Tumor-specific Drug Release Research Articles

Biodegradable CoSnO3 nanozymes modulate pH-responsive graphene quantum dot release for synergistic chemo-sonodynamic-nanocatalytic cancer therapy

Albeit nanozymes are widely applied for nanocatalytic therapy (NCT), the unsatisfactory catalytic activity of nanozymes accompanied by complex tumor microenvironment (TME) greatly pose a barrier to the therapeutic effect of NCT. Moreover, developing a high-efficiency nanozyme with biodegradability is still a huge challenge, which hinders their further clinical translation. Herein, pH-responsive biodegradable CoSnO3 nanocubes are synthesized and employed as sonosensitizers and nanozymes due to their narrow bandgaps (1.6 eV) and Co2+/Sn4+-mediated multi-enzyme activities. After depositing the graphene quantum dot (GQD) topoisomerase inhibitors on CoSnO3 nanocubes, the heterojunction-fabricated GQD/CoSnO3 shows cascaded amplification of ROS generation, which is ascribed to the inhibition of electron-hole pair recombination, Co2+-mediated peroxidase (POD)-mimic catalytic reaction to generate OH, Co3+/Sn4+-mediated depletion of overexpressed GSH, and catalytic decomposition of endogenous H2O2 for providing more O2 for enhanced SDT. More importantly, GQD/CoSnO3 heterojunctions are slowly degraded in the weakly acidic TME, resulting the tumor-specific release of GQDs after completion of SDT, which could induce DNA damage and cell apoptosis for chemotherapy to further enhanced the antitumor efficacy. The synergetic therapeutic efficacy of GQD/CoSnO3 heterojunctions through chemotherapy, SDT, and NCT could realize “three-in-one” multimodal oncotherapy to completely eliminate tumors without recurrence. This work provides a paradigm of exploring pH-responsive biodegradable nanozymes as a drug carrier to realize tumor-specific drug release for enhanced SDT and NCT.

Sensitizing chemotherapy for glioma with fisetin mediated by a microenvironment-responsive nano-drug delivery system.

Drug resistance has become an obstacle to successful cancer chemotherapies, with therapeutic agents effectively traversing the blood-brain barrier (BBB) remaining a great challenge. A microenvironment responsive and active targeting nanoparticle was constructed to enhance the penetration of drugs, leading to improved therapeutic effects. Dynamic light scattering demonstrated that the prepared nanoparticle had a uniform size. The cRGD modification renders the nanoparticle with active targeting capabilities to traverse the BBB for chemotherapy. The disulfide-bond-containing nanoparticle can be disintegrated in response to a high concentration of endogenous glutathione (GSH) within the tumor microenvironment (TME) for tumor-specific drug release, resulting in more effective accumulation. Notably, the released fisetin further increased the uptake of doxorubicin by glioma cells and exerted synergistic effects to promote apoptosis, induce cellular G2/M cycle arrest, and inhibit cell proliferation and migration in vitro. Moreover, the nanoparticle showed favorable anti-glioma effects in vivo. Our study provides a new strategy to overcome drug resistance by utilizing a natural product to sensitize conventional chemotherapeutics with well-designed targeted nanodelivery systems for cancer treatment.

Near Infrared-Activatable Biomimetic Nanoplatform for Tumor-Specific Drug Release, Penetration and Chemo-Photothermal Synergistic Therapy of Orthotopic Glioblastoma.

Glioblastoma multiforme (GBM), a highly invasive and prognostically challenging brain cancer, poses a significant hurdle for current treatments due to the existence of the blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. We present a biomimetic nanoplatform with angiopep-2-modified macrophage membrane, loaded with indocyanine green (ICG) templated self-assembly of SN38 (AM-NP), facilitating active tumor targeting and effective blood-brain barrier penetration through specific ligand-receptor interaction. Upon accumulation at tumor sites, these nanoparticles achieved high drug concentrations. Subsequent combination of laser irradiation and release of chemotherapy agent SN38 induced a synergistic chemo-photothermal therapy. Compared to bare nanoparticles (NPs) lacking cell membrane encapsulation, AM-NPs significantly suppressed tumor growth, markedly enhanced survival rates, and exhibited excellent biocompatibility with minimal side effects. This NIR-activatable biomimetic camouflaging macrophage membrane-based nanoparticles enhanced drug delivery targeting ability through modifications of macrophage membranes and specific ligands. It simultaneously achieved synergistic chemo-photothermal therapy, enhancing treatment effectiveness. Compared to traditional treatment modalities, it provided a precise, efficient, and synergistic method that might have contributed to advancements in glioblastoma therapy.

Enhanced tumor specific drug release by hypoxia sensitive dual-prodrugs based on 2-nitroimidazole

Hypoxia in cancer is important in the development of cancer-selective medicines. Here, a novel hypoxia-responsible dual-prodrug is described. We designed and synthesized 2-nitroimidazole derivatives which spontaneously release both a PYG inhibitor and gemcitabine under hypoxic conditions. One such derivative, a prodrug 9 was found to be stable against chemical and enzymatic hydrolysis, and upon chemical reduction of the nitro group on imidazole, successfully releases both drugs. In an in vitro proliferation assay using human pancreatic cells, compound 9 exhibited significant anti-proliferative effects in hypoxia but fewer effects in normoxia. Consequently, prodrug 9 should be useful for cancer treatment due to its improved cancer selectivity and potential to overcome drug resistance.

Formulation of DOX-dimer with bi-functionalized chitooligosaccharide for tumor-specific self-boosted drug release and synergistic chemo/chemodynamic therapy

The toxic side effects and possible drug resistance of the chemotherapeutics hinder their antitumor efficacy. Here, a pH/reactive oxygen species (ROS) dual-triggered nanodrug was developed for the tumor-specific self-boosted drug release and synergistic chemo/chemodynamic therapy, by formulating ROS-cleavable doxorubicin (DOX)-based dimer (DOX-TK-DOX) with bi-functionalized chitooligosaccharide (COS-Fc-TK) with ferrocenecarboxylic acid (Fc) and thioketal (TK). The resultant DOX-TK-DOX/COS-Fc-TK nanoparticles with a high DOX content of 39.70 % showed tumor-specific self-boosted drug release, which was triggered by highly toxic OH generated via Fc-catalyzed Fenton reaction of the endogenous H2O2 in tumor intracellular microenvironment. As a result, a synergistic chemo/chemodynamic therapy with combination index (CI) of 0.94 was achieved for selective treatment of tumors.

Gas therapy potentiates aggregation-induced emission luminogen-based photoimmunotherapy of poorly immunogenic tumors through cGAS-STING pathway activation

The immunologically “cold” microenvironment of triple negative breast cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H2S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn2+. Both H2S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn2+ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice.

Technetium-99m labeled core shell hyaluronate nanoparticles as tumor responsive, metastatic skeletal lesion targeted combinatorial theranostics

Achieving target specific delivery of chemotherapeutics in metastatic skeletal lesions remains a major challenge. Towards this, a dual drug loaded, radiolabeled multi-trigger responsive nanoparticles having partially oxidized hyaluronate (HADA) conjugated to alendronate shell and palmitic acid core were developed. While the hydrophobic drug, celecoxib was encapsulated in the palmitic acid core, the hydrophilic drug, doxorubicin hydrochloride was linked to the shell via a pH responsive imine linkage. Hydroxyapatite binding studies showed affinity of alendronate conjugated HADA nanoparticles to bones. Enhanced cellular uptake of the nanoparticles was achieved via HADA-CD44 receptor binding. HADA nanoparticles demonstrated trigger responsive release of encapsulated drugs in the presence of hyaluronidase, pH and glucose, present in excess in the tumor microenvironment. Efficacy of the nanoparticles for combination chemotherapy was established by >10-fold reduction in IC50 of drug loaded particles with a combination index of 0.453, as compared to free drugs in MDA-MB-231 cells. The nanoparticles could be radiolabeled with the gamma emitting radioisotope technetium-99m (99mTc) through a simple, ‘chelator free’, procedure with excellent radiochemical purity (RCP) (>90 %) and in vitro stability. 99mTc-labeled drug loaded nanoparticles reported herein constitutes a promising theranostic agent to target metastatic bone lesions. Statement of hypothesesTechnetium-99m labeled, alendronate conjugated, dual targeting, tumor responsive, hyaluronate nanoparticle for tumor specific drug release and enhanced therapeutic effect, with real-time in vivo monitoring.

Self-engineered lipid peroxidation nano-amplifier for ferroptosis-driven antitumor therapy

Ferroptosis has been extensively explored as a promising therapeutic target for cancer. Most ferroptosis inducers promote the intracellular accumulation of lipid peroxidation by depleting glutathione peroxidase 4 (GPX4). However, GPX4 suppression alone is not sufficient to trigger intracellular lipid peroxidation storm, resulting in inefficient ferroptosis induction and unsatisfactory antitumor effect. Herein, we precisely engineer a lipid peroxidation nano-amplifier based on a facile drug-deliver-drug (DDD) engineering strategy. Interestingly, FIN56 (a GPX4 inhibitor) is found to readily co-assemble with arachidonic acid (AA) into stable nanoparticles without the assistance of any excipients. Then, a disulfide bond-containing amphipathic PEG polymer is decorated on the nano-amplifier for long blood circulation and tumor-specific drug release. Notably, AA could not only be converted into abundant lipid reactive oxygen species (ROS) but also elicit membranous lipid peroxidation in tumor cells, synergistically inducing tumor ferroptosis with FIN56-mediated GPX4 depletion. As expected, the nano-amplifier exhibits potent ferroptosis-driven antitumor activity in 4 T1 breast tumor-bearing mice. This study drives a conceptual step forward in ferroptosis-driven nanotherapeutics, and offers a novel DDD co-delivery paradigm for combination cancer therapy.

Combinatorial therapeutic strategies for enhanced delivery of therapeutics to brain cancer cells through nanocarriers: current trends and future perspectives

Brain cancer is the most aggressive one among various cancers. It has a drastic impact on people's lives because of the failure in treatment efficacy of the currently employed strategies. Various strategies used to relieve pain in brain cancer patients and to prolong survival time include radiotherapy, chemotherapy, and surgery. Nevertheless, several inevitable limitations are accompanied by such treatments due to unsatisfactory curative effects. Generally, the treatment of cancers is very challenging due to many reasons including drugs’ intrinsic factors and physiological barriers. Blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are the two additional hurdles in the way of therapeutic agents to brain tumors delivery. Combinatorial and targeted therapies specifically in cancer show a very promising role where nanocarriers’ based formulations are designed primarily to achieve tumor-specific drug release. A dual-targeting strategy is a versatile way of chemotherapeutics delivery to brain tumors that gets the aid of combined ligands and mediators that cross the BBB and reaches the target site efficiently. In contrast to single targeting where one receptor or mediator is targeted, the dual-targeting strategy is expected to produce a multiple-fold increase in therapeutic efficacy for cancer therapy, especially in brain tumors. In a nutshell, a dual-targeting strategy for brain tumors enhances the delivery efficiency of chemotherapeutic agents via penetration across the blood-brain barrier and enhances the targeting of tumor cells. This review article highlights the ongoing status of the brain tumor therapy enhanced by nanoparticle based delivery with the aid of dual-targeting strategies. The future perspectives in this regard have also been highlighted.

PH-Responsive Liposomes of Dioleoyl Phosphatidylethanolamine and Cholesteryl Hemisuccinate for the Enhanced Anticancer Efficacy of Cisplatin.

The current study aimed to develop pH-responsive cisplatin-loaded liposomes (CDDP@PLs) via the thin film hydration method. Formulations with varied ratios of dioleoyl phosphatidylethanolamine (DOPE) to cholesteryl hemisuccinate (CHEMS) were investigated to obtain the optimal particle size, zeta potential, entrapment efficiency, in vitro release profile, and stability. The particle size of the CDDP@PLs was in the range of 153.2 ± 3.08–206.4 ± 2.26 nm, zeta potential was −17.8 ± 1.26 to −24.6 ± 1.72, and PDI displayed an acceptable size distribution. Transmission electron microscopy revealed a spherical shape with ~200 nm size. Fourier transform infrared spectroscopic analysis showed the physicochemical stability of CDDP@PLs, and differential scanning calorimetry analysis showed the loss of the crystalline nature of cisplatin in liposomes. In vitro release study of CDDP@PLs at pH 7.4 depicted the lower release rate of cisplatin (less than 40%), and at a pH of 6.5, an almost 65% release rate was achieved compared to the release rate at pH 5.5 (more than 80%) showing the tumor-specific drug release. The cytotoxicity study showed the improved cytotoxicity of CDDP@PLs compared to cisplatin solution in MDA-MB-231 and SK-OV-3 cell lines, and fluorescence microscopy also showed enhanced cellular internalization. The acute toxicity study showed the safety and biocompatibility of the developed carrier system for the potential delivery of chemotherapeutic agents. These studies suggest that CDDP@PLs could be utilized as an efficient delivery system for the enhancement of therapeutic efficacy and to minimize the side effects of chemotherapy by releasing cisplatin at the tumor site.

A sequential multistage-targeted nanoparticles for MR imaging and efficient chemo/chemodynamic synergistic therapy of liver cancer

The reasonable combination of chemotherapy and chemodynamic therapy has great potential in the treatment of cancer. In this study, a novel multifunctional nanoparticle (CDTLG NPs) with tumor tissue-cell-mitochondria-targeted, tumor-specific drug release and endogenous reactive oxygen species generation are developed for magnetic resonance imaging-guided liver cancer synergistic chemo/chemodynamic therapy. The CDTLG NPs are constructed via self-assembled of glutathione/pH-responsive prodrug, organic chemodynamic therapy agents, and magnetic resonance imaging contrast agents. Through passive targeted, the nanosized CDTLG NPs can accumulate in tumor tissue. After accumulating in hepatoma cells by active targeting, the CDTLG NPs could be destroyed under acidic and reductive intracellular environment to quickly release chemotherapy drugs doxorubicin, camptothecin, and organic chemodynamic therapy agents. Subsequently, due to mitochondrial targeting, organic chemotherapeutic drugs accumulate in the mitochondria of hepatoma cells and generate a large number of reactive oxygen species. The burst of endogenous reactive oxygen species and chemotherapy drugs release achieved synergistic chemo/chemodynamic therapy, which led to more severe cell death than monotherapies. Furthermore, the CDTLG NPs present outstanding in vivo antitumor ability without causing obvious in vivo toxicity. Thus, the study provides an intriguing strategy to chemo/chemodynamic combination therapy-based nanoparticles for enhancing antitumor efficacy.

Singlet Oxygen-Responsive Polymeric Nanomedicine for Light-Controlled Drug Release and Image-Guided Photodynamic-Chemo Combination Therapy.

Coencapsulation of chemotherapeutic agents and photosensitizers into nanocarriers can help to achieve a combination of chemotherapy and photodynamic therapy for superior antitumor effects. However, precise on-demand drug release remains a major challenge. In addition, the loaded photosensitizers usually tend to aggregate, which can significantly weaken their fluorescent signals and photodynamic activities. To address these issues, herein, a smart nanocarrier termed as singlet oxygen-responsive nanoparticle (SOR-NP) was constructed by introducing singlet oxygen (1O2)-sensitive aminoacrylate linkers into amphiphilic mPEG-b-PCL copolymers. Boron dipyrromethene (BDP) and paclitaxel (PTX) as model therapeutic agents were coloaded into an 1O2-responsive nanocarrier for realizing light-controlled drug release and combination cancer treatment. This polymeric nanocarrier could substantially relieve the aggregation of encapsulated BDP due to the presence of a long hydrophobic chain. Therefore, the formed SOR-NPBDP/PTX nanodrug could generate bright fluorescent signals and high levels of 1O2, which could mediate cell death via PDT and rupture aminoacrylate linker simultaneously, leading to collapse of SOR-NPBDP/PTX and subsequent PTX release. The light-triggered drug release and combined anticancer effects of SOR-NPBDP/PTX were validated in HepG2 and MCF-7 cancer cells and H22 tumor-bearing mice. This study provides a promising strategy for tumor-specific drug release and selective photodynamic-chemo combination treatment.

Probing the Superiority of Diselenium Bond on Docetaxel Dimeric Prodrug Nanoassemblies: Small Roles Taking Big Responsibilities.

The current state of chemotherapy is far from satisfaction, restricted by the inefficient drug delivery and the off-target toxicity. Prodrug nanoassemblies are emerging as efficient platforms for chemotherapy. Herein, three docetaxel dimeric prodrugs are designed using diselenide bond, disulfide bond, or dicarbide bond as linkages. Interestingly, diselenide bond-bridged dimeric prodrug can self-assemble into stable nanoparticles with impressive high drug loading (≈70%, w/w). Compared with disulfide bond and dicarbide bond, diselenide bond greatly facilitates the self-assembly of dimeric prodrug, and then improves the colloidal stability, blood circulation time, and antitumor efficacy of prodrug nanoassemblies. Furthermore, the redox-sensitive diselenide bond can specifically respond to the overexpressed reactive oxygen species and glutathione in tumor cells, leading to tumor-specific drug release. Therefore, diselenide bond bridged prodrug nanoassemblies exhibit discriminating cytotoxicity between tumor cells and normal cells, significantly alleviating the systemic toxicity of docetaxel. The present work gains in-depth insight into the impact of diselenide bond on the dimeric prodrug nanoassemblies, and provides promising strategies for the rational design of the high efficiency-low toxicity chemotherapeutical nanomedicines.

Tumor-specific fluorescent Cdots-based nanotheranostics by acid-labile conjugation of doxorubicin onto reduction-cleavable Cdots-based nanoclusters.

Carbon quantum dots (Cdots) have attracted more and more interests in bioimaging and tumor theranostics. However, their practical application has been limited due to the small particle size and non-tumor-specific fluorescence. Here, reduction-cleavable disulfide-linked Cdots-based nanoclusters were fabricated to conjugate doxorubicin (DOX) via an acid-labile hydrazone bond. Owing to the pH and reduction dual-stimuli responsiveness, the proposed Cdots-based nanotheranostics possessed unique tumor-specific fluorescent property and tumor-specific controlled drug release performance, indicating their promising potential for the in-situ real-time fluorescent monitoring of therapeutic response in future tumor therapy.

A pH-Responsive Charge-Reversal Drug Delivery System with Tumor-Specific Drug Release and ROS Generation for Cancer Therapy.

IntroductionPoor cell uptake and incomplete intracellular drug release are the two major challenges for polymeric prodrug-based drug delivery systems (PPDDSs) in cancer treatment.MethodsHerein, a PPDDS with pH-induced surface charge-reversal and reactive oxygen species (ROS) amplification for ROS-triggered self-accelerating drug release was developed, which was formed by encapsulating a ROS generation agent (vitamin K3 (VK3)) in pH/ROS dual-sensitive polymetric prodrug (PEG-b-P(LL-g-TK-PTX)-(LL-g-DMA)) based micelle nanoparticles (denoted as PVD-NPs).ResultsThe surface charge of the PVD-NPs can change from negative to positive for enhanced cell uptake in response to tumor extracellular acidity pH. After internalization by cancer cells, PVD-NPs demonstrate dual drug release in response to intracellular ROS-rich conditions. In addition, the released VK3 can produce ROS under the catalysis by NAD(P)H:quinone oxidoreductase-1, which facilitates tumor-specific ROS amplification and drug release selectively in cancer cells to enhance chemotherapy.ConclusionBoth in vitro and in vivo experiments demonstrated that the PVD-NPs showed significant antitumor activity in human prostate cancer.

Research progress on triptolide functionalized nanoparticulate drug delivery systems for tumor treatment

Nowadays,the advantages of traditional Chinese medicine(TCM) for treatment of tumors are increasingly prominent.Triptolide shows wide-spectrum and highly effective anti-tumor activity. Moreover,nano-carrier-based triptolide drug delivery system is more powerful in improving water solubility and pharmacokinetic behavior of the drug,but it is easy to cause toxic and side effects that should not be neglected on human body. Because of tumor vascular heterogeneity and PEGylation dilemma,nanoparticulate drug delivery systems need to overcome multiple physiological and pathological barriers from drug administration to functioning. It is difficult for traditional triptolide nanoparticulate drug delivery systems to achieve active accumulation of nano-drug in tumor tissues and specific drug release in tumor target site solely relying on enhanced permeability and retention effect of solid tumor,limiting their application and clinical transformation in treatment of tumors. Based on the traditional nano-preparation system,the new functionalized nano-drug delivery system further enhances the nano-drug enrichment,penetration and controlled release at the tumor sites,which is of great significance in improving bioavailability,anti-tumor efficacy and reducing the side effects of drugs. In this paper,we summarized and analyzed the researches on new triptolide functionalized nano-drug delivery system from four perspectives,including tumor active targeting,tumor microenvironment response,polymer-drug conjugates,and multidrug co-delivery for tumor treatment,expecting to provide ideas for in-depth research and clinical application of triptolide and some other active anti-tumor TCM ingredients.

NIR-Triggered Multifunctional and Degradable Nanoplatform Based on an ROS-Sensitive Block Copolymer for Imaging-Guided Chemo-Phototherapy.

Imaging-guided chemo-phototherapy based on multifunctional nanocarriers has emerged as a promising and high-efficient cancer treatment because of the inevitable limitations of single therapy. Herein, a near-infrared (NIR) light-activated degradable polymeric nanoplatform was fabricated for chemo-phototherapy. An NIR photosensitizer, IR780, and a chemotherapeutic drug, doxorubicin (DOX), were efficiently coloaded within a reactive oxygen species (ROS)-sensitive polymeric micelle based on an amphiphilic copolymer with degradable thioketal (TK) linkages. The obtained spherical nanoparticles (denoted as (IR780/DOX)@PTK) exhibited a notable photodynamic and photothermal effect upon NIR light exposure. Furthermore, due to the rapid cleavage of TK linkers induced by ROS generated from NIR-activated IR780, (IR780/DOX)@PTK also showed an NIR light-induced degradable feature, which can be used for light-triggered tumor-specific drug release and lead to ignorable systematic toxicity after biodegradation and drug delivery. Under the guidance of NIR fluorescence and photothermal dual modal imaging, (IR780/DOX)@PTK exhibited excellent tumor accumulation after intravenously injection into 4T1-tumor-bearing mice. As verified in both in vitro and in vivo study, (IR780/DOX)@PTK presented a significant tumor suppression effect by synergistic chemo-phototherapy.

Reactive oxygen species-responsive amino acid-based polymeric nanovehicles for tumor-selective anticancer drug delivery.

Stimuli-triggered drug delivery systems have been recognized as a crucial strategy to achieve on-demand drug release at the tumor for improving therapeutic efficacy. In this work, novel biocompatible and biodegradable reactive oxygen species (ROS)-responsive amino acid- based polymeric micelles were developed for tumor-specific drug release triggered by high ROS levels in cancer cells, which were composed of amphiphilic poly(aspartic acid) (PASP) derivatives (PASP-BSer) with phenylborate serine (BSer) side groups as the ROS-responsive unit. A series of PASP-BSer conjugates with different degree of substitution (DS) were synthesized, and their self-assembly and H2O2-responsive behaviors were investigated to optimize the structure of PASP-BSer. In vitro drug loading and release studies confirmed that the optimized PASP-BSer micelles could effectively encapsulate the model anticancer drug doxorubicin (Dox) and exhibit desirable H2O2-triggered release behaviors. More importantly, Dox-loaded PASP-BSer micelles showed high selective cytotoxicity against A549 cancer cells than L929 normal cells. Accordingly, PASP-BSer micelles have significant potential as on-demand drug carriers for anticancer therapy.

Abstract B040: Electrospun implantable anticancer device comprising immune adjuvant photo-responsive nanoparticles with checkpoint blockade for effective cancer therapy

Abstract An implantable anticancer device (IAD) that can eradicate local regional breast cancer recurrence (LRR), inhibit metastasis as well as to enhance the breast reconstruction during/after therapy is proposed. The IAD is developed by combining nanofiber-based chemo-photothermal therapy platform with check point blockade immunotherapy. Here we developed a coreshell electrospun nanofiber encapsulated with drug conjugated MoS2 as chemo-photothermal agent along with imiquimod as an immune response modifier. The near-infrared laser exposure to IADs can generate tumor-associated antigens from primary tumors, which in the presence of released imiquimod from IADs can show vaccine-like functions. Moreover, the nanofiber matrix will enable the sustained and tumor-specific anticancer drug release with a minimum initial burst release and the repeated photothermal capability to ensure the synergistic inhibition of tumor recurrence. In addition to that, the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4) in combination with the generated immunologic responses will be able to attack remaining tumor cells causing metastasis inhibition with strong immunologic memory effect, which can shield against the tumor recurrence after the post elimination of initial tumors. The IAD nanofiber morphology resembles the extra cellular matrix (ECM) enrich the reconstruction of poor breast cosmesis resulted from the surgical treatment, by supporting the lipofilling of the surgical residual cavity to induce the adipogenic process. So, in this work we propose that the tumor associated antigens created in situ after photothermal therapy by the immune adjuvant nanofiber IAD could show vaccine-like functions, which in combination with checkpoint blockade show strong antitumor immune responses for effective cancer immunotherapy as a potential platform for synergistic inhibition of LRR and a great promise for the in situ breast reconstruction ability for better breast cosmesis. Citation Format: Afeesh Rajan Unnithan, Arathyram Ramachandra Kururp Sasikala, Chan Hee Park, Cheol Sang Kim. Electrospun implantable anticancer device comprising immune adjuvant photo-responsive nanoparticles with checkpoint blockade for effective cancer therapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B040.

Chemotherapy of Breast Cancer Cells Using Novel pH-Responsive Cellulose-Based Nanocomposites.

Purpose: The objective of the current study was to compare the anticancer efficacy of doxorubicin-loaded cellulose based magnetic (Fe3O4), zinc oxide (ZnO) nanoparticles on and free doxorubicin (DOX) on MCF-7 breast cancer cells. Methods: Novel pH-sensitive cellulose-graft poly acrylic acid based Fe3O4 (Cellulose-g-PAAg- PAcMNPs) and ZnO (Cellulose-g-PAA-g-PAcZnO) nanocomposites were synthesized via polymerization of acrylic acid and modified 3-(trimethoxysilyl) propyl methacrylate onto the cellulosic backbone via reversible addition-fragmentation chain transfer (RAFT) method. Results: Cellulose-g-PAA-g-PAcMNPs and Cellulose-g-PAA-g-PAcZnO nanocarriers with mean diameter of 15 and 38 nm were prepared successfully. DOX was loaded effectively to the ZnO and Fe3O4 nanocarriers via complexing and electrostatic force with great encapsulation efficiency of 99.07% and 98.92%, respectively. DOX-loaded nanocarriers showed obvious pHdependent tumor specific drug release pattern. MTT assay results indicated that IC50 of the DOX loaded Cellulose-g-PAA-g-PAcZnO, DOX loaded Cellulose-g-PAA-g-PAcMNPs and free DOX after 48 hours treatment with MCF7 cell lines were about 24.03, 49.27 and 99.76 μg mL−1, respectively. Therefore both DOX nanoformulations significantly increase antitumor ability compared to free DOX (P < 0.05). The results of MTT assay and DAPI staining revealed that DOX-loaded Cellulose-g-PAA-g-PAcZnO NPs show higher chemotherapy efficiency in MCF7 breast cancer cell line compare to the DOX-loaded Cellulose-g-PAA-g-PAcMNPs due to high interaction of ZnO with DOX. Conclusion: The formation of the complexes between the DOX and ZnO nanoparticles at the chelating sites of the quinone and the phenolic oxygen molecules of DOX, lead to more sustained drug release and enhanced chemotherapy effectiveness by increasing the intracellular concentration of DOX.