Despite great efforts and advancement in the treatment of cancer,tumor recurrence and metastasis remain significant challenges and demand novel therapy strategies.Recently,advances in biomaterials and drug delivery sy...Despite great efforts and advancement in the treatment of cancer,tumor recurrence and metastasis remain significant challenges and demand novel therapy strategies.Recently,advances in biomaterials and drug delivery systems have facilitated the development of the local therapy of cancer,among which electrospun nanofibrous scaffolds show great promise owing to their porous structure,relatively large surface area,high drug loading capacity,similarity with the native extracellular matrix,and possibility of the combination of various therapies.Here,we review this rapidly developing field of electrospun nanofibrous scaffolds as a drug delivery system for cancer local therapy,in particular addressing stimuli-responsive drug release,as well as its combination with stem cell and immune therapy.Challenges and future perspectives are also discussed.展开更多
In this paper, a hybrid genetic algorithm （GA） is proposed for the traveling salesman problem （TSP） with pickup and delivery （TSPPD）. In our algorithm, a novel pheromone-based crossover operator is advanced that...In this paper, a hybrid genetic algorithm （GA） is proposed for the traveling salesman problem （TSP） with pickup and delivery （TSPPD）. In our algorithm, a novel pheromone-based crossover operator is advanced that utilizes both local and global information to construct offspring. In addition, a local search procedure is integrated into the GA to accelerate convergence. The proposed GA has been tested on benchmark instances, and the computational results show that it gives better convergence than existing heuristics.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
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
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
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
Lidocaine hydrochloride(LIDH) as an anesthetic is widely used in local anesthesia. Dissolving microneedles(MNs) have great application value in the field of skin anesthesia. However, the limited drug-loading of dissol...Lidocaine hydrochloride(LIDH) as an anesthetic is widely used in local anesthesia. Dissolving microneedles(MNs) have great application value in the field of skin anesthesia. However, the limited drug-loading of dissolving MNs is an existing challenge that affects clinical use. In this study, we have screened isomaltulose(ISO) as the proper matrix material for the MNs by using molecular dynamics(MD) simulation. Our findings indicate that ISO has good compatibility with LIDH, and the LIDH-loaded ISO MNs(LI-MNs) have high drug-loading capacity. The drug-loading capacity of LI-MNs could reach 80%, and it could effectively puncture the skin. In addition, the preparation method of customized LI-MNs was established based on three-dimensional(3D) printing technology. It was shown that the administration time of LI-MNs could be controlled within 3 min. Also, the LI-MNs were able to provide the local anesthetic efficacy within2 min and sustained for more than 2 h. Significantly, LI-MNs had more efficient drug efficacy compared to the topical creams and the majority of existing LIDH-loaded dissolving MNs. They even provided a longer duration of action than the injections. Overall, the LI-MNs with high drug-loading have a promising application prospect.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
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
基金supported by the Natural Science Foundation of China(81930051 and 51873107)Shanghai Talent Development Fund(2018099).
文摘Despite great efforts and advancement in the treatment of cancer,tumor recurrence and metastasis remain significant challenges and demand novel therapy strategies.Recently,advances in biomaterials and drug delivery systems have facilitated the development of the local therapy of cancer,among which electrospun nanofibrous scaffolds show great promise owing to their porous structure,relatively large surface area,high drug loading capacity,similarity with the native extracellular matrix,and possibility of the combination of various therapies.Here,we review this rapidly developing field of electrospun nanofibrous scaffolds as a drug delivery system for cancer local therapy,in particular addressing stimuli-responsive drug release,as well as its combination with stem cell and immune therapy.Challenges and future perspectives are also discussed.
文摘In this paper, a hybrid genetic algorithm （GA） is proposed for the traveling salesman problem （TSP） with pickup and delivery （TSPPD）. In our algorithm, a novel pheromone-based crossover operator is advanced that utilizes both local and global information to construct offspring. In addition, a local search procedure is integrated into the GA to accelerate convergence. The proposed GA has been tested on benchmark instances, and the computational results show that it gives better convergence than existing heuristics.
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 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 National Key Research and Development Program of China (No.2021YFF1200800)the Sichuan Science and Technology Program (Nos.2021JDTD0001,2022YFQ0004)the Natural Science Foundation of Sichuan Province (No.2023NSFSC1629)。
文摘Lidocaine hydrochloride(LIDH) as an anesthetic is widely used in local anesthesia. Dissolving microneedles(MNs) have great application value in the field of skin anesthesia. However, the limited drug-loading of dissolving MNs is an existing challenge that affects clinical use. In this study, we have screened isomaltulose(ISO) as the proper matrix material for the MNs by using molecular dynamics(MD) simulation. Our findings indicate that ISO has good compatibility with LIDH, and the LIDH-loaded ISO MNs(LI-MNs) have high drug-loading capacity. The drug-loading capacity of LI-MNs could reach 80%, and it could effectively puncture the skin. In addition, the preparation method of customized LI-MNs was established based on three-dimensional(3D) printing technology. It was shown that the administration time of LI-MNs could be controlled within 3 min. Also, the LI-MNs were able to provide the local anesthetic efficacy within2 min and sustained for more than 2 h. Significantly, LI-MNs had more efficient drug efficacy compared to the topical creams and the majority of existing LIDH-loaded dissolving MNs. They even provided a longer duration of action than the injections. Overall, the LI-MNs with high drug-loading have a promising application prospect.
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.
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.
