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.

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.

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.

Delivery efficiency of periadventitial approach in comparison of intravascular delivery: an assessment of pharmacokinetics in porcine arteries

Objective To investigate the delivery efficacy of periadventitial delivery of125I-iododeoxyuridine 125I-IUdR) in comparison of intravascular delivery to determine the optimal delivery method for inhibiting post-angioplasty restenosis. Methods In 8 pigs, one side carotid, subclavian and iliac arteries of each pig were injured by balloon angioplasty with a 20% overstretches. Then, 4 mCi of 125I-IUdR was delivered at each targeted vessel with periadventitial method in 4 pigs （periadventitial group） and with intravascular method via a porous balloon catheter in other 4 pigs （intravascular group）. The animals survived for 5 hours and the blood radioactivity was investigated prior to and hourly after procedure until sacrifice. The targeted vessels and renal arteries （for control） were harvested for gamma-counting and histological observation. Meanwhile, the radioactivity in thyroid, liver, bladder, small bowel and each kidney also were measured to determine the biodistribution of125I. The activities of125I presented in arterial and tissue specimens were compared between the two delivery groups. The targeted arteries were histologically observed and the ratio of intima to media （I∶M ratio） was calculated. Results The target arterial walls in the periadventitial group had 3.4 times as much of125I radioactivity as in the intravascular group, respectively （P=0.038）; the blood activity in intravascular group was significantly higher than periadventitial group immediate after procedure （P<0.05） and intravascular delivery resulted in much higher activity in urine than periadventitial delivery （P<0.05）. The systemic biodistributions of125I-IUdR in the organs were slightly higher in the intravascular group （P>0.05）. The mean I: M ratios in both groups were 0.05 without additional injury at the vessel wall. Conclusion The periadventitial delivery offered substantial advantage over intravascular approach with high local delivery efficacy. The apparent redistribution rate is more rapid following intravascular delivery.

Disposition of nanoparticle-based delivery system via inner ear administration

The inner ear is difficult to access by conventional systemic drug delivery due to formidable physiological and anatomic barriers.There is an increasing interest in the treatment of inner ear disorders by topical application of drugs to the inner ear.One of the most important issues to overcome before full clinical application is the development of smart delivery systems for drugs to the target sites and controlled release in the inner ear.This is an area where nanoparticles will play an extremely important role.These submicron particles have exhibited improved biocompatibility,in vivo stability,target specificity,and cell/tissue uptake and internalization of the encapsulated therapeutic agents,leading to a decrease in the dose required and a decrease in side effects.This unique combination of properties makes nanoparticles a novel delivery device,which fulfils the requirements for inner ear application.This review will summarize recent findings and applications of various nanoparticle-based systems like poly(D,L-lactic/glycolic acid) nanoparticles,magnetic nanoparticles,lipid nanoparticles,liposomes,polymersomes,hydroxyapatite nanoparticles,and silica nanoparticles in the field of inner ear drug delivery.Moreover,the review will provide an insight into the future strategies of nanoparticle-based cochlear drug delivery.In conjunction,physiological considerations related to inner ear administration will be highlighted.The routes and applications for local inner-ear drug delivery will also be mentioned.In closing,this review will give an overview of the potential future development in inner ear administration with nanoparticles.

Drug delivery systems for colorectal cancer chemotherapy

Colorectal cancer causes the third most common type of malignant tumors with high morbidity and mortality.Chemotherapy is currently one of the most effective and common treatments for colorectal cancer.However,the poor water solubility of some chemotherapeutics,untargeted drug delivery,and the undesirable systemic side effects of conventional treatment remain the major issues for colorectal cancer chemotherapy.Fortunately,drug delivery systems(DDS)based on biomaterials have been widely investigated and found to be capable of resolving those issues with good performance.Therefore,the main goal of this review is to summarize and discuss the progress and potential advantages of different DDS for colorectal cancer chemotherapy.We not only reviewed the nanocarriers used to improve the solubility of chemotherapeutics,including liposomes,micelles,and nanoparticles,but also discussed targeted DDS based on specific ligand-receptor recognition and tumor microenvironmental stimulus responses.Furthermore,locally administered systems based on hydrogels and microspheres,which have been shown to increase drug accumulation at the tumor site while decreasing systemic toxicity,were also emphasized.DDS provides a good option for improving the efficacy of chemotherapy in the treatment of colorectal cancer.

经皮局部麻醉与透皮给药技术的研究进展

作为一种非侵入式给药方法,透皮给药可以克服传统注射给药引起的不适、经肝脏代谢的首过消除效应等弊端,具有方便、安全、无痛等优势。近年来,随着经皮渗透机制的深入研究以及透皮技术的更新迭代,各种经皮局部麻醉制剂与透皮给药方式层出不穷。本文主要概述经皮局部麻醉药物以及透皮给药技术的进步和新方法,展望未来的研究方向,为经皮局部麻醉领域的研究提供参考。

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

载药纳米微球在血管组织中的吸收

目的 研究载药纳米微球在血管组织中的吸收情况，为局部用药防治血管成形术后再狭窄提供理论依据。方法 用超声乳化 /溶剂挥发法制备含抗细胞增生药 2－氨基色酮的聚乳酸聚乙醇酸共聚物（ PLGA）纳米微球，建立纳米微球体内、体外动脉吸收实验模型，评价纳米微球的血管吸收性；分别用环氧化物、氰基丙烯酸异丁酯、纤维蛋白原、粘连蛋白、溴化双十二烷基二甲基铵 (DMAB)、磷脂及 Lipofectin对纳米微球进行表面修饰以增加其血管吸收率。结果 纳米微球的粒径小于 200 nm，含药量为 15％左右，电镜下观察为光滑的球形；用正电性表面活性剂 DMAB表面修饰纳米微球，可极大地提高其血管吸收率；纳米微球在血管中驻留后，可维持局部较高药物浓度达 2 d。 结论 纳米微球有可能作为心血管疾病局部药物治疗的载体。

米诺环素软膏局部治疗慢性牙周炎的临床疗效

目的评价盐酸米诺环素软膏局部应用治疗慢性牙周炎的疗效。方法选择30例慢性牙周炎患者,共80颗牙,全口洁治和根面平整后,以患者一侧患牙局部应用派丽奥盐酸米诺环素软膏为实验组,对侧同名患牙局部应用牙康(甲硝唑棒)为对照组,于基线、基线后8、16周检测临床指标:菌斑指数(plaque index,PLI)、龈沟出血指数(sulcus bleeding index,SBI)、探诊深度(probing depth,PD)。结果实验组与对照组基线时临床指标无显著性差异;基线后8周、16周,两组临床指标均显著比各自基线时有改善。基线后8周,实验组PLI、PD显著低于对照组,SBI无显著差异;基线后16周,实验组菌斑指数PLI、SBI、PD均显著低于对照组。结论派丽奥局部应用治疗慢性牙周炎短期内可以显著缓解牙周炎症状,且效果优于牙康。

盐酸米诺环素牙周条治疗牙周炎的临床研究

目的 :评价牙周局部应用盐酸米诺环素牙周条辅助治疗牙周炎的临床效果。方法 :选择成人慢性牙周炎患者 42例 ,左右侧对应牙 ,牙周袋深度≥ 4mm ,且探诊出血的牙位点 2 5 2个 ,采用随机单盲对照法 ,分为实验组和对照组 ,基础治疗后实验组牙周袋内放药 ,每周 1次 ,共 3次 ,对照组不放药。于基线、治疗后第 6周、第 12周时 ,观察菌斑指数 (PLI)、牙周袋深度 (PD)、探诊后出血 (BOP)等指标。结果 :治疗后第 6周和第 12周时 ,两组各观察指标比基线时有明显的改善 (P <0 .0 1)。两次复查时 ,实验组改善均优于对照组 ,两组相比具有显著性差异 (P <0 .0 1)。结论 :局部应用盐酸米诺环素牙周条治疗牙周炎 ,能够有效地改善临床症状 ,获得较好的临床效果。

盐酸米诺环素软膏牙周袋内药物释放特征的体内研究

目的研究重度慢性牙周炎患者牙周袋内应用2%盐酸米诺环素软膏后的局部药物释放特征。方法重度慢性牙周炎患者基础治疗后在牙周袋内置入2%盐酸米诺环素软膏0.05 ml,于置药前及置药后不同时段用滤纸法取龈沟液,用高效液相色谱法(HPLC)检测药物含量,计算置药不同时段龈沟液中的药物浓度。结果用HPLC分析标准品盐酸米诺环素的药物浓度与峰面积呈线性正相关,牙周袋中的盐酸米诺环素浓度可维持>1μg/ml达5 d。结论确定了2%盐酸米诺环素软膏局部应用后的药物释放特征,药物可在牙周袋内较长时间地保持较高的药物浓度,显示它是一种缓释制剂。

抗感染纳米羟基磷灰石局部药物缓释微球的研制及体外释药实验

目的研制抗感染纳米羟基磷灰石(nano-HA)药物缓释微球,为骨髓炎的治疗提供一新型的局部药物缓释系统(DDS)。方法采用nano-HA为载药核心载体,外包裹生物相容性好且可降解的聚羟基丁酸酯-羟基戊酸酯共聚物/聚乙二醇(PHBV/PEG),承载硫酸庆大霉素(GM)制成nano-HA-PHBV/PEG-GM缓释微球,研究其结构及体外释药特性。结果微球具有明显缓释作用,90mgDDS体外释放实验显示第1天释放量为165.2μg/mL,其后下降并以较低水平稳定释放,维持有效释药时间在28d以上。结论抗感染nano-HA药物缓释微球具有良好的体外缓释作用,有广泛的应用前景。

应用双球囊灌注导管局部注射紫杉醇对犬冠状动脉支架内再狭窄的预防作用

目的评价应用双球囊灌注导管在犬冠状动脉内局部注射紫杉醇预防支架内再狭窄的安全性和有效性。方法随机选取15只杂种犬作为实验组,5只作为对照组,选取合适的左冠状动脉作为靶血管,制造球囊损伤模型,然后应用双球囊灌注导管对损伤处局部注射药物,实验组局部注射20μmol/L紫杉醇10 ml,对照组局部注射生理盐水10 ml,灌注时间为(26.45±5.18)s,然后在靶血管段植入3.0 mm×8 mm的316L不锈钢金属裸支架。3个月后行冠状动脉造影复查、冠状动脉内光学相干断层成像(OCT)、组织学检查,测量两组靶血管支架内最窄处的新生内膜厚度、残余管腔面积、新生内膜面积、支架面积、外弹力膜面积和狭窄程度。结果冠状动脉造影复查结果示对照组再狭窄发生率显著高于实验组,差异有统计学意义(60%比33.33%,P<0.05)。冠状动脉内OCT测量结果示实验组与对照组新生内膜厚度分别为(0.19±0.08)mm和(0.38±0.03)mm,新生内膜面积为(1.52±0.49)mm2和(2.51±0.47)mm2,残余管腔面积为(3.50±0.66)mm2和(2.78±0.57)mm2,狭窄程度为(30.13±8.56)%和(47.40±4.50)%,两组间差异均有统计学意义(P均<0.05)。组织学检查结果示实验组与对照组新生内膜厚度分别为(0.22±0.10)mm和(0.47±0.05)mm,新生内膜面积为(1.85±0.78)mm2和(3.43±0.25)mm2,残余管腔面积为(3.15±0.43)mm2和(1.85±0.55)mm2,狭窄程度为(36.00±10.97)%和(65.40±8.23)%,两组间比较差异也均有统计学意义(P均<0.05)。两组支架均完全内皮化,无血栓及瘤样扩张形成。结论应用双球囊灌注导管冠状动脉内局部注射紫杉醇预防支架内再狭窄是安全有效的。

纳米粒子携带地塞米松局部腔内注射预防球囊损伤后再狭窄的实验研究

目的 探讨地塞米松纳米粒子局部腔内灌注在球囊损伤后再狭窄预防中的应用。方法 球囊损伤兔髂动脉后在损伤局部单次注射 (共 3min)纳米粒子、生理盐水或单纯损伤 ,观察纳米粒子的生物相容性。纳米粒子包被地塞米松在同样动物模型中局部单次给药 ,在术后 3h、3d、7d和 14d采用免疫分析法分别测定局部组织和血浆地塞米松浓度。球囊损伤兔髂动脉 ,分别给予局部纳米粒子 (包被地塞米松 )、静脉纳米粒子 (包被地塞米松 )治疗 ,在术后 2 1d观察损伤血管内膜的增生。结果 纳米粒子局部单次注射并未引起过度的内膜增生。局部单次注射纳米粒子 ,局部组织地塞米松药物浓度在术后 3h >5 0 0 0ng/mg干重组织 ;药物在局部组织持续达 14d之久 ;而血浆药物浓度在局部注射 3小时后后即不能测定。局部纳米粒子 (包被地塞米松 )治疗组与静脉给药组与对照组比较能明显减轻内膜增生 ,且内膜 /中膜比减少 37 9%。结论 纳米粒子具有很好的生物相容性 ;纳米粒子携带地塞米松局部单次给药能够延长局部药物作用时间达 14d ,并能有效减少新生内膜的形成。

c-myc反义寡核苷酸涂层支架局部植入给药在体分布及对细胞凋亡的影响

目的 :评价c myc反义寡核苷酸 (ASODN)经铂 -铱合金明胶蛋白涂层支架局部应用后 ,药物在组织中的分布及对血管平滑肌细胞凋亡的影响。方法 :将携带羧基荧光素 (FAM )标记c mycASODN的国产铂 铱合金明胶蛋白涂层支架 (5 5 0 μg/支架 )置入兔颈动脉 (n =6 ) ,术后 4 5min、2h、6h分别取材 ,荧光显微镜下观察药物在脏器中的分布。另取家兔 32只 ,对照组 16只置入明胶蛋白涂层支架 ;处理组 16只置入携带c mycASODN明胶蛋白涂层支架。术后 7、14、30、90d(均n =4 ) ,取置入支架血管 ,行组织病理学检查 ,观察新生内膜增殖、细胞凋亡和c myc表达。结果 :给药后镜下观察药物主要分布于靶点血管。处理组平均新生内膜厚度与新生内膜面积均较对照组小(均P <0 .0 1)。术后 30d在新生内膜中观察到明显的细胞凋亡 ,90d时单位面积内凋亡细胞数显著高于 30d ;同时 ,处理组VSMC的凋亡数显著高于对照组。对照组新生内膜中c myc蛋白免疫组化及原位杂交均为阳性 ,处理组术后 7、14d为阴性 ,30、90d为弱阳性。结论 :明胶蛋白涂层支架介导的局部给药简便、可行。c mycASODN在体导入后 ,抑制VSMC增殖 ,诱导VSMC凋亡。

微透析采样进行蛇床子软膏的皮肤局部药动学研究

目的建立蛇床子素在体皮肤微透析采样方法,研究蛇床子软膏在SD大鼠体内的局部药动学。方法采用浓差法考察浓度、流速对探针体外回收率的影响;减量法研究探针的体内回收率稳定性。SD大鼠植入皮肤探针后将蛇床子软膏涂敷于探针所在皮肤表面,测定微透析液中蛇床子素浓度,绘制药时曲线,计算药动学参数。结果随着灌流速度的增大,探针体外回收率有所下降,且回收率大小与蛇床子素的浓度无关;探针体内回收率为(44.29±1.28)%,体内12 h基本保持稳定;蛇床子软膏给药后,蛇床子素在皮肤组织内的透皮速率约为9.3402μg/min,AUC0-t为8105.4μg/(mL·min),平均滞留时间为979.8 min,能较长时间维持在较高水平。结论在体皮肤微透析法可用于蛇床子软膏局部药动学研究。

壳多糖对骨巨细胞瘤的治疗意义

目的：确定壳多糖（几丁糖）是否可作为骨巨细胞瘤治疗的药物载体。方法：用壳多糖及壳多糖联合阿霉素、顺氨氯铂及甲氨蝶呤对骨巨细胞瘤进行体外敏感实验（ＭＴＴ法）。结果：单纯壳多糖对骨巨细胞瘤在体外无抑制作用（抑制率为１．８％），壳多糖联合阿霉素、顺氨氯铂及甲氨蝶呤分别较单独应用相同浓度（血浆峰值浓度）药物的抑制率要高，但无显著差异（Ｐ＞０．０５）。结论：壳多糖可以作为阿霉素、顺氨氯铂及甲氨蝶呤的良好缓释载体。由于骨巨细胞瘤要求化疗药物浓度较高（阿霉素、顺氨氯铂及甲氨蝶呤的血浆峰值浓度的抑制率分别为１７．０６％，１５．８７％，７．０９％），不适合常规的静脉及局部给药。故壳多糖与敏感药物制成的缓释系统用于局部治疗可在降低术后复发率上起到较为积极的作用。

布替萘芬霜剂局部给药对家兔慢性毒性实验研究

目的 :观察布替萘芬霜剂长期大剂量皮肤局部使用对家兔的慢性毒性作用。方法 :将 2 4只家兔随机分成 4组 :对照组、布替萘芬高 (2 0 % )、中 (10 % )、低 (5 % )剂量组 ,连续皮肤局部使用 1个月后 ,进行全身情况、血液学、血液生化、组织学检查。结果 :除敷药的局部皮肤有些异常外 ,实验组家兔全身情况、血液学参数、血液生化指标、组织学检查与对照组相比均无明显差异。结论 :布替萘芬局部给药安全 ,临床应用可靠。