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This retrospective study compared the efficacy and safety of nedaplatin-based chemoradiotherapy and cisplatin-based chemoradiotherapy in stage II-IVa nasopharyngeal carcinoma (NPC) patients. Patients treated with cisplatin-based or nedaplatin-based chemoradiotherapy between January 2012 and December 2015 were evaluated. Survival was estimated by the Kaplan‒Meier method and compared by the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. A cohort of 538 NPC patients was enrolled. There were no significant differences in the 5-year overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), or distant metastasis-free survival (DMFS) between the cisplatin and nedaplatin groups. During the whole treatment course, patients in the cisplatin group had higher incidences of grade 3‒4 vomiting and anorexia, while patients in the nedaplatin group had higher incidences of grade 3‒4 leucopenia and mucositis. In terms of late toxicities, patients in the cisplatin group had a higher incidence of xerostomia. In multivariate analysis, T stage, N stage, and clinical stage were prognostic factors for OS, PFS, and DMFS. In subgroup analyses, nedaplatin-based chemotherapy achieved comparable treatment outcomes in specific populations stratified by age, sex, ECOG PS score and clinical stage. Cisplatin and nedaplatin are effective choices for stage II-IVa NPC patients, with a different spectrum of side effects. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of Wen-Luo-Tong Granules (WLT) local administration in the treatment of patients with peripheral neuropathy (PN) induced by chemotherapy or target therapy. Methods: This study is a randomized, double-blinded, and placebo-controlled trial. Seventy-eight patients with PN induced by chemotherapy or target therapy were enrolled from China-Japan Friendship Hospital between July 2019 and January 2020. They were randomly assigned to WLT (39 cases) and control groups (39 cases) using a block randomization method. The WLT group received WLT (hand and foot bath) plus oral Mecobalamin for 1 week, while the control group received placebo plus oral Mecobalamin. The primary endpoint was PN grade evaluated by the National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE). The secondary endpoints included quantitative touch-detection threshold, neuropathy symptoms, Quality of Life Questionnaire-Chemotherapy Induced Peripheral Neuropathy (QLQ-CIPN20), and Quality of Life Questionnaire-Core30 (QLQ-C30). Results: After treatment, the PN grade in the WLT group was significantly lower than that in the control group (1.00 ± 0.29 vs. 1.75 ± 0.68, P<0.01). The total effective rate in the WLT group was significantly higher than that in the control group (82.05% vs. 51.28%, P<0.01). Compared with the control group, the touch-detection thresholds at fingertips, neuropathy symptom score, QLQ-CIPN 20 (sensory scale, motor scale, autonomic scale, and sum score), and QLQ-C30 (physical functioning, role functioning, emotional functioning, and global health) in the WLT group significantly improved after treatment (P<0.01 or P<0.05). Conclusion: WLT local administration was significantly effective in the treatment of patients with PN induced by chemotherapy or target therapy. (Trial registration No. ChiCTR1900023862) [ABSTRACT FROM AUTHOR]

PLGA nanotherapeutics though representing a most promising platform for targeted cancer therapy are confronted with low stability and insufficient tumor cell uptake. Here, we report that hyaluronic acid (HA) coated PLGA nanoparticulate docetaxel (DTX-HPLGA) is particularly robust and can effectively target and suppress orthotopic human lung cancer. DTX-HPLGA was easily prepared with a small size of 154 nm and negative surface charge of − 22.7 mV by nanoprecipitation and covalent coating with HA. DTX-HPLGA displayed a low IC 50 of 0.91 μg/mL in CD44 + A549 cells and a prolonged elimination half-life of 4.13 h in nude mice. Interestingly, DTX-HPLGA demonstrated 4.4-fold higher accumulation in the cancerous lung than free DTX, reaching a remarkable level of 13.7 %ID/g at 8 h post-injection, in orthotopic human A549 lung cancer-bearing mice. Accordingly, DTX-HPLGA exhibited significantly better inhibition of tumor growth than free DTX, leading to healthy mice growth and markedly improved survival time. DTX-HPLGA with easy fabrication, excellent stability and tumor accumulation, effective tumor suppression, and low side effects is of particular interest for targeted chemotherapy of lung cancers. [ABSTRACT FROM AUTHOR]

Cyclic RGD peptide-functionalized reversibly core-crosslinked biodegradable poly(ethylene glycol)- b -poly(ε-caprolactone) (PEG-PCL) micelles (cRGD-RCCMs) were designed and developed for highly potent and targeted glioma chemotherapy. To achieve crosslinkable core, dithiolane-functionalized trimethylene carbonate (DTC) was incorporated into PCL block. Interestingly, cRGD-RCCMs displayed a high doxorubicin (DOX) loading content of ∼18 wt%, small hydrodynamic size of ∼50 nm, and excellent colloidal stability with minimum drug leakage under physiological conditions while fast DOX release under cytoplasmic-mimicking reductive environments. MTT, confocal microscopy and flow cytometry measurement results pointed out that cRGD-RCCMs with 30% cRGD surface density (cRGD30-RCCMs) showed an evident selectivity, efficient cytoplasmic drug release, and superior antitumor activity to clinically used pegylated liposomal doxorubicin (DOX-LPs) in α v β 3 integrin overexpressing U87MG glioblastoma cells. Strikingly, DOX-loaded cRGD30-RCCMs demonstrated a prolonged circulation time showing an elimination half-life of ∼4.7 h, three times exceeding that of the non-crosslinked counterparts, and a remarkably enhanced tumor accumulation of 7.7%ID/g. Furthermore, in vivo therapeutic studies revealed that DOX-loaded cRGD30-RCCMs effectively suppressed tumor growth, significantly prolonged survival time, and lessened side effects in subcutaneous U87MG glioblastoma-bearing nude mice. These reversibly core-crosslinked multifunctional biodegradable micelles might be developed into advanced and clinically viable targeted anticancer nanomedicines. Statement of Significance Nanomedicines based on biodegradable micelles and nanoparticles offer a most promising treatment for malignant tumors. The therapeutic outcomes of current nanomedicines are, however, trimmed by their instability, low tumor retention, inefficient tumor cell uptake, and inferior drug release control. We report herein that cRGD-functionalized, rapidly glutathione-responsive, and reversibly core-crosslinked biodegradable micellar doxorubicin based on PEG-PCL block copolymer mediates potent and targeted glioma chemotherapy, affording significantly better treatment efficacy and lower systemic toxicity than the non-crosslinked micellar doxorubicin and clinically used pegylated liposomal doxorubicin controls. These reversibly core-crosslinked multifunctional biodegradable micelles have emerged as a robust, simple, versatile, and safe nanoplatform that might elegantly bridge the gap between the scientific and translational anticancer nanomedicine research. [ABSTRACT FROM AUTHOR]

The chemotherapy of hematological cancers is challenged by its poor selectivity that leads to low therapeutic efficacy and pronounced adverse effects. Here, we report that doxorubicin encapsulated in lipoic acid-crosslinked hyaluronic acid nanoparticles (LACHA-DOX) mediate highly efficacious and targeted inhibition of human hematological cancers including LP-1 human multiple myeloma (MM) and AML-2 human acute myeloid leukemia xenografted in nude mice. LACHA-DOX had a size of ca. 183 nm and a DOX loading content of ca. 12.0 wt.%. MTT and flow cytometry assays showed that LACHA-DOX possessed a high targetability and antitumor activity toward CD44 receptor overexpressing LP-1 human MM cells and AML-2 human acute myeloid leukemia cells. Thein vivoandex vivoimages revealed that LACHA-DOX achieved a significantly enhanced accumulation in LP-1 and AML-2 tumor xenografts. Notably, LACHA-DOX effectively suppressed LP-1 as well as AML-2 tumor growth and drastically increased mice survival rate as compared to control groups receiving free DOX or PBS. Histological analyses exhibited that LACHA-DOX caused little damage to the major organs like liver and heart. This study provides a proof-of-concept that lipoic acid-crosslinked hyaluronic acid nanoparticulate drugs may offer a more safe and effective treatment modality for CD44 positive hematological malignancies. [ABSTRACT FROM AUTHOR]

Background: The current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP). The role of radiotherapy (RT) after complete response (CR) to RCHOP in patients with DLBCL remains unclear. This systematic review with a meta-analysis is an attempt to evaluate this role. Methods: Studies that evaluated RT versus no-RT after CR to RCHOP for DLBCL patients were searched in databases. Hazard ratios (HR) with their respective 95% confidence intervals (CI) were calculated using a random-effects model. Results: A total of 4 qualified retrospective studies (633 patients) were included in this review. The results suggested that RT improved overall survival (OS; HR 0.33, 95% CI 0.14-0.77) and progression-free/event-free survival (PFS/EFS; HR 0.24, 95% CI 0.11-0.50) in all patients compared with no-RT. In a subgroup analysis of patients with stage III-IV DLBCL, RT improved PFS/EFS (HR 0.19, 95% CI 0.07-0.51) and local control (HR 0.12, 95% CI 0.03-0.44), with a trend of improving OS (HR 0.35, 95% CI 0.12-1.05). Conclusion: Consolidation RT could significantly improve outcomes of DLBCL patients who achieved a CR to RCHOP. However, the significance of these results was limited by these retrospective data. Further investigation of the role of consolidation RT in the rituximab era is needed. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Summary: Biodegradable polymeric micelles have emerged as one of the most promising platforms for targeted and controlled anticancer drug delivery due to their excellent biocompatibility, prolonged circulation time, enhanced accumulation in tumor, and in vivo degradability. Notably, several micellar anticancer drugs, with clear advantages of decreased side effects and improved drug tolerance, have advanced to different phases of clinical trials. The therapeutic outcomes are, however, far from optimal, due to issues of low in vivo stability, poor tumor penetration, inefficient cellular uptake, slow intracellular drug release, etc. This review highlights recent developments in functional biodegradable micelles for safe and efficient cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Inrecent years, polymeric nanoparticles have appeared as a mostviable and versatile delivery system for targeted cancer therapy.Various in vivo studies have demonstrated that virus-sized stealthparticles are able to circulate for a prolonged time and preferentiallyaccumulate in the tumor site via the enhanced permeability and retention(EPR) effect (so-called “passive tumor-targeting”).The surface decoration of stealth nanoparticles by a specific tumor-homingligand, such as antibody, antibody fragment, peptide, aptamer, polysaccharide,saccharide, folic acid, and so on, might further lead to increasedretention and accumulation of nanoparticles in the tumor vasculatureas well as selective and efficient internalization by target tumorcells (termed as “active tumor-targeting”). Notably,these active targeting nanoparticulate drug formulations have shownimproved, though to varying degrees, therapeutic performances in differenttumor models as compared to their passive targeting counterparts.In addition to type of ligands, several other factors such as in vivostability of nanoparticles, particle shape and size, and ligand densityalso play an important role in targeted cancer chemotherapy. In thisreview, concept and recent development of polymeric nanoparticlesconjugated with specific targeting ligands, ranging from proteins(e.g., antibodies, antibody fragments, growth factors, and transferrin),peptides (e.g., cyclic RGD, octreotide, AP peptide, and tLyp-1 peptide),aptamers (e.g., A10 and AS1411), polysaccharides (e.g., hyaluronicacid), to small biomolecules (e.g., folic acid, galactose, bisphosphonates,and biotin), for active tumor-targeting drug delivery in vitro andin vivo are highlighted and discussed. With promise to maximize therapeuticefficacy while minimizing systemic side effects, ligand-mediated activetumor-targeting treatment modality has become an emerging and indispensableplatform for safe and efficient cancer therapy. [ABSTRACT FROM AUTHOR]

Glioma is a highly challenging human malignancy as drugs typically exhibit a low blood-brain barrier (BBB) permeability as well as poor glioma selectivity and penetration. Here, we report that tandem nanomicelles co-functionalized with brain tumor-targeting and cell-penetrating peptides, Angiopep-2 and TAT, enable a highly efficacious and specific anti-glioma chemotherapy. Interestingly, tandem nanomicelles with 20 mol% Angiopep-2 and 10 mol% TAT linked via long and short poly(ethylene glycol)s, respectively, while maintaining a high glioma cell selectivity display markedly enhanced BBB permeation, glioma accumulation and penetration, and glioma cell uptake. We further show that docetaxel-loaded tandem nanomicelles have a long blood circulation time in mice and significantly better inhibit orthotopic U87MG human glioma than the corresponding Angiopep-2 single peptide-functionalized control, leading to an improved survival rate with little adverse effects. These tandem nanomicelles uniquely combining brain tumor-targeting and cell-penetrating functions provide a novel and effective strategy for targeted glioma therapy. [ABSTRACT FROM AUTHOR]

Nanotheranostics is a rapidly growing field combining disease diagnosis and therapy, which ultimately may add in the development of ‘personalized medicine’. Here, we designed and developed bioresponsive and fluorescent hyaluronic acid-iodixanol nanogels (HAI-NGs) for targeted X-ray computed tomography (CT) imaging and chemotherapy of MCF-7 human breast tumors. HAI-NGs were obtained with a small size of ca. 90 nm, bright green fluoresence and high serum stability from hyaluronic acid-cystamine-tetrazole and reductively degradable polyiodixanol-methacrylate via nanoprecipitation and a photo-click crosslinking reaction. Notably, paclitaxel (PTX)-loaded HAI-NGs showed a fast glutathione-responsive drug release. Confocal microscopy displayed efficient uptake of HAI-NGs by CD44 overexpressing MCF-7 cells via a receptor-mediated mechanism. MTT assays revealed that HAI-NGs were nontoxic to MCF-7 cells even at a high concentration of 1 mg/mL whereas PTX-loaded HAI-NGs exhibited strong inhibition of MCF-7 cells. The in vivo pharmcokinetics, near-infrared imaging and biodistribution studies revealed that HAI-NGs significantly prolonged the blood circulation time and enhanced tumor accumulation of PTX. Interestingly, significantly enhanced CT imaging was observed for MCF-7 breast tumors in nude mice via either intratumoral or intravenous injection of HAI-NGs as compared to iodixanol. HAI-NGs fluoresence was distributed thoughout the whole tumor indicating deep tumor penetration. PTX-loaded HAI-NGs showed effective suppression of tumor growth with little systemic toxicity. HAI-NGs appear as a “smart” theranostic nanoplatform for the treatment of CD44 positive tumors. [ABSTRACT FROM AUTHOR]

Nanomedicines based on biodegradable micelles offer a most promising treatment for malignant tumors. Their clinical effectiveness, however, remains to be improved. Here, we report that self-crosslinkable and intracellularly decrosslinkable micellar nanoparticles (SCID-Ms) self-assembled from novel amphiphilic biodegradable poly(ethylene glycol)- b -poly(dithiolane trimethylene carbonate) block copolymer achieve high-efficiency targeted cancer chemotherapy in vivo . Interestingly, doxorubicin (DOX)-loaded SCID-Ms showed favorable features of superb stability, minimal drug leakage, long circulation time, triggered drug release inside the tumor cells, and an unprecedented maximum-tolerated dose (MTD) of over 100 mg DOX equiv./kg in mice, which was at least 10 times higher than free drug. The in vivo studies in malignant B16 melanoma-bearing C57BL/6 mice revealed that DOX-SCID-Ms at a dosage of 30 mg DOX equiv./kg could effectively suppress tumor growth and prolong mice survival time without causing obvious systemic toxicity. Moreover, DOX-SCID-Ms could be readily decorated with a targeting ligand like cRGD peptide. The biodistribution studies showed that cRGD20/DOX-SCID-Ms had a high tumor accumulation of 6.13% ID/g at 6 h post injection, which was ca. 3-fold higher than that for clinically used pegylated liposomal doxorubicin (DOX-LPs). Accordingly, cRGD20/DOX-SCID-Ms exhibited significantly better therapeutic efficacy and lower side effects than DOX-LPs in B16 melanoma-bearing mice. These self-regulating biodegradable micellar nanoparticles offer a robust, multifunctional and viable nanoplatform for targeted cancer chemotherapy. [ABSTRACT FROM AUTHOR]

It is still a major challenge for targeted cancer chemotherapy to design stable biodegradable micellar drug delivery systems which show a rapid and complete intracellular drug release. Here, reversibly core-crosslinked pH-responsive biodegradable micelles were developed based on poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate- co -pyridyl disulfide carbonate) [PEG-P(TMBPEC- co -PDSC)] copolymers and investigated for intracellular doxorubicin (DOX) release. PEG-P(TMBPEC- co -PDSC) copolymers formed micelles with a small size of 58.6 nm were readily crosslinked by the addition of dithiothreitol (DTT). Notably, in vitro release studies showed that under physiological conditions only ca. 19.9% of DOX was released from the reversibly crosslinked micelles in 24 h at a low micelle concentration of 40 μg/mL. The release of DOX was accelerated at pH 5.0 or in the presence of 10 mM glutathione (GSH) at pH 7.4, in which 64.2% and 44.1% of DOX was released, respectively, in 24 h. The drug release was further boosted at pH 5.0 and 10 mM GSH, with 98.8% of DOX released in 12 h. Moreover, DOX release was also facilitated by a 4 h incubation at pH 5.0 followed by incubation at pH 7.4 with 10 mM GSH. Confocal microscopy indicated that DOX was delivered and released into the nuclei of RAW 264.7 cells following a 12 h incubation with DOX-loaded reversibly crosslinked micelles. MTT assays revealed that DOX-loaded reversibly crosslinked micelles had much higher antitumor activity than irreversibly crosslinked controls, with low IC 50 values of 1.65 and 1.14 μg/mL for HeLa and RAW 264.7 cells, respectively, following a 48 h incubation. The blank crosslinked micelles had a low cytotoxicity of up to a concentration of 0.8 mg/mL. These reversibly crosslinked pH-sensitive biodegradable micelles with superior extracellular stability but activated intracellular drug release provide a novel platform for tumor-targeting drug delivery. [ABSTRACT FROM AUTHOR]

The therapeutic performance of biodegradablemicellar drugs isfar from optimal due to existing challenges like poor tumor cell uptakeand intracellular drug release. Here, we report on ligand-directedreduction-sensitive shell-sheddable biodegradable micelles based onpoly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) copolymeractively delivering doxorubicin (DOX) into the nuclei of target cancercells, inducing superb in vitro antitumor effects. The micelles wereconstructed from PEG-SS-PCL and galactose-PEG-PCL (Gal-PEG-PCL) blockcopolymers, in which Gal-PEG-PCL was designed with a longer PEG thanthat in PEG-SS-PCL (6.0 vs 5.0 kDa) to fully expose Gal ligands ontothe surface of micelles for effective targeting to hepatocellularcarcinoma cells. PEG-SS-PCL combining with 10 or 20 wt % of Gal-PEG-PCLformed uniform micelles with average sizes of 56.1 and 58.2 nm (denotedas PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20, respectively). The in vitrorelease studies showed that about 81.1 and 75.0% DOX was releasedin 12 h from PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles undera reducing condition containing 10 mM dithiothreitol (DTT). In contrast,minimal DOX release (<12%) was observed for PEG-SS-PCL/Gal10 andPEG-SS-PCL/Gal20 micelles under nonreducing conditions as well asfor reduction-insensitive Gal-PEG-PCL and PEG-PCL/Gal20 micelles inthe presence of 10 mM DTT. MTT assays in HeLa and HepG2 cells showedthat DOX-loaded PEG-SS-PCL/Gal20 micelles exhibited apparent targetabilityand significantly enhanced antitumor efficacy toward asialoglycoproteinreceptor (ASGP-R)-overexpressing HepG2 cells with a particularly lowhalf maximal inhibitory concentration (IC50) of 1.58 μgDOX equiv/mL, which was comparable to free DOX and approximately sixtimes lower than that for nontargeting PEG-SS-PCL counterparts underotherwise the same conditions. Interestingly, confocal microscopyobservations using FITC-labeled PEG-SS-PCL/Gal20 micelles showed thatDOX was efficiently delivered and released into the nuclei of HepG2cells in 8 h. Flow cytometry revealed that cellular DOX level in HepG2cells treated with DOX-loaded PEG-SS-PCL/Gal20 micelles was much greaterthan that with reduction-insensitive PEG-PCL/Gal20 and nontargetingPEG-SS-PCL controls, signifying the importance of combining shell-sheddingand active targeting. Ligand-directed, reduction-sensitive, shell-sheddable,and biodegradable micelles have emerged as a versatile and potentplatform for targeted cancer chemotherapy. [ABSTRACT FROM AUTHOR]