Factors for postoperative recurrence of orbital solitary fibrous tumor: an analysis of long-term clinical follow-up results from a Chinese tertiary hospital.

BACKGROUND: This study analyzed the clinical features, imaging manifestations, histopathology, immunohistochemistry, and surgical approaches of the orbital solitary fibrous tumor (OSFT), as well as the factors for postoperative recurrence of such disease. METHODS: The clinical data of 16 patients with OSFT treated in our center from 2003 to 2020 were analyzed retrospectively, and the clinical symptoms, treatment methods, and follow-up results were recorded. RESULTS: Of the 16 patients, 8 were females (50.0 %) and 8 were males (50.0 %); the average age of treatment was 37 ± 7 years and the median follow-up time was 74 (8, 228) months. Sixteen patients with OSFT underwent a total of 29 operations, of which 12 were transorbital approach operations and 17 were transfronto-orbital approach operations. Ten patients (10/16, 62.5 %) had recurrence. The recurrence rate of transorbital approach operations was 83.3 % (10/12), and the recurrence rate of transfronto-orbital approach operations was 17.6 % (3/17). No patients had treatment-related complications. CONCLUSIONS: The main pathological feature of OSFT is a benign tumor. OSFT has a tendency to grow toward the cranio-orbital junction. The postoperative recurrence rate of OSFT is relatively high, so complete tumor resection is very important for prognosis. Inappropriate surgical approaches can lead to incomplete removal of the tumor and cause recurrence. Choosing the correct operation approach according to the position of the OSFT in the orbit and complete removal of the dura mater and bone affected by the tumor is crucial for the prognosis. Nevertheless, regular long-term follow-up after complete resection is necessary.

The Significance of The Detection of Serum Lactate Dehydrogenase, Hypersensitive C-Reactive Protein, and N-Terminal Pro-Brain Natriuretic Peptide for the Evaluation of the Severity and Progression of Pediatric Patients with Traumatic Brain Injury.

OBJECTIVE: This study aimed to investigate changes in the levels of serum lactate dehydrogenase (LDH), hypersensitive C-reactive protein (hs-CRP), and N-terminal pro-brain natriuretic peptide (NT-proBNP) in pediatric patients with traumatic brain injury and the clinical significance of detecting these changes for the evaluation of injury severity and patient progress. METHODS: A retrospective study was conducted on 40 pediatric patients admitted to the Tongren Hospital of China Capital Medical University with traumatic brain injury between January 2018 and December 2019. Immunoturbidimetric assay and electrochemiluminescence were used to detect the serum levels of LDH, hs-CRP, and NT-proBNP. Correlation analysis was used to determine the degree of association between the indicators and the sensitivity and specificity of each indicator. RESULTS: The serum levels of LDH, hs-CRP, and NT-proBNP in the poor-prognosis group were higher than those in the good-prognosis group, and the differences were statistically significant (P < 0.05). CONCLUSION: The detection of serum LDH, hs-CRP, and NT-proBNP might be of great significance for the evaluation of the severity of a traumatic brain injury, disease progression, and the prognosis of pediatric patients with traumatic brain injury. The combined detection of the relevant indicators could provide more effective sensitivity and specificity and therefore offer better guidance and assistance in clinical practice.

The outcome of surgical and non-surgical treatments for traumatic optic neuropathy: a comparative study of 685 cases.

Background: The choice and efficacy of surgical or/and surgical treatments for traumatic optic neuropathy (TON) remained controversial by now. This study aims to present the outcomes of surgical and nonsurgical treatments for TON in our center. Methods: A total of 685 consecutive patients were retrospectively included in the study. And divided into surgical and non-surgical groups. All cases were treated with corticosteroids for 3 days after admission. Endoscopic optic decompression was applied to 479 patients of surgical group; The other 206 patients of nonsurgical were administered with corticosteroids alone. The visual outcomes before and after treatment were compared with Wilcoxon rank and tests. The improvement rate between two groups were compared with chi-square test. Results: The visual acuity (VA) after treatment was significantly better than that before treatment (P=0.000). Overall VA improvement rate in the surgical group was better than that in non-surgical group (42.8% vs. 35.4%) with no significant difference (P=0.072). The VA improvement rate was significant greater in the surgical group than that in the non-surgical group in the patients with NLP before treatment (P=0.028). The VA improvement rate was better in the surgical group than that in the non-surgical group (71.9% vs. 57.8%) but with no significant difference. The final overall VA was 0.1 or better in 43 cases; 104 cases were able to count fingers; hand motion (HM) became perceivable in 132 cases; light perception (LP) was achieved in 53 cases; and no light perception (NLP) remained in 353 cases. Conclusions: Endoscopic optic nerve decompression (EOND) combined with corticosteroids or corticosteroids alone could reach the improvement for patients with TON. The EOND combined with corticosteroids could achieve better VA improvement in patients with NLP.

Comparison of two surgical methods for the treatment of optic pathway gliomas in the intraorbital segment: an analysis of long-term clinical follow-up, which evaluates the surgical outcomes.

BACKGROUND: This study analyzes two kinds of surgical methods for the treatment of optic pathway gliomas (OPGs) in the intraorbital segment, as well as the surgical outcomes of OPGs. METHODS: The clinical data of 86 patients with OPGs treated in our center was analyzed retrospectively, and the clinical symptoms, treatment methods, and follow-up results were recorded. RESULTS: For OPGs in the intraorbital segment, the optic nerve sheath incision was performed to remove a tumor while retaining the optic nerve sheath in Group 1 (n=36). The optic nerve sheath and the tumor were simultaneously removed without retaining the optic nerve sheath in group 2 (n=50). The effects of the design of the surgical methods on the post-surgical outcome are: One patient (1/36, 2.8%) had recurrence in Group 1 and one patient (1/50, 2.0%) had recurrence in group 2. The differences in the surgical outcomes of the two groups regarding exophthalmos, conjunctiva swelling, eye movement disorder, and ptosis were found to be statistically significant (P<0.05). Compared with group 2, the surgical outcomes in the postoperative phase of Group 1 were more satisfactory. CONCLUSIONS: The two surgical methods do not increase the recurrence rate of tumors. The resection of OPGs through an optic nerve sheath incision was found to be an ideal surgical method for reducing complications in the postoperative phase and for providing better surgical outcomes.

Prognosis Analysis and Clinical Features of Orbital Cavernous Venous Malformations With Refractory Insidious Onset.

OBJECTIVE: The present study aims to analyse the clinical presentation, treatment and prognosis of a group of patients with orbital cavernous venous malformation (OCVM) with an insidious onset. METHOD: The clinical data of 35 patients with OCVM treated at our centre between 2003 and 2020 were retrospectively analysed. The OCVMs were classified as one of six types (I-VI) according to the orbital position of the tumour. The clinical characteristics, treatment methods and follow-up results were recorded. RESULTS: A total of 35 patients with OCVM under the optic nerve sheath in the orbital apex area or the common tendon ring (Types I and II) were included in the present study. In 20 cases (57.1%), patients were misdiagnosed with optic neuritis, and in 20 cases (57.1%), the tumour was not identified based on imaging. The presentation was acute or subacute in 23 cases (65.7%). All patients underwent surgery: transnasal surgery in 22 cases (62.9%) and craniotomy in 13 cases (37.1%). A total of 9 patients (25.7%) experienced postoperative complications, and 17 patients (48.6%) experienced vision improvement. The average patient age at first diagnosis was 43.3 ± 10.3 years, and the median follow-up period was 64.5 months. Overall, 14 patients (40%) experienced postoperative complications: postoperative blindness in 6 cases, postoperative vision loss in 8 cases and orbital apex syndrome in 7 cases. CONCLUSION: Patients with Type I and Type II OCVMs are the most complex cases. They have an insidious onset and are associated with a high rate of misdiagnosis and missed diagnosis. Acute and subacute decreases in visual acuity are mainly caused by OCVM haemorrhage. The difficulty of surgical treatment and the poor prognosis of postoperative vision are characteristics of this tumour. Transnasal surgery and craniotomy can be used to remove OCVMs located in the common tendon ring or optic canal as well as those involving the intracranial area through the supraorbital fissure. Meanwhile, the orbital approach (orbitotomy) has proven to be an effective method of treating OCVMs not involving the deep orbital apex and intracranial area.

Renal function as a predictor of outcomes in patients with hypertrophic cardiomyopathy: A cohort study of a hospitalized population.

BACKGROUND: The relationship between renal function and outcomes among patients with hypertrophic cardiomyopathy (HCM) remains undefined. We sought to investigate the prevalence of renal dysfunction and its prognostic value in HCM patients. METHODS: A total of 581 patients with HCM were consecutively recruited. The chronic kidney disease epidemiology equation was used to estimate the glomerular filtration rate (eGFR). Patients were divided into 2 eGFR categories: ≥60 or <60 ml/min/1.73 m2. The predictive value of renal function was assessed using Cox regression. RESULTS: The proportions of eGFR 60-90 ml/min/1.73 m2 and <60 ml/min/1.73 m2 were 41.8% and 15.3%, respectively. Estimated GFR independently predicted the risk of all-cause mortality [HR 0.98, 95% confidence interval (CI) 0.96-0.99, P < 0.001]. Compared to those with eGFR ≥ 60 ml/min/1.73 m2, patients with eGFR < 60 ml/min/1.73 m2 were independently associated with all-cause mortality (HR, 3.42 95% CI 1.86-6.28), cardiovascular mortality (HR 2.98, 95% CI 1.36-6.50) and combined adverse outcomes (HR 1.60, 95% CI 1.02-2.49). HRs for all-cause mortality with renal dysfunction were attenuated in patients with older ages (P for interaction = 0.034). CONCLUSIONS: Renal dysfunction is a common comorbidity in HCM. Renal function is an independent predictor of outcomes in patients with HCM. These findings highlight the clinical importance of renal dysfunction in HCM.

Role of delayed wider endoscopic optic decompression for traumatic optic neuropathy: a single-center surgical experience.

BACKGROUND: The aim of the present study was to discuss the efficacy of delayed wider endoscopic optic decompression in traumatic optic neuropathy (TON). METHODS: A total of 479 patients were treated with corticosteroids and delayed wider endoscopic optic decompression, including the injury-to-surgery interval, within 2 weeks in patients with no light perception (NLP), and within 1 month in patients with residual eyesight. Based on the traditional decompression range, the superior wall of the optic canal was further decompressed. The preoperative and postoperative visual acuities (VAs) were reviewed, and the therapeutic efficacy was analyzed. RESULTS: The final VA was 0.1 or better in 29 cases, finger count in 79 cases, hand motion in 99 cases, light perception (LP) in 25 cases, and NLP in 247 cases. A total of 136 patients (136/383, 35.5%) recovered after NLP treatment, and 78 patients (69/96, 71.9%) had improved residual eyesight. The improvement rate in patients with residual eyesight was significantly higher than that of patients with NLP (P<0.01). Moreover, the total VA after treatment was better than that before surgery (P<0.01). CONCLUSIONS: Delayed wider optic nerve decompression plus corticosteroids remains an effective and safe therapeutic strategy for patients with delayed treatment intervals of more than 1 week, especially for those with residual eyesight within 1 month.

[Online diagnosis of the conversion of methane to C2 hydrocarbons under glow discharge plasma at atmospheric pressure].

Optical emission spectroscopy (OES) was adopted for the first time by our group for in situ diagnosis of the conversion of CH4-H2 under glow discharge plasma at atmospheric pressure with rotary electrodes. The emission of excited species such as excited radicals and atoms (C, CH, C2, H and H2) was detected in the spectra range of 300-700 nm. The spectrum of hydrogen atom was used to figure out the plasma excitation temperature by a Boltzmann plot scheme. It was evaluated that the excitation temperature of hydrogen plasmas under varied discharge conditions is in the range of 6300-6600 K. The electron density was calculated based on spectral profile of H lines and its order is about 10(20) m(-3).

[Spectroscopic investigation of the argon plasma discharge in quartz capillary at atmospheric pressure].

An arc plasma discharge with a long length of 20 cm was generated in a quartz capillary between two hollow needle electrodes in argon at atmospheric pressure with use of the sinusoidal power supply operating at 45 kHz, which was characterized by a very high electron density. The spectroscopic method of optical emission was employed to diagnose the characteristic parameters of the arc plasma discharge in the quartz capillary. The gas temperature was determined by simulating the OH A-X(0, 0) vibrational band around 300 nm and comparison with measured spectrum by means of optical emission spectroscopy. Furthermore, the electron density was measured by means of Stark broadening of the profile of Hbeta at 486.1 nm. The electron temperature was determined using a Boltzmann plot method. The experiment results show that in the argon arc plasma discharge generated in the quartz capillary at atmospheric pressure, the gas temperature of plasma is about (1 100 +/- 50)K, the electron density at the gas temperature of 1 100 K is approximately 10(14) cm(-3), and the corresponding electron temperature is (14 515 +/- 500)K. This work has accumulated some significant experimental parameters for the treatment of inner surface of large length-to-radius-ratio insulated dielectric tube using plasma, and the results are of great importance to the applications of this type of atmospheric-pressure plasma discharge.

A novel design of a polynuclear co-delivery system for safe and efficient cancer therapy.

We report a novel and easy-to-fabricate polynuclear nanoparticle based on the collaborative re-assembly of nanoparticles as a robust chemogene co-delivery platform. Specifically, the polynuclear nanoparticle carrying DOX and siBcl-2 exerts remarkable co-delivery efficiency, increases tumour cell apoptosis and inhibits tumour cell proliferation in vitro and in vivo.

[Trans-cranio-naso-orbital approach in treatment of ethmoid sinus malignant tumors: analysis of 39 cases].

OBJECTIVE: To summarize the experience in treatment of ethmoid sinus malignant tumors via trans-cranio-naso-orbital approach. Post-operationally follow-up was conducted in 27 cases for 3.5 years (3 months to 7 years). METHODS: The clinical data of 39 patients with ethmoid sinus malignant tumors, 25 males and 14 females, aged 42 (20 - 65), with the chief complaints of nasal airway obstruction, rhinorrhagia, nasal neoplasm, exophthalmos, decreased vision, facial numbness, disturbance of consciousness, etc, who underwent resection of tumor via trans-cranio-naso-orbital approach retrospectively. Pre-operational MR showed that the tumor invaded the anterior cranial fossa in 38 cases, invading the orbit in 31 cases, invaded the pterygopalatine fossa in 5 cases, invaded the middle cranial fossa and cavernous sinus in 3 cases. RESULTS: Tumor total removal was achieved in 32 cases (including removal en bloc in 9 cases), and subtotal removal in 7 cases. Pathological examination diagnosed 10 cases as with olfactory neuroblastoma, 8 cases with adenocarcinoma, 7 cases with squamous cell carcinoma, 6 cases with pallima carcinoma, 4 cases with unclassified sarcoma, 3 cases with undifferentiated carcinoma, and 1 case with schneiderian carcinoma. Postoperatively, temporal CSF leak was found in 5 cases. There was no intracranial or wound infection. Local recurrence was found in 8 cases, 1 case had lung metastasis, and 4 cases died 1 month to 6 years postoperatively. CONCLUSION: Adequate exposure of the ethmoid sinus tumor involving the anterior cranial fossa and orbit can be obtained via suitable trans-cranio-naso-orbital approach, and by this approach the tumor can be removed en bloc. This approach is relatively safe and with few complications.

Transferrin-inspired vehicles based on pH-responsive coordination bond to combat multidrug-resistant breast cancer.

A novel biomimetic drug delivery system (BDDS) inspired by the pH-dependent ferric ion-transport and release manner of transferrin (Tf) was developed for combating multidrug-resistant breast cancer. Tf-inspired carrier was synthesized by modifying bovine serum albumin (BSA) with histamine (HA) through amide reaction to provide superior specific coordination sites for ferric ion-drug complexes, and self-assembled into nanoparticles (NPs) induced by coordination bond. Tf-inspired NPs were prepared via environment-friendly method, and well redispersed in saline after lyophilization. When internalized into tumor cells by SPARC (secreted protein acidic and rich in cysteine) mediated endocytosis, Tf-inspired NPs bypassed and decreased the P-glycoprotein-mediated drug efflux and led to more effective treatment of multidrug-resistant breast cancer compared with free drugs both in vitro and in vivo due to the enhanced cellular uptake and rapid pH-responsive drug release. Moreover, Tf-inspired NPs exhibited good biocompatibility and low systemic toxicity. Thus, our results demonstrate that Tf-inspired NPs based on coordination bond represent as a smart drug delivery strategy to combat multidrug-resistant cancer and have great potential for clinical applications in cancer therapy.

In vivo synergistic antitumor effect and safety of siRNA and lonidamine dual-loaded hierarchical targeted nanoparticles.

Based on development of nano-delivery system, co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) has exerted a promising advantage in cancer therapy. In this work, the superiority of synergistic therapy and safety of the hierarchical targeted co-delivery system loaded with siRNA and lonidamine (LND) were evaluated. The in vivo tumor accumulation ability and cancer growth inhibition effect of the polymer-blend nanocarriers were evaluated by a H22 subcutaneous sarcoma model. Moreover, hematoxylin and eosin (H&E) staining and transferase-mediated dUTP nick end-labeling (TUNEL) staining of tumor sections from each group were compared to assess the therapeutic efficacy. The dual-loaded nanocarriers had better tumor accumulation ability, remarkably inhibited growth of solid tumor in a synergistic manner, even significantly decreased hepatotoxicity of LND, and had good in vivo biocompatibility whereas LND alone showed serious hepatotoxicity. We believed that the dual-loaded hierarchical targeted delivery system with high effectiveness and biocompatibility would provide a promising approach for cancer combination therapy.

Polyamine metabolism-based dual functional gene delivery system to synergistically inhibit the proliferation of cancer.

Polyamine content, which is associated with tumor growth, can be regulated by ornithine decarboxylase (ODC) and S-adenosyl methionine decarboxylase (SAMDC), two key enzymes in polyamine biosynthesis. Here we aim to develop a pH-responsive cationic poly(agmatine) based on a polyamine analogue-agmatine that can dually function as a gene delivery vector as well as an anticancer agent by inhibiting ODC after intracellular degradation. The core-shell nanoparticles, formed by poly(agmatine)/SAMDC siRNA complex as a core, were coated with bovine serum albumin for better in vivo circulation stability and tumor targeting. When the nanoparticles were taken up by tumor cells via endocytosis and degraded in endosome, the released agmatine and SAMDC siRNA can synergistically inhibit polyamines biosynthesis, inducing inhibition of tumor proliferation. Our study offered a potential way in tumor therapy based on polyamine metabolism.

One-step assembly of polymeric demethylcantharate prodrug/Akt1 shRNA complexes for enhanced cancer therapy.

This report demonstrated a one-step assembly for co-delivering chemotherapeutics and therapeutic nucleic acids, constructed by integrating drug molecules into a nucleic acid condensing polymeric prodrug through degradable linkages. Demethylcantharate was selected as the model drug and pre-modified by esterifying its two carboxylic groups with 2-hydroxyethyl acrylate. The synthesized demethylcantharate diacrylate was then used to polymerize with linear polyethyleneimine (PEI 423) through a one-step Michael-addition reaction. The obtained cationic polymeric demethylcantharate prodrug was used to pack Akt1 shRNA into complexes through a one-step assembly. The formed complexes could release the parent drug demethylcantharate and Akt1 shRNA through the hydrolysis of ester bonds. Cellular assays involving cell uptake, cytotoxicity, and cell migration indicated that demethylcantharate and Akt1 shRNA co-delivered in the present form significantly and synergistically suppress the growth and metastasis of three human cancer cells. This work suggests that incorporating drug molecules into a nucleic acid-packing cationic polymer as a polymeric prodrug in a degradable form is a highly convenient and efficient way to co-deliver drugs and nucleic acids for cancer therapy.

[Endoscopic decompression of optic canal].

OBJECTIVE: To evaluate the effectiveness of endoscope in the treatment of optic nerve injury. METHODS: Thirteen patients with fracture at the inner and lower walls of optical canal underwent endoscopic decompression. The posterior 1/3 of the middle concha, the posterior ethmoid sinus and sphenoid sinus were opened, chips of bone and old hematocele were scavenged, and the optic ring of the optic canal was polished; however, the sheath of the optic nerve remained intact. In 2 cases with the dura broken at the cranial part of optic nerve, the broken site was covered with mucosa of middle concha, and the sphenoid sinus and the middle nasal meatus were covered with oil ribbon gauze. Three days after the operation, the ribbon gauze was pulled put, however, if cerebro-spinal fluid leakage was suspected, the ribbon gauze was pulled out 7-10 days after. After the operation the visual acuity improvement reaching one grade or more and improvement of visual field were defined as effective. RESULTS: Five of the 6 patients without light perception before the operation showed improvement in visual acuity. The other 7 patients with residual visual acuity all recovered to different extents. CONCLUSION: A mini-invasive surgery, decompression of optic canal with endoscope is effective in decompressing optic nerve, decreasing the injury of optic nerve, and the patients recover quickly after operation.

[Resection of optic nerve sheath meningioma via transcranio-orbital approach].

OBJECTIVE: To investigate the clinical effect of early stage operation for optic nerve sheath meningioma. METHODS: Retrospective study The clinical data of 21 cases of optic nerve sheath meningioma, 6 males and 25 females, aged 39 (12-60), with the chief complaints of loss of vision in 13 eyes (including 6 blind eyes) and proptosis in 8 eyes who underwent resection of the tumors via transcranio-orbital approach were analyzed retrospectively. Radiology showed 15 tumors growing along the optic nerve and enclosing it (flat type), 5 of which showed intracranial invasion; and other 6 of which had the tumors located on one side of optic nerve with spherical shape (nodular type) without intracranial invasion. The patients were followed up for 2-6 years. RESULTS: Total resection was accomplished in 15 cases, and partial removal in 6 cases. Function of oculomotor nerve was preserved in 17 cases, and function of abducent nerve was preserved in 18 cases, visual function was successfully preserved in the 2 cases of small tumor. Tumor recurred in two cases. CONCLUSION: Resection of optic nerve sheath meningioma via transcranio-orbital approach has the advantage of totally removing the tumor and preserving the function of the oculomotor and abducent nerves, preventing tumor from intracranial invasion. Early stage operation is recommended. Visual function may be preserved in the cases of small tumors.

[Emission spectra of hydroxyl radical generated in air corona discharge].

In this paper, the relative emission intensity of the 309 nm transition band of hydroxyl radical (OH) was measured by a CCD imaging spectrometer in a pin-plane corona discharge scheme of one atmosphere pressure air injected with unsaturated water vapor from the central hole of the used pins. The influences of several factors on the OH radical production were investigated by relative emission intensity measurement. The production of OH radical increased with a limited increment of water vapor concentration in the mixed gas. Compared with positive DC corona discharges, more OH radicals were generated in positive pulsed corona discharges and less in negative DC corona discharges. The spatial distribution of OH radical production was also observed. Most OH radicals were produced within the range of 5 mm off the discharge pin electrode. In conclusion, this means of optical emission spectroscopy, compared with more sophisticated laser fluorescence measurements used for plasma OH production diagnostics investigation, is simpler and more effective for characterizing the OH radical potential for pollutant oxidation.

Surgical Indications of Exploring Optic Canal and Visual Prognostic Factors in Neurosurgical Treatment of Tuberculum Sellae Meningiomas.

BACKGROUND: Tuberculum sellae meningiomas (TSMs) present a special symptom because of the adherence and compression to the optic nerve, optic artery, and the chiasm. A significant number of patients with TSMs appear visual deficits. This study aimed to investigate the surgical indications of exploring the optic canal and visual prognostic factors in the neurosurgical treatment of TSMs. METHODS: Totally 21 patients with TSM, who were operated from September 2007 to August 2011 in the Department of Neurosurgery, Tongren Hospital were enrolled in this study. Results of orbital computed tomography (CT) and magnetic resonance imaging (MRI), visual acuity, Goldmann visual field test, orbital color Doppler flow imaging (CDI) test in these patients were retrospectively analyzed. RESULTS: Visual deficit and optic canal involvement (OCI) were detected in all the 21 patients. Fourteen patients had bone proliferation within the area of the optic canal. After the operation, visual outcomes were improved in 13 patients, unchanged in 7 patients, and deteriorated in 1 patient. All the 21 patients performed orbital CDI test preoperatively, the results showed that if the peak systolic velocity (PSV) of central retinal artery (CRA) value was ≤ 8 cm/s, the visual outcome would be better. CONCLUSIONS: The surgical indications of exploring optic canal in TSM cases included: (1) The neuroimaging evidences of OCI (CT and/or MRI); (2) PSV of CRA in orbital CDI test was ≤ 8 cm/s; (3) visual acuity was below 0.1; (4) visual field deficit. The PSV of CRA in CDI test could be a prognostic factor for visual outcomes of TSMs.

Mitochondria apoptosis pathway synergistically activated by hierarchical targeted nanoparticles co-delivering siRNA and lonidamine.

The mitochondria-mediated apoptosis pathway is an effective option for cancer therapy due to the presence of cell-suicide weapons in mitochondria. However, anti-apoptotic proteins that are over-expressed in the mitochondria of many malignant tumors, such as Bcl-2 protein, could allow the cancer cells to evade apoptosis, greatly reducing the efficacy of this type of chemotherapy. Here, we constructed a hierarchical targeted delivery system that can deliver siRNA and chemotherapeutic agents sequentially to tumor cells and mitochondria. In detail, the copolymer TPP-CP-LND (TCPL) was synthesized by the mitochondria-targeting ligand triphenylphosphine (TPP) and therapeutic drug lonidamine (LND) conjugated to the polyethyleneimine in chitosan-graft-PEI (CP), and then complexed with siRNA. Followed, the complexes were coated with poly(acrylic acid)-polyethylene glycol-folic acid (PPF) copolymer to form a hierarchical targeted co-delivery system (TCPL/siRNA/PPF NPs). The TCPL/siRNA/PPF NPs had a neutral surface charge, were stable in plasma and exhibited pH-responsive shell separation. Remarkably, the TCPL/siRNA/PPF NPs simultaneously released siBcl-2 into the cytoplasm and delivered LND to mitochondria in the same cancer cell after FA-directed internalization, and even synergistically activated mitochondria apoptosis pathway. This work demonstrated the potential of RNA-interference and mitochondria-targeted chemotherapeutics to collaboratively stimulate the mitochondria apoptosis pathway for cancer therapy.