Local Delivery of C-myc Antisense Oligodeoxynucleotide by Gelatin Coated Platinium-Iridium Stent to Prevent Restenosis in a Normal Rabbit Carotid Artery

Objectives To investigate the feasibility and effect of local deliveryof c-myc antisense oligodeoxynucleotide (ASODN) by gelatin coated Platinium-Iridium stent to prevent restenosis in a normal rabbit carotid artery. Methods Gelatin coated Platinium-Iridium stent were implanted in the right carotid arteries of 32 rabbits under vision. Animals were randomized to the control group and the treated group receiving c-myc ASODN (n=16 respectively).7, 14, 30,90 days following the stenting procedure, morphometry for caculation of neointimal area and mean neointimal thickness were performed.The expression of c-myc protein was detected by immunohistochemical methods. Results 32 stents were successfully implanted into the right carotid arteries in 32 animals.Morphometric analysis showed that neointimal area and mean neointimal thickness siginificantly increased continuously up to 12 weeks after stent implantation,and at each time point , neointimal area and mean neointimal thickness were siginificantly smaller in the treated group than control group. (P<0.001,respectively).c-myc protein expression was weak positive or negative in treated group and positive in control group. Conclusions Gelatin coated Platinium-Iridium stent mediated local delivery of c- myc ASODN is feasibility , and it can inhibit neointimal hyperplasia to prevent restenosis in a normal rabbit carotid artery.

Distribution of C - myc Antisense Oligonucleotides in Rabbits after Local Delivery by Implanted Gelatin Coated Platinium - Iridium Stent

Objectives To assess thefeasibility, efficiency and tissue distribution of local delivered c - myc antisense oligonucleotides (ASODN) by implanted gelatin coated Platinium - Iridium (Pt -Ir) stent. Methods Gelatin coated Pt - Ir stent which absorbed carboxyfluorescein - 5 - succimidyl ester (FAM) labeled c - myc ASODN were implanted in the right carotid arteries of 6 rabbits under vision. Blood samples were collected at the indicated times. The target artery, left carotid artery, heart , liver and kidney obtained at 45 minutes , 2 hours and 6 hours. The concentration of c - myc ASODN in plasma and tissues were determined by Thin Layer Fluorome-try. Tissue distribution of c - myc ASODN were assessed by fluorescence microscopy. Results At 45 min, 2 h, 6 h, the concentration of FAM labeled c -myc ASODN in target artery was 244. 39, 194. 44, 126. 94(μg/g tissues) respectively, and the delivery efficiency were 44. 4% , 35. 4% and 23. 1% respectively. At the same indicated time point, the plasma concentration was 8. 41, 5. 83, 14. 75 (μg/ml) respectively. Therefore c - myc ASODN concentrations in the target vessel were 29, 33 and 9 -fold higher than that in the plasma. There was circumferential distribution of labeled c - myc in the area of highest fluorescein coinciding with the site of medial dissecting from stent-ing, and the label was most intense in target vessel media harvested at 45 min time point and then dispersed to adventitia. Conclusions Gelatin coated Pt - Ir stent mediated local delivery of c - myc ASODN is feasible and efficient. The localization of ASODN is mainly in target vessel wall.

In vitro Anticancer Efficacy by Magnetic Targeted Nanocarrier with Local Delivery of Paclitaxel

A magnetic nanoparticles-loaded polymeric nanocarrier was developed. Amphiphilic copolymer, methoxy polyethylene glycol-poly（D,L-lactide-co-glycolide）（MPEG-PLGA） could self-assemble to form nanomicelle with the help of emulsion-solvent evaporation technique. This nanocarrier with core-shell structure was loaded with magnetic iron oxide nanoparticles（IONPs） and anticancer drug paclitaxel（PTX）. The hydrodynamic diameter of IONPs-PTX-loaded nanocarrier showed an average size of 110 nm with a polydispersity index（PDI） of 0.136, and its zeta potential was （-4.76±0.36） mV. The drug-loading content and encapsulation efficiency were 4.47% and 31.28%, respectively. In vitro drug release experiment was performed and a sustained release profile was observed. 3-（4,5-Dimethyl-2-thiazolyl）-2,5-diphenyl-2-H-tetrazolium bromide（MTT） assay indicated that IONPs-PTX-loaded nanocarrier showed comparable cytotoxicity with free paclitaxel. When an external magnetic field was applied, the nanocarrier significantly localized at the target area, demonstrating that the nanocarrier could be used for potential magnetic targeted drug delivery.

Local dose-dense chemotherapy for triple-negative breast cancer via minimally invasive implantation of 3D printed devices

Dose-dense chemotherapy is the preferred first-line therapy for triple-negative breast cancer(TNBC),a highly aggressive disease with a poor prognosis.This treatment uses the same drug doses as conventional chemotherapy but with shorter dosing intervals,allowing for promising clinical outcomes with intensive treatment.However,the frequent systemic administration used for this treatment results in systemic toxicity and low patient compliance,limiting therapeutic efficacy and clinical benefit.Here,we report local dose-dense chemotherapy to treat TNBC by implanting 3D printed devices with timeprogrammed pulsatile release profiles.The implantable device can control the time between drug releases based on its internal microstructure design,which can be used to control dose density.The device is made of biodegradable materials for clinical convenience and designed for minimally invasive implantation via a trocar.Dose density variation of local chemotherapy using programmable release enhances anti-cancer effects in vitro and in vivo.Under the same dose density conditions,device-based chemotherapy shows a higher anticancer effect and less toxic response than intratumoral injection.We demonstrate local chemotherapy utilizing the implantable device that simulates the drug dose,number of releases,and treatment duration of the dose-dense AC(doxorubicin and cyclophosphamide)regimen preferred for TNBC treatment.Dose density modulation inhibits tumor growth,metastasis,and the expression of drug resistance-related proteins,including p-glycoprotein and breast cancer resistance protein.To the best of our knowledge,local dose-dense chemotherapy has not been reported,and our strategy can be expected to be utilized as a novel alternative to conventional therapies and improve anti-cancer efficiency.

A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong disability.Currently,there are no FDA-approved therapies available to promote nerve regeneration.Tacrolimus accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve surgery.The authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug exposure.Tacrolimus is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days.Size and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible byproducts.Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic delivery.Given its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

PREVENTING RESTENOSIS FOLLOWING PTCA

Whether InfusaSleeve(IS) catheter can deliver antisense oligodeoxynucleotide (ODNs) following arterial denuation is unknown. We evaluate the feasibility of local endoluminal delivery of Cmyc ODNs to the site of arterial denudation by using IS catheter and to determine the biological importance of these effects. IS catheter was introduced into right side of iliac artery of 21 rabbits after angioplasty of iliac artery. Animals were randomized to the control group (n=6) receiving saline injection and the treated group receiving cmyc antisense (n=15, 1 mg ODNs per vessel). In two weeks and 40 days following the operation, angiography was performed. Morphometric analyses were carried out in balloondenuded iliac arteries. The expression of cmyc protein was detected by using a mouse monoclonal antibody to cmyc. Morphometric analyses carried out at 40 days after transcatheter cmyc antisense oligomer administration. The results showed that maximal neointimal area was reduced from 76637(105 m2) in the control group (n=6) to 404102(105 m2) in the antisense treated group (n=6, P<005). These changes in vascular remodeling following denuding injury resulted in an increase in residual luman from 2050% in the control group to 7090% in the antisensetreated group. Cmyc protein expression was virtually undetectable at baseline in locally ODNsdelivered arteries and detectable in control denuded arteries. The results show that: Single IS transcatheter administration allowed endoluminal delivery of ODNs to the site of arterial injury; cmyc antisense oligomer reduced the formation of neointime in denuded arteries, implying a therapeutic potential of this approach.

Biomaterial scaffold-based local drug delivery systems for cancer immunotherapy

Immunotherapy has attracted tremendous attention due to the remarkable clinical successes for treating a broad spectrum of tumors. One challenge for cancer immunotherapy is the inability to control localization and sustain concentrations of therapeutics at tumor sites. Local drug delivery systems(LDDSs) like the biomaterial scaffold-based drug delivery systems have emerged as a promising approach for delivering immunotherapeutic agents facilely and intensively in situ with reduced systemic toxicity. In this review, recent advances in biomaterial scaffold-based LDDSs for the administration of immunotherapeutic agents including vaccines, immunomodulators, and immune cells are summarized. Moreover, codelivery systems are also evaluated for local immunotherapy-involving combination anti-tumor therapy,including chemotherapy-immunotherapy, photothermal-immunotherapy, and other combination therapies. Finally, the current challenges and future perspectives on the development of next-generation LDDSs for cancer immunotherapy are discussed.

Hydrogel-based contact lens achieve prolonged,local drug delivery to the eye

With the support by the National Natural Science Foundation of China,the research group led by Prof.Jiang Gangbiao(蒋刚彪)at the Department of Pharmaceutical Engineering,College of Materials and Energy,South China Agricultural University,in collaboration with the research group led by Prof.Yuan

Camptothecin@HMSNs/thermosensitive hydrogel composite for applications in preventing local breast cancer recurrence

Camptothecin has a strong tumor killing ability for a variety of tumor cells with its special anti-cancer mechanism including the breast cancer. However, because of its infinite hydrophobic property, its clinical application has been greatly limited. Early prevention of loco regional recurrence for the breast cancer is critical for patients who have undergone breast-conserving therapy. In the study,CPT was used for the inhibition of the recurrence after the operation. The hollow mesoporous silica nanoparticles were used as the carrier to improve the hydrophilic property and increase its bioavailability with the high loading capacity. The ability of the cellular uptake and antitumor activity was increased. Hydrogel was the ideal carrier for local therapy, so the CPT@HMSNs were loaded into the PLEL thermo sensitive hydrogel to be injected into the tumor sites after the tumor was resected. The recurrence was reduced in the group of CPT-HMSNs-PLEL and the side effect of CPT was decreased. They exhibit distinguished potential as drug carrier for local delivery.

Sustained co-delivery of 5-fluorouracil and cis-platinum via biodegradable thermo-sensitive hydrogel for intraoperative synergistic combination chemotherapy of gastric cancer

Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide,posing a severe threat to human health.Surgical resection remains the most preferred option for gastric cancer treatment.However,for advanced gastric cancer,the curative effect of surgical resection is usually limited by the local recurrence,peritoneal carcinomatosis,or distal metastasis.Intraoperative chemotherapy is an attractive in situ adjuvant treatment strategy to reduce the recurrence and metastasis after surgical resection.Here,we designed a 5-fluorouracil(5-FU)and cis-platinum(DDP)co-delivery system based on a biodegradable temperature-sensitive hydrogel(PDLLA-PEG-PDLLA,PLEL)for intraoperative adjuvant combination chemotherapy of gastric cancer.This 5-FU+DDP/PLEL hydrogel system characterized by a special sol-gel phase transition in response to physiological temperature and presented sustained drug release in vitro and in vivo.A strong synergistic cell proliferation inhibition and apoptosis promotion of 5-FU+DDP/PLEL were observed against gastric cancer MKN45-luc cells.After intraperitoneal injection,the dual-drug loaded hydrogel formulation showed superior anti-tumor effects than the single-drug carrying hydrogels and combination of free 5-FU and DDP on the gastric cancer peritoneal carcinomatosis model.The use of hydrogel for dual-drug delivery had benefited to fewer side effects as well.What’s more,we established a mouse model for postsurgical residual tumors and peritoneal carcinomatosis of gastric cancer,in which the intraoperative administration of 5-FU+DDP/PLEL also remarkably inhibited the local recurrence of the orthotopic tumors and the growth of the abdominal metastatic tumors,resulting in an extended lifetime.Hence,this developed dual-drug loaded hydrogel system has great potential in the intraoperative chemotherapy of gastric cancer,that suggests a clinically-relevant and valuable option for postsurgical management of gastric cancer.

Intravesical chemotherapy synergize with an immune adjuvant by a thermo-sensitive hydrogel system for bladder cancer

Surgical resection remains the prefer option for bladder cancer treatment.However,the effectiveness of surgery is usually limited for the high recurrence rate and poor prognosis.Consequently,intravesical chemotherapy synergize with immunotherapy in situ is an attractive way to improve therapeutic effect.Herein,a combined strategy based on thermo-sensitive PLEL hydrogel drug delivery system was developed.GEM loaded PLEL hydrogel was intravesical instilled to kill tumor cells directly,then PLEL hydrogel incorporated with CpG was injected into both groins subcutaneously to promote immune responses synergize with GEM.The results demonstrated that drug loaded PLEL hydrogel had a sol-gel phase transition behavior in response to physiological temperature and presented sustained drug release,and the PLEL-assisted combination therapy could have better tumor suppression effect and stronger immunostimulating effect in vivo.Hence,this combined treatment with PLEL hydrogel system has great potential and suggests a clinically-relevant and valuable option for bladder cancer.

Injectable thermo-sensitive hydrogel enhances anti-tumor potency of engineered Lactococcus lactis by activating dendritic cells and effective memory T cells

Engineered bacteria have shown great potential in cancer immunotherapy by dynamically releasing therapeutic payloads and inducing sustained antitumor immune response with the crosstalk of immune cells.In previous studies,FOLactis was designed,which could secret an encoded fusion protein of Fms-related tyrosine kinase 3 ligand and co-stimulator OX40 ligand,leading to remarkable tumor suppression and exerting an abscopal effect by intratumoral injection.However,it is difficult for intratumoral administration of FOLactis in solid tumors with firm texture or high internal pressure.For patients without lesions such as abdominal metastatic tumors and orthotopic gastric tumors,intratumoral injection is not feasible and peritumoral maybe a better choice.Herein,an engineered bacteria delivery system is constructed based on in situ temperature-sensitive poloxamer 407 hydrogels.Peritumoral injection of FOLactis/P407 results in a 5-fold increase in the proportion of activated DC cells and a more than 2-fold increase in the proportion of effective memory T cells(TEM),playing the role of artificial lymph island.Besides,administration of FOLactis/P407 significantly inhibits the growth of abdominal metastatic tumors and orthotopic gastric tumors,resulting in an extended survival time.Therefore,these findings demonstrate the delivery approach of engineered bacteria based on in situ hydrogel will promote the efficacy and universality of therapeutics.

Dual-functional porous and cisplatin-loaded polymethylmethacrylate cement for reconstruction of load-bearing bone defect kills bone tumor cells

Malignant bone tumors are usually treated by resection of tumor tissue followed by filling of the bone defect with bone graft substitutes.Polymethylmethacrylate(PMMA)cement is the most commonly used bone substitute in clinical orthopedics in view of its reliability.However,the dense nature of PMMA renders this biomaterial unsuitable for local delivery of chemotherapeutic drugs to limit the recurrence of bone tumors.Here,we introduce porosity into PMMA cement by adding carboxymethylcellulose(CMC)to facilitate such local delivery of chemotherapeutic drugs,while retaining sufficient mechanical properties for bone reconstruction in load-bearing sites.Our results show that the mechanical strength of PMMA-based cements gradually decreases with increasing CMC content.Upon incorporation of≥3%CMC,the PMMA-based cements released up to 18%of the loaded cisplatin,in contrast to cements containing lower amounts of CMC which only released less than 2%of the cisplatin over 28 days.This release of cisplatin efficiently killed osteosarcoma cells in vitro and the fraction of dead cells increased to 91.3%at day 7,which confirms the retained chemotherapeutic activity of released cisplatin from these PMMA-based cements.Additionally,tibias filled with PMMA-based cements containing up to 3%of CMC exhibit comparable compressive strengths as compared to intact tibias.In conclusion,we demonstrate that PMMA cements can be rendered therapeutically active by introducing porosity using CMC to allow for release of cisplatin without compromising mechanical properties beyond critical levels.As such,these data suggest that our dual-functional PMMA-based cements represent a viable treatment option for filling bone defects after bone tumor resection in load-bearing sites.