Massive Chylous Leakage After Endoscopic Thyroidectomy with Central Lymph Node Dissection: A Case Report.

BACKGROUND Massive chylous leakage represents a rare yet potentially life-threatening complication following neck dissection, and its occurrence is even less common in the context of endoscopic thyroid surgery. Chylous leakage poses significant clinical management challenges, encompassing prolonged hospitalization, nutritional deficiencies, electrolyte imbalances, and the potential for infection. It is imperative for surgeons to remain vigilant and proactive in recognizing and managing chylous leakage to mitigate its potential impact on patient outcomes. CASE REPORT A 37-year-old woman presented with a thyroid nodule, and subsequent fine-needle aspiration biopsy confirmed the diagnosis of papillary thyroid carcinoma. She then underwent endoscopic thyroidectomy with central lymph node dissection via a bilateral areola approach and experienced significant postoperative chylous leakage. Various conservative management strategies were used to treat the leak, including fasting, parenteral nutrition, maintenance of electrolyte balance, and continuous infusion of somatostatin. After failure of a series of conservative treatments, the patient underwent a reoperation to address the leak via the initial approach. After identification of the leak site, the residual end of the lymphatic vessel was clamped with a biological clamp, and no further chylous leakage was observed. The drainage was removed 4 days after the second operation, and the patient was discharged on the fifth day. During follow-up, no abnormalities were observed. CONCLUSIONS Managing significant chylous leakage poses a challenge for surgeons. This complication is rare following endoscopic thyroidectomy with central lymph node dissection, and there remains a lack of experience in effective prevention and treatment. We aim to raise awareness through our case report.

A coordinative modular assembly-constructed self-reinforced nano-therapeutic agent for effective antitumor-immune activation.

Immunosuppressive microenvironment and poor immunogenicity are two stumbling blocks in anti-tumor immune activation. Tumor associated macrophages (TAMs) play crucial roles in immunosuppressive microenvironment, while immunogenic cell death (ICD) is a typical strategy to boost immunogenicity. Herein, we developed a coordinative modular assembly-based self-reinforced nanoparticle, (CaO2/TA)-(Fe3+/BSA) which integrated CaO2, Fe3+-tannic acid coordinated networks and albumin under the instruction of molecular dynamics simulation. (CaO2/TA)-(Fe3+/BSA) could significantly enhance Fenton reaction through Fe3+ self-reduction and H2O2 self-sufficiency, and simultaneously increased intracellular accumulation of Ca2+. The self-augmented Fenton reaction with sufficient reactive oxygen species effectively repolarized TAMs and elicited ICD with Ca2+ overload. Besides, (CaO2/TA)-(Fe3+/BSA) was confirmed to self-reinforce deep tumor drug delivery by "treatment-delivery" positive feedback based on gp60-mediated transcytosis and M2-like macrophages repolarization-mediated perfusion promotion. Resultantly, (CaO2/TA)-(Fe3+/BSA) effectively alleviated immunosuppression, provoked local and systemic immune response and potentiated anti-PD-1 antibody therapy. Our strategy highlights a facile and controllable approach to construct penetrated effective antitumor nano-immunotherapeutic agent.

PGR-KITLG signaling drives a tumor-mast cell regulatory feedback to modulate apoptosis of breast cancer cells.

The immune microenvironment constructed by tumor-infiltrating immune cells and the molecular phenotype defined by hormone receptors (HRs) have been implicated as decisive factors in the regulation of breast cancer (BC) progression. Here, we found that the infiltration of mast cells (MCs) informed impaired prognoses in HR(+) BC but predicted improved prognoses in HR(-) BC. However, molecular features of MCs in different BC remain unclear. We next discovered that HR(-) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. Mechanistically, in HR(+) BC, the KIT ligand (KITLG), a major mast cell growth factor in recruiting and activating MCs, could be transcriptionally upregulated by the progesterone receptor (PGR), and elevate the production of MC-derived granulin (GRN). GRN attenuates TNFα-induced apoptosis in BC cells by competitively binding to TNFR1. Furthermore, disruption of PGR-KITLG signaling by knocking down PGR or using the specific KITLG-cKIT inhibitor iSCK03 potently enhanced the sensitivity of HR(+) BC cells to MC-induced apoptosis and exerted anti-tumor activity. Collectively, these results demonstrate that PGR-KITLG signaling in BC cells preferentially induces GRN expression in MCs to exert anti-apoptotic effects, with potential value in developing precision medicine approaches for diagnosis and treatment.

The diagnostic value of GICA used for intraoperative lymph node FNA-Tg measurement to evaluate thyroid cancer metastases.

Objective: It is crucial to diagnose lymph node (LN) metastases (LNM) before or during thyroid carcinoma surgery. Measurement of thyroglobulin (Tg) in the fine needle aspirate washout (FNA-Tg) is useful to assist in the diagnosis of LNM for papillary thyroid carcinoma (PTC). This study aimed to assess the diagnostic performance of a new technique based on a colloidal gold-based immunochromatographic assay (GICA) for intraoperative FNA-Tg in diagnosing LNM. Clinical trial information: This study is registered with chictr.org.cn, ID: ChiCTR2200063561 (registered 11 September, 2022). Methods: This prospective study enrolled 51 PTC patients who underwent cervical LN dissection. A total of 150 LNs dissected from the central and lateral compartments were evaluated by FNA-Tg-GICA at three different time points and compared with frozen sections and the conventional Tg measurement method electrochemiluminescence immunoassay (ECLIA). Receiver operating characteristic curve (ROC) and area under the curve (AUC), cutoff value to discriminate benign and malignant LNs, sensitivity, specificity, and accuracy were provided. Results: The cutoff value of FNA-Tg to predict LNM was 110.83 ng/mL for ECLIA and 13.19 ng/mL, 38.69 ng/mL, and 77.17 ng/mL for GICA at 3, 10, and 15 min, respectively. There was no significant difference between the AUCs of GICA at different time points compared to using ECLIA and frozen sections. Besides, the diagnostic performance of GICA and ECLIA showed no significant difference in evaluating LNM from central and lateral compartments or between the TgAb-positive subgroup and TgAb-negative subgroup. Conclusion: GICA is a promising method for intraoperative FNA-Tg measurement and has high value in predicting LNM. It may be a novel alternative or supplementary method to frozen section or ECLIA.

Surgical methods of total thyroidectomy for differentiated thyroid cancer: a systematic review and Bayesian network meta-analysis.

BACKGROUND: Emerging remote-access surgical methods are utilized to treat differentiated thyroid cancer. The study aimed to compare the surgical integrity, safety, efficacy, and postoperative experience of patients among common surgical methods. METHODS: The PubMed, Medline, Cochrane Library, Web of Science, and EMBASE databases were searched from their inception until March 2023. Pairwise meta-analysis and Bayesian network meta-analysis were performed. The surface under the cumulative ranking curve (SUCRA) was used to illuminate the probability that each method would be the best for each outcome. RESULTS: Thirty-two studies comprising 7042 patients were included. Robotic bilateral axillo-breast approach (RBABA) and robotic gasless transaxillary approach (RGAA) retrieved fewer lymph nodes (LNs) than open thyroidectomy (OT). RBABA showed a significantly lower permanent recurrent laryngeal nerve (RLN) palsy rate than OT. According to SUCRA values, endoscopic transoral approach (EOA) ranked the highest in retrieved LNs (0.84), the proportion of stimulated serum thyroglobulin less than 1.0 ng/ml (0.77), and the pain score (0.77). Endoscopic bilateral areola approach (EBAA) ranked the highest in the transient RLN palsy rate (0.72). The endoscopic gasless transaxillary approach (EGAA) ranked the highest in the transient hypoparathyroidism rate (0.78). RBABA ranked the highest in the rate of permanent RLN palsy (0.94) and hypoparathyroidism (0.77). OT ranked the highest in operative time (0.92). CONCLUSIONS: Each surgical method of total thyroidectomy has benefits and limitations. EOA performed the best in maintaining surgical integrality and reducing the pain score, while taking a long operative time. Generally, RBABA showed the best advantage in protecting parathyroid glands and RLN but with the longest operative time. OT had the best advantage in operative time. Therefore, OT and EOA are ideal methods for patients with a higher risk of central LN metastasis. RBABA and EOA may not be suitable for elderly patients or those with high anesthesia risk.

Intraoperative strategies in identification and functional protection of parathyroid glands for patients with thyroidectomy: a systematic review and network meta-analysis.

BACKGROUND: This study aimed to assess the benefits and limitations of four intraoperative visualization of parathyroid gland (IVPG) strategies in the identification and functional protection of parathyroid glands (PGs). METHODS: We searched PubMed, the Cochrane Central Register of Controlled Trials, CNKI, EMBASE, Web of Science and Google Scholar databases until 30 June 2023. Four IVPG strategies were composed of the naked eyes (NE) and three imaging strategies: autofluorescence (AF), indocyanine green fluorescence (ICGF), and carbon nanoparticles (CN). We performed a pairwise meta-analysis (PMA) for direct comparisons and a Bayesian network meta-analysis (NMA) for indirect comparisons. RESULTS: A total of 29 eligible studies were included. According to NMA and PMA, AF had significantly lower rates of postoperative hypocalcemia and hypoparathyroidism, PG inadvertent resection, and PG auto-transplantation compared to NE, while had significantly higher rate of PG identification. CN showed significantly lower rates of postoperative hypocalcemia and hypoparathyroidism, and PG inadvertent resection compared to NE in PMA and NMA. ICGF showed a significantly higher rate of PG auto-transplantation compared to NE in PMA and AF in NMA. According to SUCRA values, AF showed the best advantage in reducing the rate of postoperative hypocalcemia (0.85) and PG inadvertent resection (0.89), and increasing the rate of PG identification (0.80). CN had the greatest advantage in reducing the rate of postoperative hypoparathyroidism (0.95). ICGF ranked the highest in the rate of PG auto-transplantation (0.98). CONCLUSIONS: Three imaging strategies demonstrate significant superiority over NE in the intraoperative PG identification and functional protection. AF is the best strategy in reducing the incidence of postoperative hypocalcemia, increasing the rate of PG identification, and reducing the rate of PG inadvertent resection and auto-transplantation. ICGF has great value in assessing PG viability, leading to the trend towards PG auto-transplantation. CN is the best strategy in reducing the incidence of postoperative hypoparathyroidism.

Misdiagnosis of thyroid penetration caused by fishbone ingestion: a case report and literature review.

Background: Foreign body ingestion is a common occurrence. However, thyroid penetrating injury caused by fishbone migration is rare. Case Description: In this study, we present a rare misdiagnosed case of a fishbone fixed in the thyroid with a negative diagnosis on laryngoscopy examination. A 52-year-old woman experienced severe and persistent left anterior cervical pain when eating fish. Laryngoscopic imaging at an external hospital, revealed a cyst with a maximum length of 2 cm on the epiglottis, and epiglottic cyst resection under a laryngoscope was performed. The pain was not relieved, and the patient was referred to our hospital. Computed tomography and ultrasound examinations showed a sloping foreign body with a length of approximately 2.5 cm from top to bottom in the left lobe of the thyroid gland. The possibility of a penetrating fishbone injury was considered, and the foreign body was surgically removed. Postoperative drainage, fasting, and antibiotics were prescribed for 3 days, and then the patient was discharged. Follow-ups for 40 days suggested that she had recovered well without complications. Conclusions: The presence of a migratory fishbone should be considered when a patient has a history of fishbone ingestion but laryngoscopy or esophagoscopy assessment of foreign body ingestion is negative.

PDT-sensitized ROS-responsive dextran nanosystem for maximizing antitumor potency of multi-target drugs.

The heterogeneity of tumor microenvironment leads to uneven distribution of bio-stimuli. Thus, the multi-site delivery efficiency of responsive drug delivery systems (DDS) inner tumor was always limited. Herein, we proposed a combination strategy of photodynamic therapy (PDT) with ROS-responsive nanosystem which was constructed from dextran-phenylboronic acid pinacol ester conjugates. This combination utilized PDT to amplify and homogenize tissular oxidation level, and achieve effective multi-site response and release of multi-target drugs like gambogic acid (GA). Our research demonstrated the successful preparation of GA and protoporphyrin IX (PpIX) co-loaded nanoparticles, and the PDT-mediated spatiotemporal controlled multi-site drug release in simulated conditions. Furthermore, data from in vitro and in vivo researches on B16F10 cells, HUVEC, and B16F10-bearing C57BL/6 mice potently confirmed the enhanced multi-mechanism regulations of GA mediated by the effective and homogeneous tumoral release. This tactic based on bio-stimuli amplification and homogenization proposes a paradigm to maximize the potency of multi-target drugs.

A pHe sensitive nanodrug for collaborative penetration and inhibition of metastatic tumors.

Current chemotherapies for metastatic tumors are seriously restricted by limited drug infiltration and deficient disturbance of metastasis-associated complex pathways involving tumor cell autocrine as well as paracrine loops in the microenvironment (TME). Of note, cancer-associated fibroblasts (CAFs) play a predominant role in shaping TME favoring drug resistance and metastasis. Herein, we constructed a tumor extracellular pH (pHe) sensitive methotrexate-chitosan conjugate (MTX-GC-DEAP) and co-assembled it with quercetin (QUE) to achieve co-delivered nanodrugs (MTX-GC-DEAP/QUE). The pHe sensitive protonation and disassembly enabled MTX-GC-DEAP/QUE for stroma-specific delivery of QUE and positive-charged MTX-GC-DEAP molecular conjugates, thereby achieving deep tumor penetration via the combination of QUE-mediated CAF inactivation and adsorption-mediated transcytosis. On the basis of significantly promoted drug availability, a strengthened "omnidirectional" inhibition of pre-metastatic initiation was generated both in vitro and in vivo from the CAF inactivation-mediated reversion of metastasis-promoting environments as well as the inhibition of epithelial-mesenchymal transition, local and blood vessel invasion via QUE-mediated direct regulation on tumor cells. Our tailor-designed versatile nanodrug provides a deep insight into potentiating multi-faceted penetration of multi-mechanism-based regulating agents for intensive metastasis inhibition.

Factors in the occurrence and restoration of hypoparathyroidism after total thyroidectomy for thyroid cancer patients with intraoperative parathyroid autotransplantation.

Introduction: Postoperative hypoparathyroidism (POH) is the most common and important complication for thyroid cancer patients who undergo total thyroidectomy. Intraoperative parathyroid autotransplantation has been demonstrated to be essential in maintaining functional parathyroid tissue, and it has clinical significance in identifying essential factors of serum parathyroid hormone (PTH) levels for patients with parathyroid autotransplantation. This retrospective cohort study aimed to comprehensively investigate influential factors in the occurrence and restoration of POH for patients who underwent total thyroidectomy with intraoperative parathyroid autotransplantation (TTIPA). Method: This study was conducted in a tertiary referral hospital, with a total of 525 patients who underwent TTIPA. The postoperative serum PTH levels were collected after six months, and demographic characteristics, clinical features and associated operative information were analyzed. Results: A total of 66.48% (349/525) of patients who underwent TTIPA were diagnosed with POH. Multivariate logistic regression indicated that Hashimoto's thyroiditis (OR=1.93, 95% CI: 1.09-3.42), P=0.024), the number of transplanted parathyroid glands (OR=2.70, 95% CI: 1.91-3.83, P<0.001) and postoperative blood glucose levels (OR=1.36, 95% CI: 1.06-1.74, P=0.016) were risk factors for POH, and endoscopic surgery (OR=0.39, 95% CI: 0.22-0.68, P=0.001) was a protective factor for POH. Multivariate Cox regression indicated that PTG autotransplantation patients with same-side central lymph node dissection (CLND) (HR=0.50; 95% CI: 0.34-0.73, P<0.001) demonstrated a longer time for increases PTH, and female patients (HR=1.35, 95% CI: 1.00-1.81, P=0.047) were more prone to PTH increases. Additionally, PTG autotransplantation with same-side CLND (HR=0.56, 95% CI: 0.38-0.82, P=0.003) patients had a longer time to PTH restoration, and patients with endoscopic surgery (HR=1.54, 95% CI: 1.04-2.28, P=0.029) were more likely to recover within six months. Conclusion: High postoperative fasting blood glucose levels, a large number of transplanted PTGs, open surgery and Hashimoto's thyroiditis are risk factors for postoperative POH in TTIPA patients. Elevated PTH levels occur earlier in female patients and patients without CLND on the transplant side. PTH returns to normal earlier in patients without CLND and endoscopic surgery on the transplant side.

Combined Use of Autofluorescence and Indocyanine Green Fluorescence Imaging in the Identification and Evaluation of Parathyroid Glands During Total Thyroidectomy: A Randomized Controlled Trial.

Background and objectives: Accurate identification and evaluation of the parathyroid glands (PGs) intraoperatively is critical to reduce the incidence of postoperative hypoparathyroidism after total thyroidectomy. Near-infrared fluorescence imaging (NIFI), including the autofluorescence (AF) and indocyanine green fluorescence (ICGF) imaging, is a promising technique to protect PGs. This study aimed to assess whether the combined use of AF and ICGF could reduce the incidence of postoperative hypoparathyroidism and improve the identification and evaluation of PGs during total thyroidectomy. Methods: This randomized controlled trial enrolled 180 patients who were randomized into two groups and underwent total thyroidectomy with unilateral or bilateral central lymph node dissection. In the control group, the PGs were identified and evaluated by the naked eye. In the NIFI group, AF was used to identify the PGs and ICGF was applied to assess the blood perfusion of the PGs in situ. The primary outcome was the incidence of postoperative hypoparathyroidism. The secondary outcomes included the number of identified PGs, autotransplanted PGs, and known preserved PGs in situ. Results: The incidence of postoperative transient hypoparathyroidism was significantly lower in the NIFI group than in the control group (27.8% vs. 43.3%, P = 0.029). More PGs were identified in the NIFI group than in the control group (3.6 ± 0.5 vs. 3.2 ± 0.4, P < 0.001). No significant difference was observed in the number of autotransplanted PGs between the two groups (P = 0.134). Compared with the control group, a greater number of known PGs were preserved in situ in the NIFI group (1.3 ± 0.6 vs. 1.0 ± 0.5, P < 0.001). In the NIFI group, only 4.5% of the patients with at least one well-perfused PG (ICG score of 2) developed postoperative hypoparathyroidism, which was significantly lower than that of the control group (34.6%, P < 0.001). Conclusion: Combined use of AF and ICGF during total thyroidectomy reduces the risk of transient postoperative hypoparathyroidism, enhances the ability to identify and preserve PGs, and improves the accuracy of evaluating the perfusion of PGs during surgery. Clinical Trial Registration: Chinese Clinical Trial Register (www.chictr.org.cn), identifier ChiCTR2100045320. Registered on April 12, 2021.

BAHD1 serves as a critical regulator of breast cancer cell proliferation and invasion.

Breast cancer patients with lymphatic metastasis suffer from poor prognoses. There is an urgent need for controlling lymph node metastasis, but it has proven challenging so far. Here, we implemented LASSO analysis of The Cancer Genome Atlas database to identify genes related to lymph node metastasis and prognosis, and 15 genes were selected. We constructed a functional protein association network and univariate Cox regression to identify significant genes. The results showed that BAHD1 could be predictive of lymph node metastasis as well as prognosis. In vitro studies demonstrated that BAHD1 exerted appreciable effects on the proliferation, migration, and invasion capacity of breast cancer cells. Furthermore, downregulation of BAHD1 induced cell cycle arrest in G1 phase. Additionally, the mRNA levels of CCND1, CDK1 and YWHAZ were decreased upon BAHD1 silencing. These findings indicate that the expression of BAHD1 is essential in the progression of breast cancer, which may provide novel therapeutic and diagnostic clues and insights into the prevention of lymph node metastasis in breast cancer.

Comparison of endoscopic thyroidectomy by complete areola approach and conventional open surgery in the treatment of differentiated thyroid carcinoma: A retrospective study and meta-analysis.

Background: The feasibility of endoscopic thyroidectomy by complete areola approach (ETCA) remains controversial. This study was conducted by combining our clinical data with the data obtained from a systematic review literature search to examine the effectiveness and safety of ETCA compared with conventional open thyroidectomy (COT) in differentiated thyroid carcinoma (DTC). Methods: A total of 136 patients with a diagnosis of DTC who underwent unilateral thyroidectomy with central neck dissection from August 2020 to June 2021 were enrolled. The enrolled patients were divided into the ETCA group (n = 73) and the COT group (n = 63). The operative time, intraoperative bleeding volume, number of removed lymph nodes, number of metastatic lymph nodes, postoperative drainage volume, length of postoperative hospital stay, postoperative parathyroid hormone (PTH) levels, and complications were analyzed. Then, a systemic review and comprehensive literature search were conducted by using PubMed, Google Scholar, Embase, Web of Science, CNKI, Wanfang, and VIP database up to June 2022. Review Manager software version 5.3 was used for the meta-analysis. Results: The results of clinical data showed that there were significant differences between the two groups in the operative time, intraoperative bleeding volume, removed lymph nodes, and postoperative drainage volume. There were no statistical differences in the length of postoperative hospital stay, number of metastatic lymph nodes, postoperative PTH level, and complications. In the systematic review and meta-analysis, 2,153 patients from fourteen studies (including our data) were ultimately included. The results of the meta-analysis found that ETCA had a longer operative time, larger postoperative drainage volume, and lower intraoperative bleeding volume. In terms of the length of postoperative hospital stay, the number of removed lymph nodes, and surgical complications, there was no significant difference between the two groups. Conclusion: ETCA poses lower surgical bleeding and better cosmetic appearance compared with COT, while the length of operation and postoperative drainage in ETCA is less favorable compared with COT. In addition, ETCA is not inferior to COT in terms of the postoperative hospitalization stay, the number of removed lymph nodes, and surgical complications. Given its overall advantages and risks, ETCA is an effective and safe alternative for patients with cosmetic concerns.

Deeply Infiltrating iRGD-Graphene Oxide for the Intensive Treatment of Metastatic Tumors through PTT-Mediated Chemosensitization and Strengthened Integrin Targeting-Based Antimigration.

A limited infiltration and the subsequent low effective drug concentration result in poor chemotherapeutic outcomes against tumors, and even further promote tumor resistance and metastatic. Herein, iRGD-modified graphene oxide (GO) nanosheets (IPHG) are developed for the intensive treatment of metastatic tumors using focus-specific penetrated delivery together with photothermal therapy-mediated chemosensitization and photothermal therapy-strengthened integrin targeting-based antimigration. In vitro and in vivo data verified the mechanism of the tumor-selective infiltration of IPHG is based on a rigid 2D structure-associated advantage regarding hemodynamics and endothelial contact, followed by iRGD-endowed transendothelial and intratumoral transport. Once IPHG-DOX-penetrated 4T1 tumors are exposed to near-infrared irradiation, hyperthermia stress and photothermal therapy-elevated effective drug concentrations result in chemosensitization and prominent tumor suppression. Meanwhile, the specific binding of iRGD to integrins and photothermal therapy leads to the synergistic perturbation of cytoskeleton remodeling and subsequent impairment of cell motility and metastasis. The tailored design of IPHG validates a promising paradigm for drug delivery to combat tumor resistance and metastasis resulting from poor target access for single chemotherapy.

Redox-sensitive hyaluronic acid-cholesterol nanovehicles potentiate efficient transmembrane internalization and controlled release for penetrated "full-line" inhibition of pre-metastatic initiation.

Metastatic breast cancer is a major cause of cancer-related mortality worldwide. The tumor-specific penetration and triggered drug release for "full-line" inhibition of pre-metastatic initiation are of essential importance in improving mortality rates. Here, a crosslinked, redox-sensitive amphiphilic conjugate (cHLC) was constructed with a combination of features, including hyaluronic acid (HA)-mediated tumor active targeting, lipoic acid (LA) core-crosslinking based bio-stability and reducibility, and lipid raft anchoring-promoted HA-mediated endocytosis through cholesterol (CHO) modification for the penetrated co-delivery of paclitaxel (PTX) and the multi-targeted anti-metastatic agent, silibinin (SB). Resultantly, the nanodrug (cHLC/(PTX + SB)) demonstrated enhanced tumor cytoplasm-selective rapid drug delivery in a 4T1 model both in vitro and in vivo. The released SB efficiently sensitized cells to PTX treatment and inhibited the whole process of pre-metastatic initiation including epithelial-to-mesenchymal transition (EMT), local and blood vessel invasion. The exquisite design of this delivery system provides a deep insight into enhancing focus accessibility of multi-targeted drugs for an efficient inhibition of tumor metastasis.

Hypoxia-Sensitive Zwitterionic Vehicle for Tumor-Specific Drug Delivery through Antifouling-Based Stable Biotransport Alongside PDT-Sensitized Controlled Release.

A hypoxia-sensitive zwitterionic vehicle, DHigh-PEI-(A+P), with the ability for antifouling-mediated, stable biotransport and a photodynamic therapy (PDT)-sensitized hypoxic response for spatiotemporal controlled drug release, was developed for the tumor-specific delivery of chemotherapeutics and biomacromolecules. The amphiphilic DHigh-PEI-(A+P) was constructed from a betaine monomer (DMAAPS), a photosensitizer (PpIX), and an azobenzene-4,4'-dicarboxylic acid-modified polyethylenimine. Herein paclitaxel (PTX) was selected as a common model drug to verify the functions of the designed polymer. First, DHigh-PEI-(A+P) was demonstrated to spontaneously coassemble with PTX in aqueous solution with high drug loading (>35%). The desirable antifouling ability of DHigh-PEI-(A+P) was independently verified by efficient 4T1 endocytosis in serum alongside systemic tumor targeting. Furthermore, PpIX-mediated PDT was verified to aggravate and homogenize a hypoxic microenvironment at the cell and tissue levels for a sharp responsive disassembly of DHigh-PEI-(A+P) and thus a robust drug release in a well-controlled manner. As a result, DHigh-PEI-(A+P) amplified the therapeutic outcome of PTX on orthotopic 4T1 mouse models with minimal collateral damage. We proposed that DHigh-PEI-(A+P) may serve as a tailor-designed universal vehicle for the tumor-specific delivery of drugs with distinct physicochemical properties.

Tumor microenvironment remodeling-based penetration strategies to amplify nanodrug accessibility to tumor parenchyma.

Remarkable advances in nano delivery systems have provided new hope for tumor prevention, diagnosis and treatment. However, only limited clinical therapeutic effects against solid tumors were achieved. One of the main reasons is the presence of abundant physiological and pathological barriers in vivo that impair tumoral penetration and distribution of the nanodrugs. These barriers are related to the components of tumor microenvironment (TME) including abnormal tumor vasculature, rich composition of the extracellular matrix (ECM), and abundant stroma cells. Herein, we review the advanced strategies of TME remodeling to overcome these biological obstacles against nanodrug delivery. This review aims to offer a perspective guideline for the implementation of promising approaches to facilitate intratumoral permeation of nanodrugs through alleviation of biological barriers. At the same time, we analyze the advantages and disadvantages of the corresponding methods and put forward possible directions for the future researches.

Biomineralization-inspired dasatinib nanodrug with sequential infiltration for effective solid tumor treatment.

The complex blood environment, heterogenic enhanced permeability and retention (EPR) effect, and dense matrix comprise the primary "leakage obstacles" impeding specific accumulation and penetration of nanodrugs against solid tumors, thus forming a key bottleneck for their clinical application. Herein, we present a biomineralization-inspired dasatinib (DAS) nanodrug (CIPHD/DAS) that sequentially permeates all of the abovementioned hindrances for efficient treatment of solid tumors. CIPHD/DAS exhibited a robust hybrid structure constructed from an iRGD-modified hyaluronic acid-deoxycholic acid organic core and a calcium phosphate mineral shell. In vitro and in vivo data demonstrated the mechanism of sequential tumoral infiltration was based on mineral-stiffened blood circulation with decreased premature drug leakage, iRGD-endowed tumor-specific transendothelial transport for "first-order promotion of accumulation" and DAS-mediated restoration of fibrotic stromal homeostasis for "second-order promotion of penetration". Resultantly, CIPHD/DAS showed remarkable distal drug availability in desmoplastic 4T1/CAFs orthotropic mouse models and significantly suppressed tumor growth and metastasis. This optimized strategy with sequential permeabilization of the capital "leakage obstacles" validates a promising paradigm to conquer the "impaired delivery and penetration" associated bottleneck of nanodrugs in the clinical treatment of solid tumors.

Novel Chitosan Derivatives with Reversible Cationization and Hydrophobicization for Tumor Cytoplasm-Specific Burst Co-delivery of siRNA and Chemotherapeutics.

Despite the great potential of combination therapy based on siRNA and chemotherapeutics, an efficient vehicle with abilities of well drug co-loading, synchronizing in vivo trafficking, and target-specific co-burst release remains elusive, which results in a suboptimal synergistic potency. Herein, a novel chitosan amphiphile (PEI-ss-HECS-ss-OA, HSPO) with glutathione (GSH)-reversible cationization and hydrophobicization by polyethylenimine (PEI) and octylamine (OA), respectively, was developed for this purpose. HSPO spontaneously assembled in aqueous solution to be a micellar system and effectively co-encapsulated the two drugs with an adjustable dosage ratio. With a surface charge inversion strategy by hyaluronic acid (HA) coating, the HA(HSPO) co-delivery micelles with a negative surface charge (-21.45 ± 1.44 mV) and suitable size (192.52 ± 7.41 nm) selectively accumulated into CD44 overexpressed A549 tumors through a combination of passive and active targeting mechanism. Then, tumor cytoplasm-selective co-burst release was obtained through GSH triggered collapse of the amphiphilic assembly alongside a decrease of positive charge condensation, finally leading to an enhanced synergistic antitumor effect with a superior inhibition ratio of 86.63%. Overall, this study validated the great promise of HSPO as an efficient site-specific rapid co-trafficking vehicle of siRNA and chemotherapeutics for a remarkable synergistic tumor inhibition.