy (PDT) is a powerful technique photochemically tailored for activating apoptosis of malignant cells. Although PDT has shown promise in several clinical applications, malignant cells in hypoxic regions are often resistant to PDT due to the transport limitation of therapeutics and the oxygen-dependent nature of PDT. Herein, we present an innovative strategy for overcoming the limits of PDT in tumor hypoxia using bone marrow-derived monocytes as cellular vehicles for co-transport of oxygen and red light activatable photosensitizer, chlorin e6 (Ce6). Superparamagnetic iron oxide nanoparticle/Ce6/oxygen-loaded polymer bubbles were prepared and internalized into tumortropic monocytes. These functional bubbles were found harmless to cellular hosts without external triggers. Nevertheless, the therapeutic monocytes exhibited a superior performance in inhibiting tumor growth on Tramp-C1 tumor-bearing mice (C57BL/6J) upon the treatments of tumors with high frequency magnetic field and red light laser (660 nm). Histological examinations of the tumor sections confirmed the successful cellular transport of therapeutic payloads to tumor hypoxia and the pronounced antitumor effect elicited by combined hyperthermia/photodynamic therapy along with the additional oxygen supply. This work demonstrates that this oxygen/therapeutic co-delivery via tumortropic monocytes toward tumor hypoxia is promising for improving PDT efficacy.