A Review on Nano-Based Drug Delivery System for Cancer Chemoimmunotherapy

Although notable progress has been made on novel cancer treatments,the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients.Chemoimmunotherapy,combining chemotherapeutics and immunotherapeutic drugs,has emerged as a promising approach for cancer treatment,with the advantages of cooperating two kinds of treatment mechanism,reducing the dosage of the drug and enhancing therapeutic effect.Moreover,nano-based drug delivery system(NDDS)was applied to encapsulate chemotherapeutic agents and exhibited outstanding properties such as targeted delivery,tumor microenvironment response and site-specific release.Several nanocarriers have been approved in clinical cancer chemotherapy and showed significant improvement in therapeutic efficiency compared with traditional formulations,such as liposomes(Doxil R,Lipusu R),nanoparticles(Abraxane R)and micelles(Genexol-PM R).The applications of NDDS to chemoimmunotherapy would be a powerful strategy for future cancer treatment,which could greatly enhance the therapeutic efficacy,reduce the side effects and optimize the clinical outcomes of cancer patients.Herein,the current approaches of cancer immunotherapy and chemoimmunotherapy were discussed,and recent advances of NDDS applied for chemoimmunotherapy were further reviewed.

Micelles as potential drug delivery systems for colorectal cancer treatment

Despite the significant progress in cancer therapy,colorectal cancer(CRC)remains one of the most fatal malignancies worldwide.Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment.However,the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability,non-selective tumor targeting mechanisms,non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects.Over the last decade,there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations.Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates.Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect.They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site.They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer.Given that combination therapy is the new strategy implemented in cancer therapy,polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes.They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy.Here,we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment.We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.

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.

Advances in Transdermal Drug Delivery for Cancer Therapy

Transdermal drug delivery offers a promising alternative to traditional cancer therapies by providing a non-invasive,controlled,and targeted delivery of therapeutic agents.This paper explores the advancements,benefits,and challenges associated with transdermal drug delivery systems(TDDS)in cancer treatment.It highlights the mechanisms of action,key technologies,and the potential impact on patient outcomes.By examining recent studies and clinical trials,this paper aims to provide a comprehensive overview of the efficacy,safety,and prospects of transdermal drug delivery in oncology.

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.

Role of targeting ferroptosis as a component of combination therapy in combating drug resistance in colorectal cancer

Colorectal cancer(CRC)is a form of cancer that is often resistant to chemotherapy,targeted therapy,radiotherapy,and immunotherapy due to its genomic instability and inflammatory tumor microenvironment.Ferroptosis,a type of non-apoptotic cell death,is characterized by the accumulation of iron and the oxidation of lipids.Studies have revealed that the levels of reactive oxygen species and glutathione in CRC cells are significantly lower than those in healthy colon cells.Erastin has emerged as a promising candidate for CRC treatment by diminishing stemness and chemoresistance.Moreover,the gut,responsible for regulating iron absorption and release,could influence CRC susceptibility through iron metabolism modulation.Investigation into ferroptosis offers new insights into CRC pathogenesis and clinical management,potentially revolutionizing treatment approaches for therapy-resistant cancers.

Progress in transdermal drug delivery systems for cancer therapy

Transdermal drug delivery is an appealing option except for oral and hypodermic administration.With the advancement of skin penetration strategies,various anticancer therapeutics ranging from liphilic small-molecule drugs to hydrophilic biomacromolecules,can be administered transdermally,offering an optional regimen to treat skin cancers.In addition,the activation of the skin immune systems can also assist the treatment of distal sites.Current approaches on enhancing the transdermal delivery efficacy of anticancer drugs are summarized in this review.We also survey recent advances in micro-and nanotechnology-based transdermal formulations for cancer treatment,such as chemotherapy,gene therapy,immunotherapy,phototherapy and combination therapy.New penetration enhancers,materials,formulations and their hypothesized mechanisms for transdermal delivery are highlighted.Advantages and limitations regarding the state-of-the-art transdermal delivery technologies,as well as future perspective are also discussed.

Erythrocyte-derived drug delivery systems in cancer therapy

As natural blood components,erythrocytes were good candidates for being used as drug delive ry systems to improve the pharmacokinetics,biocompatibility and many other aspects of different drugs.The advantages brought by erythrocytes making erythrocyte-derived drug delivery systems,also known as erythrocyte carriers,suitable for various anti-cancer agents,especially newly invented agents like nanoparticles,which were characterized by their undesired systematic toxicity,anaphylactic reactions and poor biocompatibility.Current researches on erythrocyte carriers in ca ncer therapy showed inspiring results in four major aspects:cancer enzyme therapy,delivering chemotherapeutic agents,combining with nanoparticles,and several other anti-cancer agents for gene or immune therapy.This novel delivering system was now undergoing the translation process from laboratory to clinical practice.Erythrocyte carriers for cancer enzyme therapy have entered the stage of clinical trial and have showed promising outcomes,and others were still at pre-clinical stage.In summary,erythrocyte-derived drug delivery system might play an indispensable role in the management of cancer in the future.

Cisplatin and paclitaxel co-delivery nanosystem for ovarian cancer chemotherapy

We have designed and developed an effective drug delivery system using biocompatible polymer of poly(ethylene glycol)-polyaspartic acid(mPEG-PAsp)for co-loading the chemotherapy drugs paclitaxel(PTX)and cisplatin(CP)in one nano-vehicle.This study aimed to improve the anti-cancer effi-cacy of combinations of chemotherapy drugs and reduce their side effects.mPEG-PAsp-(PTX/Pt)nano-micelles disperse well in aqueous solution and have a narrow size distribution(37.863.2 nm)in dynamic light scattering(DLS).Drug release profiles found that CP released at pH 5.5 was signifi-cantly faster than that at pH 7.4.MPEG-PAsp-(PTX/Pt)nano-micelles displayed a significantly higher tumor inhibitory effect than mPEG-PAsp-PTX nano-micelles when the polymer concentrations reached 50 lg/mL.Our data indicated that polymer micelles of mPEG-PAsp loaded with the combined drug exert synergistic anti-tumor efficacy on SKOV3 ovarian cells via different action mechanisms.Results from our studies suggested that mPEG-PAsp-(PTX/Pt)nano-micelles are promising alternatives for carrying and improving the delivery of therapeutic drugs with different water solubilities.

Complications and comorbidities associated with antineoplastic chemotherapy:Rethinking drug design and delivery for anticancer therapy

Despite the considerable advancements in chemotherapy as a cornerstone modality in cancer treatment,the prevalence of complications and pre-existing diseases is on the rise among cancer patients along with prolonged survival and aging population.The relationships between these disorders and cancer are intricate,bearing significant influence on the survival and quality of life of individuals with cancer and presenting challenges for the prognosis and outcomes of malignancies.Herein,we review the prevailing complications and comorbidities that often accompany chemotherapy and summarize the lessons to learn from inadequate research and management of this scenario,with an emphasis on possible strategies for reducing potential complications and alleviating comorbidities,as well as an overview of current preclinical cancer models and practical advice for establishing bio-faithful preclinical models in such complex context.

Biomedical polymers: synthesis, properties, and applications

Biomedical polymers have been extensively developed for promising applications in a lot of biomedical fields, such as therapeutic medicine delivery, disease detection and diagnosis, biosensing, regenerative medicine, and disease treatment. In this review, we summarize the most recent advances in the synthesis and application of biomedical polymers, and discuss the comprehensive understanding of their property-function relationship for corresponding biomedical applications. In particular, a few burgeoning bioactive polymers, such as peptide/biomembrane/microorganism/cell-based biomedical polymers, are also introduced and highlighted as the emerging biomaterials for cancer precision therapy. Furthermore, the foreseeable challenges and outlook of the development of more efficient, healthier and safer biomedical polymers are discussed. We wish this systemic and comprehensive review on highlighting frontier progress of biomedical polymers could inspire and promote new breakthrough in fundamental research and clinical translation.

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

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

Anti-tumor Activity of Biodegradable Polymer-paclitaxel Conjugated Micelle Against Mice U14 Cervical Cancers

Two kinds of paclitaxel（PTX） conjugate micelles,of which one contained 25%（mass fraction） PTX [M（PTX）] and the other contained 22.5%（mass fraction） of PTX and 1.4%（mass fraction） of folate（FA）[FA-M（PTX）],were prepared for cell apoptosis and anti-tumor activity evaluation on U14 cervical cancer mouse models in comparison with 0.9%（mass fraction） saline（control） and equivalent Taxol.Seven days after tail intravenous injection of the drugs,the mice were sacrificed to measure the tumor masses.The average tumor masses were 4.26,2.89,2.63,and 2.17 g for the control,Taxol,M（PTX） and FA-M（PTX） groups,respectively.The inhibition rates of tumor growth calculated for the three drug groups were 32%,38% and 49%,respectively.Flow cytometry（FC） analysis and terminal deoxynucleotidyl transferase（TdT）-mediated deoxyuridine triphosphate（dUTP） nick end labeling（TUNEL） assay were conducted on the cancer tissues.The cell apoptosis rates based on the FC data and the TUNEL data were 20%,31%,37%,42%,and 10%,22%,26%,34%,respectively,both showing statistically significant differences（P〈0.05） between three drug groups and the control group,and between the FA-M（PTX） group and the other two drug groups.In conclusion,the composite FA-M（PTX） micelles can be used for U14 cervical cancer treatment.

Targeted chemotherapy via HER2-based chimeric antigen receptor(CAR)engineered T-cell membrane coated polymeric nanoparticles

Cell membrane-derived nanoparticles(NPs)have recently gained popularity due to their desirable features in drug delivery such as mimicking properties of native cells,impeding systemic clearance,and altering foreign body responses.Besides NP technology,adoptive immunotherapy has emerged due to its promise in cancer specificity and therapeutic efficacy.In this research,we developed a biomimetic drug carrier based on chimeric antigen receptor(CAR)transduced T-cell membranes.For that purpose,anti-HER2 CAR-T cells were engineered via lentiviral transduction of anti-HER2 CAR coding lentiviral plasmids.Anti-HER2 CAR-T cells were characterized by their specific activities against the HER2 antigen and used for cell membrane extraction.Anti-cancer drug Cisplatin-loaded poly(D,L-lactide-co-glycolic acid)(PLGA)NPs were coated with anti-human epidermal growth factor receptor 2(HER2)-specific CAR engineered T-cell membranes.Anti-HER2 CAR-T-cell membrane-coated PLGA NPs(CAR-T-MNPs)were characterized and confirmed via fluorescent microscopy and flow cytometry.Membrane-coated NPs showed a sustained drug release over the course of 21 days in physiological conditions.Cisplatin-loaded CAR-T-MNPs also inhibited the growth of multiple HER2+cancer cells in vitro.In addition,in vitro uptake studies revealed that CAR-T-MNPs showed an increased uptake by A549 cells.These results were also confirmed via in vivo biodistribution and therapeutic studies using a subcutaneous lung cancer model in nude mice.CAR-T-MNPs localized preferentially at tumor areas compared to those of other studied groups and consisted of a significant reduction in tumor growth in tumor-bearing mice.In Conclusion,the new CAR modified cell membrane-coated NP drug-delivery platform has demonstrated its efficacy both in vitro and in vivo.Therefore,CAR engineered membrane-coated NP system could be a promising cell-mimicking drug carrier that could improve therapeutic outcomes of lung cancer treatments.

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

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

Co-delivery of paclitaxel and gemcitabine via folic acid-conjugated polymeric multi-drug nanoparticles (FA-PMDNPs) for the treatment of breast cancer

Multi-drug delivery focuses on different signaling pathways in cancer cells and has synergistic antiproliferative effects.In this manuscript,we developed folic acid(FA)-conjugated polymeric multi-drug nanoparticles(FA-PMDNPs)consisting of poly-L-lysine(PLL)and poly glutamic-conjugated PTX/GEM(PGA-PTX and PGA-GEM)for FA receptor-targeted synergistic breast cancer therapy.The carboxyl-rich structure of PGA provided plenty reaction sites and negative charge for drug loading.Transmission electron microscopy(TEM)results showed that FA-PMDNPs had uniform particle size and spherical morphology.The hemolysis study proved that FA-PMDNPs had good biocompatibility.In vitro cell viability and in vivo studies showed that FA-PMDNPs more effectively inhibited the proliferation of FA receptor(FR)-overexpressing breast cancer cells(4T1)than the pure drugs.Consequently,these results demonstrated that FA-PMDNPs could be effectively targeted at cancer cells compared with free drugs,indicating their strong potential as efficient multi-drug-carrying nano-platforms for cancer treatment.

Recent advances of bioresponsive polymeric nanomedicine for cancer therapy

A bioresponsive polymeric nanocarrier for drug delivery is able to alter its physical and physicochemical properties in response to a variety of biological signals and pathological changes,and can exert its therapeutic efficacy within a confined space.These nanosystems can optimize the biodistribution and subcellular location of therapeutics by exploiting the differences in biochemical properties between tumors and normal tissues.Moreover,bioresponsive polymer-based nanosystems could be rationally designed as precision therapeutic platforms by optimizing the combination of responsive elements and therapeutic components according to the patient-specific disease type and stage.In this review,recent advances in smart bioresponsive polymeric nanosystems for cancer chemotherapy and immunotherapy will be summarized.We mainly discuss three categories,including acidity-sensitive,redox-responsive,and enzyme-triggered polymeric nanosystems.The important issues regarding clinical translation such as reproducibility,manufacture,and probable toxicity,are also commented.

肿瘤靶向性高分子纳米载体研究现状与展望

综述了肿瘤靶向性高分子纳米载体在抗肿瘤药物的靶向性输送和控制释放方面的研究进展,并详细介绍了被动肿瘤靶向性、主动靶向性、生物可降解性、pH敏感性、还原敏感性、酶敏感性和温度敏感性高分子纳米载体的研究现状,展望了该研究领域的发展方向.

抗癌药物靶向制剂的研究现状

抗癌靶向药物制剂能使药物选择性地与靶组织在细胞或亚细胞水平上发生反应,使药物能够可控性地分布,并于靶区持续缓慢地释放药物,有效降低其对正常组织的毒副作用,从而提高化疗疗效。针对目前国内外正在研究并取得了一定进展的抗癌靶向药物制剂,进行了全面客观的综述。通过大量文献,从靶向治疗设计模式、靶向制剂的分类、抗癌靶向药物载体及影响药物靶向性的因素等方面进行探讨。发现尽管靶向制剂广泛应用于临床尚需时日,但它们对于克服肿瘤治疗中的毒副作用,从而提高疗效具有不可忽视的作用。

生物医用高分子在癌症药物治疗中的应用

利用生物医用高分子作载体，化学结合或物理包裹抗肿瘤化学药物、生物工程药物和放射药物，制剂通过植入或靶向运输至肿瘤区域，可增强药物在运输及吸收过程中的稳定性，提高药物的生物利用度；药物以一定速率从制剂中缓慢释放，可简化服用程序，在肿瘤区域维持较高的药物浓度，同时降低药物对全身的毒副作用。本文综述了生物医用高分子在高分子导向药物、抗肿瘤药物聚合物微球制剂。