Starburst Diblock Polyprodrugs: Reduction-Responsive Unimolecular Micelles with High Drug Loading and Robust Micellar Stability for Programmed Delivery of Anticancer Drugs.

Polymeric prodrug based on therapeutic nanomedicine has demonstrated great promise for effective tumor growth inhibition, however, the drawbacks of low drug-loading and weak micellar stability limit its application for clinical cancer therapy. Herein, a reduction-responsive starburst block copolymer prodrug CCP [ß-cyclodextrin (ß-CD)-PCPTXX-POEGMA, XX: SS or CC] has been developed for cancer therapy. And CCP is composed of ß-CD-Br core with multiple reactive sites, as well as a diblock copolymer containing hydrophobic polymerized camptothecin (PCPT) prodrug chain and hydrophilic poly[(ethylene glycol) methyl ether methacrylate] (OEGMA) chain. A family of CCP polymeric prodrugs with different drug loading contents (up to 25%) and various sizes of unimolecular micelles (UMs) (around 30 nm) were obtained by adjusting the block ratio of PCPTXX and POEGMA. On account of the amphiphilic structure feature, CPP could take shape water-soluble UMs in aqueous medium with excellent micellar stability. Under imitatively reductive tumor microenvironment, anticancer drug CPT could rapidly escape from CCP UMs in terms of disulfide bond breakage. However, this behavior is strongly refrained in the physiological environment. In vitro and in vivo outcome confirmed that CCP UMs showed excellent performance of sufficient tumor accumulation, high-efficiency tumor growth inhibition and low-toxicity for healthy tissues. Based on these gratifying therapeutic efficacy, it is believed that as-present starburst prodrug strategy can offer a brand-new insight for high-efficiency therapeutic nanoplatforms for chemotherapy application.

Acid-Activatable Theranostic Unimolecular Micelles Composed of Amphiphilic Star-like Polymeric Prodrug with High Drug Loading for Enhanced Cancer Therapy.

Stimuli-responsive nanomedicine with theranostic functionalities with reduced side-effects has attracted growing attention, although there are some major obstacles to overcome before clinical applications. Herein, we present an acid-activatable theranostic unimolecular micelles based on amphiphilic star-like polymeric prodrug to systematically address typical existing issues. This smart polymeric prodrug has a preferable size of about 35 nm and strong micellar stability in aqueous solution, which is beneficial to long-term blood circulation and efficient extravasation from tumoral vessels. Remarkably, the polymeric prodrug has a high drug loading rate up to 53.1 wt%, which induces considerably higher cytotoxicity against tumor cells (HeLa cells and MCF-7 cells) than normal cells (HUVEC cells) suggesting a spontaneous tumor-specific targeting capability. Moreover, the polymeric prodrug can serve as a fluorescent nanoprobe activated by the acidic microenvironment in tumor cells, which can be used as a promising platform for tumor diagnosis. The superior antitumor effect in this in vitro study demonstrates the potential of this prodrug as a promising platform for drug delivery and cancer therapy.

Primary silicone oil tamponade and internal limiting membrane peeling for retinal detachment due to macular hole in highly myopic eyes with chorioretinal atrophy.

BACKGROUND: Retinal detachment (RD) secondary to macular hole (MH) is a common complication in highly myopic eyes, usually leading to a poor visual prognosis. The purpose of this study was to evaluate the surgical outcome of silicone oil (SO) tamponade and internal limiting membrane (ILM) peeling in the treatment of RD caused by MH (MHRD) in highly myopic eyes with chorioretinal atrophy, and to identify clinical factors associated with the anatomical outcomes. METHODS: We retrospectively reviewed 21 eyes of 21 highly myopic patients affected by RD secondary to MH and chorioretinal atrophy. All eyes were treated with pars plana vitrectomy (PPV) with ILM peeling and SO tamponade. Anatomical success was defined as reattachment of the retina with the closure of the MH, as assessed by optical coherence tomography (OCT), after SO removal. Logistic regression was performed to determine the clinical factors influencing anatomical success. RESULTS: The mean patient age was 59.95 years [standard deviation (SD), 10.39; range, 34-77 years] and the mean axial length was 30.58 mm (SD, 1.52; range, 27.99-34.51 mm). After the first surgical procedure, the anatomical success rate was 61.9% (13 eyes in 21 eyes), with initial retinal attachment of 16 eyes (76.2%). A second surgical approach was performed for the five eyes with persistent or recurrent RD, and the final retinal reattachment rate was 100% (21/21). Logistic regression analysis showed that no specific factors were significantly associated with anatomical success. CONCLUSIONS: Primary silicone oil tamponade and ILM peeling can be a practical treatment for repairing MHRD in highly myopic eyes with chorioretinal atrophy.

Transverse cervical vessels as recipient vessels in oral and maxillofacial microsurgical reconstruction after former operations with or without radiotherapy.

BACKGROUND: The purpose of this study was to investigate the reliability and outcome of using the transverse cervical vessel (TCV) as a recipient vessel for microvascular reconstruction in patients whose vessels in the neck region are unavailable because of previous surgery or radiotherapy. METHODS: Between January 2012 and August 2014, secondary head and neck reconstruction was performed using the TCV as a recipient vessel in eight patients who had undergone previous neck dissection and radiation therapy (n = 5). Five patients had a recurrent carcinoma, one had undergone an operation for scar release and two had been treated surgically for a second primary cancer. The anterolateral thigh flap (ALT), anteromedial thigh flap (AMT), and fibular flap were used for the reconstruction. Clinical data were recorded for each patient. RESULTS: All of the ipsilateral transverse cervical arteries were found to be free of disease. The second free flap was revascularized using the TCVs (n = 6) or the external (n = 1) or internal (n = 1) jugular vein. The free flaps used for the reconstruction included the ALT flap (n = 6), AMT flap (n = 2), and fibular flap (n = 1). All of the flaps survived without vascular events, and the patients healed without major complications. The mean follow-up time was 11 months. One patient died of distant metastases during follow-up. CONCLUSIONS: In patients who have previously undergone neck surgery with or without radiotherapy, the TCVs are reliable and easily accessible recipient vessels for microsurgical reconstruction in the oral and maxillofacial region. If the transverse cervical vein is unavailable, the internal or external jugular vein should be dissected carefully to serve as an alternative for microvascular anastomoses.

Tuberculous osteomyelitis of the mandible with diffuse swelling of the floor of the mouth: a case report.

Primary orofacial tuberculosis (TB) is uncommon, especially with regard to the jaw. We report an unusual case for which the final diagnosis was tuberculous osteomyelitis of the mandible with cervical tuberculous lymphadenitis. The follow-up examinations for our patient showed complete regression of the swelling and healing of the mandibular lesion after 4 months of TB antibiotic therapy. The purpose of the present study was to alert clinicians to our findings and encourage them to consider oral TB in the differential diagnosis for jaw lesions with multiple enlarged cervical lymph nodes.

Three-dimensional attachment morphometry and volumetric changes of masticatory muscles after free fibular flap reconstruction of the mandibular condyle.

This retrospective case-series study aimed to elucidate the three-dimensional attachment morphometric features and to quantify the volumetric changes of the masticatory muscles following free fibular flap reconstruction of the mandibular condyle. Navigation software (iPlan, version 3.0; Brainlab) was used to perform delineation and volumetric measurement of the masticatory muscles using DICOM data. In total, 30 patients were included in this retrospective case series. In 25 cases (83.33%), the lateral pterygoid muscle achieved reattachment within 6 months postoperatively. The medial pterygoid muscles on the affected side achieved ectopic attachment in all cases. However, masseter reattachment on the affected side was achieved in only three cases. On the normal side, the volumes of lateral pterygoid muscle, medial pterygoid muscle, and masseter had recovered to almost preoperative levels at 1 year postoperatively. On the affected side, the volume of medial pterygoid muscle had decreased significantly (p = 2.4e-04) at 3 months postoperatively. The volumes of lateral pterygoid muscle and masseter showed mild decreases at 3 months postoperatively, but these were not significant (p = 0.52 and p = 0.05 for the pterygoid muscle and masseter, respectively). At 6 months after surgery, with the exception of the volume of the lateral pterygoid muscle (p = 0.06), the total volume of the masticatory muscles decreased significantly on the affected side. The volumes of lateral pterygoid muscle, medial pterygoid muscle, and masseter showed significant decreases at 1 year postoperatively (p = 0.03, p = 4.7e-08, and p = 1.1e-05, respectively) on the affected side. The postoperative volumes of the masseter, medial pterygoid, and lateral pterygoid muscles showed significant decreases due to the loss of reattachment. The results of this study may not help to ascertain whether reattachment of masticatory muscles will lead to better function. As a consequence, clinical trials of higher quality are needed.

Codelivery of doxorubicin and camptothecin by dual-responsive unimolecular micelle-based ß-cyclodextrin for enhanced chemotherapy.

Tumor microenvironment (TME)-induced drug delivery technology is a promising strategy for improving low drug accumulation efficiency, short blood circulation and weak therapeutic effect. In this work, a dual-responsive (reduction- and pH-responsive) polyprodrug nanoreactor based on ß-cyclodextrin (ß-CD) was constructed for combinational chemotherapy. Specifically, the dual-responsive star polymeric prodrug was synthesized by atom transfer radical polymerization (ATRP) based on a starburst initiator of ß-CD-Br. The obtained polyprodrug contained a hydrophilic chain of poly-(ethylene glycol) methyl ether methacrylate (POEGMA) and a hydrophobic part of camptothecin (CPT) prodrug and poly[2-(diisopropylamino)ethyl methacrylate] (PDPA), denoted as ß-CD-PDPA-POEGMA-PCPT (CCDO for short). The obtained CCDO could form stable unimolecular micelles, which could be efficiently internalized by cancer cells. To enhance the curative effect, the anticancer agent doxorubicin (DOX) could be encapsulated into the hydrophobic cavity of the CCDO by hydrophobic-hydrophobic interaction. In vitro drug release studies showed that the obtained CCDO/DOX micelles controlled the release of active CPT and DOX occurring in a reductive environment and at low pH. In vitro cytotoxicity results suggested that the anticancer efficacy of dual-responsive CCDO/DOX micelles was superior to that of CCDO micelles. In addition, in vivo results verified good blood compatibility of the unimolecular micelles. This integrated dual-responsive drug delivery system may solve the low drug loading and poor controlled release problems found in traditional polymer-based drug carriers, providing an innovative and promising route for cancer therapy.

Reduction stimuli-responsive unimolecular polymeric prodrug based on amphiphilic dextran-framework for antitumor drug delivery.

We report a new reduction-responsive amphiphilic polymeric prodrug based on a linear dextran (DEX) backbone, which was conjugated with an hydrophobic camptothecin (CPT) prodrug block and an hydrophilic poly[poly(ethylene glycol) methyl ether methacrylate] (POEGMA) block [DEX-PCPT-b-POEGMA (DCO)] by atom transfer radical polymerization (ATRP). This amphiphilic prodrug has a unique molecular structure with prominent features, including strong practicability for methacrylate prodrug monomer, high drug loading rate (up to 23wt%), adjustable proportion of hydrophobic and hydrophobic portions, superior stability in aqueous solution, and easy access to cells. Introduction of a disulfide bond linker between the drug and the carrier can realize the function of reduction-responsive controlled drug-release. The experimental study indicated that the prodrug exhibited notable antitumor activity against HeLa cells and MCF-7 cells in vitro. Compared to similar DCO prodrug based on double carbon bond, the disulfide bond-conjugated DCO prodrug induced higher level of tumor cell apoptosis. Considering the drug-loading efficiency, micellar stability, cost of preparation and controlled drug release, the presented prodrug is more advantageous than traditional unimolecular prodrug and represents a promising approach for design of stimuli-responsive polymeric prodrug for effective cancer therapeutics.

Irinotecan delivery by unimolecular micelles composed of reduction-responsive star-like polymeric prodrug with high drug loading for enhanced cancer therapy.

Nanomedicine based polymeric prodrug have showed high impact in the inhibition of tumor growth due to its high therapeutic efficiency and improved biocompatibility. Herein, we synthesized a novel star-like amphiphilic copolymer [ß-CD-P(Ir-co-OEGMA), denoted as CPIO] through atom transfer radical polymerization (ATRP) to deliver the hydrophilic anticancer drug irinotecan (Ir). The polymer could form monodisperse unimolecular micelles and had excellent stability in aqueous solution. Moreover, the reduction-responsive feature of the micelles facilitated controlled release of drug, thus achieving targeted therapy and reduced toxicity to healthy cells. The in vitro cytotoxicity assays indicated that CPIO had a notable anticancer effect against HeLa and MCF-7 tumor cells. The confocal laser scanning microscopy and flow cytometry experiments revealed that CPIO micelles could be internalized into tumor cells efficiently. Furthermore, the obtained prodrug micelles produced better efficacy compared to free Ir. Moreover, the CPIO micelles showed excellent biocompatibility in vivo after intravenous injection on a mouse model. This study demonstrated that CPIO carrier could provide a rational design of a stimuli-responsive polymeric prodrug for delivery of irinotecan.

Water-soluble fluorescent unimolecular micelles: ultra-small size, tunable fluorescence emission from the visible to NIR region and enhanced biocompatibility for in vitro and in vivo bioimaging.

Fluorescent unimolecular micelles (FUMs) with multicolor emission acting as fluorescent nanoagents for optical fluorescence imaging have, for the first time, been reported. The FUMs show good water-solubility, ultra-small size, and enhanced biocompatibility, which endow the FUMs with versatile applications including organelle labeling, multicolor markers and high tumor accumulation, revealing that our design can serve as a rational strategy for the development of UM-based fluorescent nanoagents for bioprocess monitoring.

Reduction-active polymeric prodrug micelles based on α-cyclodextrin polyrotaxanes for triggered drug release and enhanced cancer therapy.

As one of the medical polymers approved by US Food and Drug Administration (FDA), poly(ethylene glycol) has low toxicity, high stability, good biocompatibility, unique physical and chemical properties. Cyclodextrin is an ideal candidate as a drug carrier due to its special structures and characteristics. These two materials were successfully assembled through chemosynthesis in combination with the hydrophilic poly(ethylene glycol) methyl ether methacrylate (OEGMA) chain and hydrophobic polymeric camptothecin (CPT) chain by atom transfer radical polymerization (ATRP). The introduction of disulfide bond of monomer was aimed to realize reduction agent-triggered release of active CPT. The obtained amphipathic prodrug [(Denoted as PC-PCPT-b-POEGMA (PCCO)] could form nano-sized polymeric micelles, which could release more than 85% of the loaded CPT via triggered cleavage of the disulfide linker. The cellular co-localization study revealed the potential pathway of drug internalization. Moreover, the PCCO micelles showed good biocompatibility in vivo after intravenous injection on a mouse model. This new CPT-loaded prodrug system could be prepared with low cost, and showed efficient and controlled drug release and favorable biocompatibility, demonstrating a promising potential as a stimuli-responsive polymeric prodrug for future clinical applications.

A critical assessment of the fibula flap donor site.

BACKGROUND: The free fibula flap has become popular for mandibular reconstruction. The purpose of this study was to propose comprehensive functional assessments of the donor site. METHODS: Thirty free fibula flaps for mandible reconstruction were prospectively enrolled in the study. Objective assessments included isokinetic testing of the ankle joint, electromyographic examination of the superficial peroneal nerve (SPN), and preoperative and postoperative foot scans. The Patient and Observer Scar Assessment Scale (POSAS) was used to subjectively assess the donor site. RESULTS: The isokinetic values of the donor side showed a significant decrease 1 year postoperatively. The results of the electromyographic test of the SPN were categorized as 3 types. The plantar center pressure shifted to the heel on the donor side 6 months postoperatively. The aesthetic outcome was satisfactory. CONCLUSION: The functional parameters of the donor site indeed declined in our assessments. Further refinements in the surgical technique are needed to improve the donor site status. © 2016 Wiley Periodicals, Inc. Head Neck 39: 279-287, 2017.

Total and near-total lower lip reconstruction: 20 years experience.

BACKGROUND: Reconstruction of total and near-total lower lip defects presents a formidable challenge for the reconstructive plastic surgeon. Many methods have been described, and each has its own advantages and disadvantages. The aim of this article is to discuss the selection of techniques and report our experience of total or near-total lower lip reconstruction. MATERIAL AND METHODS: Over a 20-year period from January 1993 to December 2013, a total of 87 patients underwent total or near-total lower lip reconstruction. Bilateral Yu's flaps were used in 61 patients, double mental neurovascular V-Y island advancement flaps in 16 patients, bilateral Mutaf's techniques in 4 patients, and reconstruction with free radial forearm flaps in 6 other patients. Drooling Rating Scale (DRS) and Patient and Observer Scar Assessment Scale (POSAS) were used to evaluate oral competency and esthetic outcomes. RESULTS: All patients underwent single-stage total or near-total lower lip reconstruction successfully. There were no flap failures. Only 1 patient who accepted the bilateral Yu's flaps developed microstomia, having difficulty in wearing her dentures postoperatively. Oral competencies were well preserved in other patients, and esthetic results were satisfactory. CONCLUSION: Based on our experience, we recommend using the bilateral local techniques or free flap introduced in this article, according to the extent of defects and the patient's general condition, to achieve a personalized ideal reconstruction of the lower lip.