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. ...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.展开更多
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 coa...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.展开更多
BACKGROUND Periodontal disease is a chronic inflammatory condition characterized by periodontal pocket formation,clinical attachment loss,and destruction of alveolar bone.Its conventional treatment primarily involves ...BACKGROUND Periodontal disease is a chronic inflammatory condition characterized by periodontal pocket formation,clinical attachment loss,and destruction of alveolar bone.Its conventional treatment primarily involves mechanical debridement and plaque control,but localized antimicrobial therapy offers site-specific advantages.While antibiotics such as metronidazole and doxycycline are commonly used,green tea extract,which is rich in epigallocatechin gallate,has been proposed as a promising alternative for local drug delivery due to its anti-inflammatory and antimicrobial properties.AIM To compare the clinical efficacy of green tea extract gel and ornidazole gel as adjuncts to scaling and root planing(SRP)in patients with periodontitis.METHODS Teeth with probing pocket depths(PPD)of 4-7 mm were selected.Participants’baseline oral hygiene index-simplified,plaque index,clinical attachment loss,and PPD were recorded.The participants were randomized into two groups:One received green tea extract gel after SRP,and the other received ornidazole gel.Subgingival drug delivery was performed,and participants refrained from brushing or interproximal cleaning for ten days.Their clinical parameters were re-evaluated after one month.RESULTS The PPD decreased significantly from baseline to one month in both groups.However,the green tea extract gel group exhibited superior outcomes to the ornidazole gel group,with a mean difference in PPD of 0.28±0.78 mm at one month(P<0.007).CONCLUSION As an adjunct to SRP,green tea extract gel showed greater efficacy in improving clinical periodontal parameters than ornidazole gel.展开更多
Periodontitis is initiated by dysbiosis of the oral microbiome.Pathogenic bacteria elicit ineffective immune responses,which damage surrounding tissues and lead to chronic inflammation.Although current treatments typi...Periodontitis is initiated by dysbiosis of the oral microbiome.Pathogenic bacteria elicit ineffective immune responses,which damage surrounding tissues and lead to chronic inflammation.Although current treatments typically aim for microbial eradication,they fail to address the significance of immune cell reactions in disease progression.Here,we searched for small molecules as drug candidates and identified a bifunctional antibiotic,azithromycin(AZM),that not only inhibits bacterial growth but also modulates immune cells to suppress inflammation.We further engineered a dissolvable microneedle patch loaded with biodegradable microparticles for local and painless delivery of AZM to the gingival tissues.Inflammatory cytokines were decreased while anti-inflammatory cytokines and M2 macrophage were increased with AZM treatments in vitro.In vivo delivery of the AZM-loaded microneedle patch demonstrated the same effects on cytokine secretion and the promotion of tissue healing and bone regeneration.In addition,microparticles containing anti-inflammatory interleukin-4 alone or in combination with separately-formulated AZM microparticles,had similar or slightly enhanced therapeutic out-comes respectively.The bimodal action of AZM obviates the necessity for separate antibacterial and immunomodulatory agents,providing a practical and streamlined approach for clinical treatment.Our findings also demonstrate the therapeutic efficacy of microparticles delivery into the soft tissues by a minimally invasive and fast-degrading microneedle patch and offer a novel therapeutic approach for the treatment of periodontitis and other diseases through immunomodulation.展开更多
Nanopipette based scanning probe technique is a versatile tool in non-contact imaging in biology.In addition to the topographic imaging,its capability of localized delivery of bio-active molecules is emerging.In this ...Nanopipette based scanning probe technique is a versatile tool in non-contact imaging in biology.In addition to the topographic imaging,its capability of localized delivery of bio-active molecules is emerging.In this mini review,we introduce the applications of nanopipette in single-cell researches with a focus on localized delivery.The working principles of three delivery modes including resistive pulse,pressure-driven flow,and electroosmotic flow-driven delivery are summarized and compared.Their applications in single-cell researches are reviewed.The current technical challenges in scanning ion conductance microscopy-based delivery,and their growing influence in medicine and pharmacologic researches are also discussed.展开更多
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 chemotherap...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.展开更多
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 appl...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.展开更多
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 a...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.展开更多
In recent years,adeno-associated viruses(AAVs)have emerged as leading vectors in gene therapy,with several FDA-approved treatments and ongoing clinical trials demonstrating their effectiveness in treating inherited re...In recent years,adeno-associated viruses(AAVs)have emerged as leading vectors in gene therapy,with several FDA-approved treatments and ongoing clinical trials demonstrating their effectiveness in treating inherited retinal diseases,hemophilia,and Duchenne muscular dystrophy,among others.However,AAV-based therapies still face challenges,including immune responses and side effects,due to high viral doses.To address these challenges,various strategies have been developed,such as creating new viral capsids,optimizing gene expression regulation,and improving delivery methods.Localized delivery is a promising direction,utilizing the tissue tropism of AAVs to reduce systemic side effects and lower the required viral dose,thus improving targeting and efficiency,especially for organs that are difficult to treat with conventional methods.These innovations have opened new pathways for the clinical application of AAVs.This review aims to provide a comprehensive summary of the various applications of AAVs,offer valuable insights for future research directions,and holds significant importance for researchers and clinicians in the field.As AAV therapy continues to evolve,this article emphasizes its transformative potential in treating genetic diseases,indicating the central role of AAV in the future of gene therapy.展开更多
The clinical need for effective bone regeneration in compromised conditions continues to drive demand for innovative solutions.Among emerging strategies,extracellular vesicles(EVs)have shown promise as an acellular ap...The clinical need for effective bone regeneration in compromised conditions continues to drive demand for innovative solutions.Among emerging strategies,extracellular vesicles(EVs)have shown promise as an acellular approach for bone regeneration.However,their efficacy is hindered by rapid sequestration and clearance when administered via bolus injection.To address this challenge,EV-functionalized scaffolds have recently been proposed as an alternative delivery strategy to enhance EV retention and subsequent healing efficacy.This review aims to consolidate recent advancements in the development of EV-functionalized scaffolds for augmenting bone regeneration.It explores various sources of EVs and different strategies for integrating them into biomaterials.Furthermore,the mechanisms underlying their therapeutic effects in bone regeneration are elucidated.Current limitations in clinical translation and perspectives on the design of more efficient EVs for improved therapeutic efficacy are also presented.Overall,this review can provide inspiration for the development of novel EV-assisted grafts with superior bone regeneration potential.展开更多
Lipid nanoparticles(LNPs)have emerged as versatile and widely utilized delivery systems in both academic research and industrial applications,offering immense potential beyond liver-targeted and infectious disease tre...Lipid nanoparticles(LNPs)have emerged as versatile and widely utilized delivery systems in both academic research and industrial applications,offering immense potential beyond liver-targeted and infectious disease treatments.Despite their success,a significant limitation of LNPs is their inherent liver tropism following systemic administration.This liver-centric accumulation represents a key bottleneck,restricting the broader therapeutic applications of LNP-based delivery systems.In this review,we explore strategies to overcome this challenge by modulating LNP composition-including ionizable lipids,helper lipids,cholesterol,and other critical components-to achieve extrahepatic targeting.We further discuss recent advancements in surface modification techniques designed to redirect LNPs to organs beyond the liver.Additionally,we highlight recent progress in local delivery approaches,which offer a direct and effective alternative for achieving extrahepatic delivery.By providing a comprehensive overview of current strategies and limitations,we aim to guide future research efforts toward fully realizing the therapeutic potential of LNP-based delivery systems.展开更多
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 arter...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.展开更多
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 su...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.展开更多
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 Agr...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展开更多
Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for the diagnosis and treatment of multiple diseases.Radiopharmaceutical therapy,which directly causes systematic and irreparable da...Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for the diagnosis and treatment of multiple diseases.Radiopharmaceutical therapy,which directly causes systematic and irreparable damage to targeted cells,has attracted increasing attention in the treatment of refractory diseases that are not sensitive to current therapies.As the Food and Drug Administration(FDA)approvals of[177Lu]Lu-DOTA-TATE,[177Lu]Lu-PSMA-617 and their complementary diagnostic agents,namely,[68Ga]Ga-DOTA-TATE and[68Ga]Ga-PSMA-11,targeted radiopharmaceutical-based theranostics(radiotheranostics)are being increasingly implemented in clinical practice in oncology,which lead to a new era of radiopharmaceuticals.The new generation of radiopharmaceuticals utilizes a targeting vector to achieve the accurate delivery of radionuclides to lesions and avoid off-target deposition,making it possible to improve the efficiency and biosafety of tumour diagnosis and therapy.Numerous studies have focused on developing novel radiopharmaceuticals targeting a broader range of disease targets,demonstrating remarkable in vivo performance.These include high tumor uptake,prolonged retention time,and favorable pharmacokinetic properties that align with clinical standards.While radiotheranostics have been widely applied in tumor diagnosis and therapy,their applications are now expanding to neurodegenerative diseases,cardiovascular diseases,and inflammation.Furthermore,radiotheranostic-empowered precision medicine is revolutionizing the cancer treatment paradigm.Diagnostic radiopharmaceuticals play a pivotal role in patient stratification and treatment planning,leading to improved therapeutic outcomes in targeted radionuclide therapy.This review offers a comprehensive overview of the evolution of radiopharmaceuticals,including both FDA-approved and clinically investigated agents,and explores the mechanisms of cell death induced by radiopharmaceuticals.It emphasizes the significance and future prospects of theranostic-based radiopharmaceuticals in advancing precision medicine.展开更多
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 ...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.展开更多
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 stud...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.展开更多
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 treat...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.展开更多
Over the past few decades,tumor immunotherapy has revolutionized the landscape of cancer clinical treatment.There is a flourishing development of combination strategies to improve the anti-tumor efficacy of mono-immun...Over the past few decades,tumor immunotherapy has revolutionized the landscape of cancer clinical treatment.There is a flourishing development of combination strategies to improve the anti-tumor efficacy of mono-immunotherapy.However,instead of a straightforward combination of multiple therapeutics,it is more preferable to pursue a synergistic effect by designing rational combinations as well as administration strategies,which are based on a comprehensive understanding of the physiological and pathological features.In this case,the timing and spatial distribution of the combination drugs become essential factors in achieving improved therapeutic outcomes.Therefore,the concept of Sequential Drug Delivery System(SDDS)is proposed to define the spatiotemporally programmed drug delivery/release through triggers of internal conditions and/or external interventions,thus complying with the dynamic disease evolution and the human immunity.This review summarizes the recent advancements inbiomaterial-based SDDSs used for spatiotemporally-tuned combination tumor immunotherapy.Furthermore,the rationales behind various engineering strategies are discussed.Finally,an overview of potential synergistic mechanisms as well as their prospects for combination immunotherapy is presented.展开更多
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...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.展开更多
文摘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.
文摘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.
文摘BACKGROUND Periodontal disease is a chronic inflammatory condition characterized by periodontal pocket formation,clinical attachment loss,and destruction of alveolar bone.Its conventional treatment primarily involves mechanical debridement and plaque control,but localized antimicrobial therapy offers site-specific advantages.While antibiotics such as metronidazole and doxycycline are commonly used,green tea extract,which is rich in epigallocatechin gallate,has been proposed as a promising alternative for local drug delivery due to its anti-inflammatory and antimicrobial properties.AIM To compare the clinical efficacy of green tea extract gel and ornidazole gel as adjuncts to scaling and root planing(SRP)in patients with periodontitis.METHODS Teeth with probing pocket depths(PPD)of 4-7 mm were selected.Participants’baseline oral hygiene index-simplified,plaque index,clinical attachment loss,and PPD were recorded.The participants were randomized into two groups:One received green tea extract gel after SRP,and the other received ornidazole gel.Subgingival drug delivery was performed,and participants refrained from brushing or interproximal cleaning for ten days.Their clinical parameters were re-evaluated after one month.RESULTS The PPD decreased significantly from baseline to one month in both groups.However,the green tea extract gel group exhibited superior outcomes to the ornidazole gel group,with a mean difference in PPD of 0.28±0.78 mm at one month(P<0.007).CONCLUSION As an adjunct to SRP,green tea extract gel showed greater efficacy in improving clinical periodontal parameters than ornidazole gel.
基金supported in part by grants from the National Institute of Dental&Craniofacial Research(R56DE029157)Center for Dental,Oral and Craniofacial Tissue Organ Regeneration(U24 DE026914)Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Award Program,and National Institute of Diabetes and Digestive and Kidney Diseases(R01DK112939).
文摘Periodontitis is initiated by dysbiosis of the oral microbiome.Pathogenic bacteria elicit ineffective immune responses,which damage surrounding tissues and lead to chronic inflammation.Although current treatments typically aim for microbial eradication,they fail to address the significance of immune cell reactions in disease progression.Here,we searched for small molecules as drug candidates and identified a bifunctional antibiotic,azithromycin(AZM),that not only inhibits bacterial growth but also modulates immune cells to suppress inflammation.We further engineered a dissolvable microneedle patch loaded with biodegradable microparticles for local and painless delivery of AZM to the gingival tissues.Inflammatory cytokines were decreased while anti-inflammatory cytokines and M2 macrophage were increased with AZM treatments in vitro.In vivo delivery of the AZM-loaded microneedle patch demonstrated the same effects on cytokine secretion and the promotion of tissue healing and bone regeneration.In addition,microparticles containing anti-inflammatory interleukin-4 alone or in combination with separately-formulated AZM microparticles,had similar or slightly enhanced therapeutic out-comes respectively.The bimodal action of AZM obviates the necessity for separate antibacterial and immunomodulatory agents,providing a practical and streamlined approach for clinical treatment.Our findings also demonstrate the therapeutic efficacy of microparticles delivery into the soft tissues by a minimally invasive and fast-degrading microneedle patch and offer a novel therapeutic approach for the treatment of periodontitis and other diseases through immunomodulation.
基金support from the National Institute of General Medical Sciences(1R35G M147172-01).
文摘Nanopipette based scanning probe technique is a versatile tool in non-contact imaging in biology.In addition to the topographic imaging,its capability of localized delivery of bio-active molecules is emerging.In this mini review,we introduce the applications of nanopipette in single-cell researches with a focus on localized delivery.The working principles of three delivery modes including resistive pulse,pressure-driven flow,and electroosmotic flow-driven delivery are summarized and compared.Their applications in single-cell researches are reviewed.The current technical challenges in scanning ion conductance microscopy-based delivery,and their growing influence in medicine and pharmacologic researches are also discussed.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Ministry of Science and ICT(MSIT)(No.2021R1A2C2012808)Technology Innovation Program(Alchemist Project)(No.20012378)funded by the Ministry of Trade,Industry&Energy(MOTIE),South Korea.
文摘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.
基金supported by the National Natural Science Foundation of China(Nos.31700869,31700868,31771096)the National Science Fund for Distinguished Young Scholars(No.NSFC31525009)+1 种基金the Fundamental Research Funds for the Central Universities/the Postdoctoral Research Foundation of Sichuan University(Nos.2017SCU12032,2017SCU12040)Sichuan Innovative Research Team Program for Young Scientists(No.2016TD0004)
文摘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.
基金supported by the German Research Foundation(DA 2255/1-1to SCD)+4 种基金a SickKids Research Training Competition(RESTRACOMP)Graduate Scholarship(to KJWS)an Ontario Graduate Scholarship(to KJWS)a grant from Natural Sciences and Engineering Research Council of Canada(NSERC)(to KJWS)a Kickstarter grant from the Institute of Biomedical Engineering(BME)at the University of Toronto(to KJWS)the Abe Frank Fund from the Riley’s Children Foundation(GHB)。
文摘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.
基金supported by the Guiding Funds of Central Government for Supporting the Development of the Local Science and Technology(2024BSB012)National Natural Science Foundation of China(No.81772833).
文摘In recent years,adeno-associated viruses(AAVs)have emerged as leading vectors in gene therapy,with several FDA-approved treatments and ongoing clinical trials demonstrating their effectiveness in treating inherited retinal diseases,hemophilia,and Duchenne muscular dystrophy,among others.However,AAV-based therapies still face challenges,including immune responses and side effects,due to high viral doses.To address these challenges,various strategies have been developed,such as creating new viral capsids,optimizing gene expression regulation,and improving delivery methods.Localized delivery is a promising direction,utilizing the tissue tropism of AAVs to reduce systemic side effects and lower the required viral dose,thus improving targeting and efficiency,especially for organs that are difficult to treat with conventional methods.These innovations have opened new pathways for the clinical application of AAVs.This review aims to provide a comprehensive summary of the various applications of AAVs,offer valuable insights for future research directions,and holds significant importance for researchers and clinicians in the field.As AAV therapy continues to evolve,this article emphasizes its transformative potential in treating genetic diseases,indicating the central role of AAV in the future of gene therapy.
基金This work was supported by the National Natural Science Foundation of China(No.31900966&82001105)the Guangdong Provincial Basic and Applied Basic Research(No.2019A1515110415)+2 种基金Shenzhen Medical Academy of Research and Translation(A2303069)the Shenzhen Basic Research Program General Project(JCYJ20220530162206012)Medicine Plus Project of Shenzhen University.
文摘The clinical need for effective bone regeneration in compromised conditions continues to drive demand for innovative solutions.Among emerging strategies,extracellular vesicles(EVs)have shown promise as an acellular approach for bone regeneration.However,their efficacy is hindered by rapid sequestration and clearance when administered via bolus injection.To address this challenge,EV-functionalized scaffolds have recently been proposed as an alternative delivery strategy to enhance EV retention and subsequent healing efficacy.This review aims to consolidate recent advancements in the development of EV-functionalized scaffolds for augmenting bone regeneration.It explores various sources of EVs and different strategies for integrating them into biomaterials.Furthermore,the mechanisms underlying their therapeutic effects in bone regeneration are elucidated.Current limitations in clinical translation and perspectives on the design of more efficient EVs for improved therapeutic efficacy are also presented.Overall,this review can provide inspiration for the development of novel EV-assisted grafts with superior bone regeneration potential.
基金supported by the start-up package from the University of Massachusetts Lowell.
文摘Lipid nanoparticles(LNPs)have emerged as versatile and widely utilized delivery systems in both academic research and industrial applications,offering immense potential beyond liver-targeted and infectious disease treatments.Despite their success,a significant limitation of LNPs is their inherent liver tropism following systemic administration.This liver-centric accumulation represents a key bottleneck,restricting the broader therapeutic applications of LNP-based delivery systems.In this review,we explore strategies to overcome this challenge by modulating LNP composition-including ionizable lipids,helper lipids,cholesterol,and other critical components-to achieve extrahepatic targeting.We further discuss recent advancements in surface modification techniques designed to redirect LNPs to organs beyond the liver.Additionally,we highlight recent progress in local delivery approaches,which offer a direct and effective alternative for achieving extrahepatic delivery.By providing a comprehensive overview of current strategies and limitations,we aim to guide future research efforts toward fully realizing the therapeutic potential of LNP-based delivery systems.
文摘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.
基金supported by the National Natural Science Foundation of China (31900945)Basic Research Program of Shenzhen(JCYJ20170412111100742, JCYJ20180507182413022)+2 种基金Fok YingTong Education Foundation for Young Teachers in the Higher Education Institutions of China (161032)Postdoctoral Science Foundation of China (2018M643175)Guangdong Province Natural Science Foundation of Major Basic Research and Cultivation Project (2018B030308003)。
文摘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.
文摘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
基金supported by the National Natural Science Foundation of China(No.82372002)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2022-RC350-04)+5 种基金the CAMS Innovation Fund for Medical Sciences(Nos.2023-I2M-2-006,2023-I2M-QJ-010,02149942,2021-I2M-1-026,2022-I2M-2-002-2,and 2021-I2M-3-001)the National Key Research and Development Programme of China(No.2022YFE0111700)the Beijing Nova Programme to K.H..This work was also supported by the Beijing Natural Science Foundation(Nos.L234044 and L248087)the Fundamental Research Funds for the Central Universities(Nos.3332023044 and 3332023151)the CIRP Open Fund of Radiation Protection Laboratories(No.ZHYLYB2021005)the China National Nuclear Corporation Young Talent Programme.
文摘Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for the diagnosis and treatment of multiple diseases.Radiopharmaceutical therapy,which directly causes systematic and irreparable damage to targeted cells,has attracted increasing attention in the treatment of refractory diseases that are not sensitive to current therapies.As the Food and Drug Administration(FDA)approvals of[177Lu]Lu-DOTA-TATE,[177Lu]Lu-PSMA-617 and their complementary diagnostic agents,namely,[68Ga]Ga-DOTA-TATE and[68Ga]Ga-PSMA-11,targeted radiopharmaceutical-based theranostics(radiotheranostics)are being increasingly implemented in clinical practice in oncology,which lead to a new era of radiopharmaceuticals.The new generation of radiopharmaceuticals utilizes a targeting vector to achieve the accurate delivery of radionuclides to lesions and avoid off-target deposition,making it possible to improve the efficiency and biosafety of tumour diagnosis and therapy.Numerous studies have focused on developing novel radiopharmaceuticals targeting a broader range of disease targets,demonstrating remarkable in vivo performance.These include high tumor uptake,prolonged retention time,and favorable pharmacokinetic properties that align with clinical standards.While radiotheranostics have been widely applied in tumor diagnosis and therapy,their applications are now expanding to neurodegenerative diseases,cardiovascular diseases,and inflammation.Furthermore,radiotheranostic-empowered precision medicine is revolutionizing the cancer treatment paradigm.Diagnostic radiopharmaceuticals play a pivotal role in patient stratification and treatment planning,leading to improved therapeutic outcomes in targeted radionuclide therapy.This review offers a comprehensive overview of the evolution of radiopharmaceuticals,including both FDA-approved and clinically investigated agents,and explores the mechanisms of cell death induced by radiopharmaceuticals.It emphasizes the significance and future prospects of theranostic-based radiopharmaceuticals in advancing precision medicine.
基金financial support from the National Natural Science Foundation of China(U21A20417,31930067)1⋅3⋅5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD18002).
文摘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.
基金supported by the National Natural Science Foundation of China (82272811 and 81930080)the Fund for Distinguished Young Scholars of Jiangsu Province (BK20230001).
文摘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.
基金financial support from the National Natural Science Foundation of China(U21A20417,31930067,and 31800797)the Sichuan Science and Technology Program(2022YFS0333,2022YFS0203)+1 种基金1⋅3⋅5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD18002)the Post-Doctor Research Project,West China Hospital,Sichuan University(2018HXBH066).
文摘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.
基金supported by the National Natural Science Foundation of China(22478438,81972894,82303820,82273882,32401048 and 22278442)the Science Fund for Distinguished Young Scholars of Jiangsu Province(BK20240098,China)+4 种基金the Natural Science Foundation of Jiangsu Province(BK20231017,China)the China Postdoctoral Science Foundation(2023M733891)the Jiangsu Funding Program for Excellent Postdoctoral Talent(317717,China)the Fundamental Research Funds for the Central Universities(2632023GR11,China)the Special Research Fund from the State Key Laboratory of Natural Medicines at China Pharmaceutical University(SKLNMZZ2024JS19).
文摘Over the past few decades,tumor immunotherapy has revolutionized the landscape of cancer clinical treatment.There is a flourishing development of combination strategies to improve the anti-tumor efficacy of mono-immunotherapy.However,instead of a straightforward combination of multiple therapeutics,it is more preferable to pursue a synergistic effect by designing rational combinations as well as administration strategies,which are based on a comprehensive understanding of the physiological and pathological features.In this case,the timing and spatial distribution of the combination drugs become essential factors in achieving improved therapeutic outcomes.Therefore,the concept of Sequential Drug Delivery System(SDDS)is proposed to define the spatiotemporally programmed drug delivery/release through triggers of internal conditions and/or external interventions,thus complying with the dynamic disease evolution and the human immunity.This review summarizes the recent advancements inbiomaterial-based SDDSs used for spatiotemporally-tuned combination tumor immunotherapy.Furthermore,the rationales behind various engineering strategies are discussed.Finally,an overview of potential synergistic mechanisms as well as their prospects for combination immunotherapy is presented.
文摘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.
