Peptide-modified Nanoparticles Research Articles

Co-delivery of protopanaxatriol/icariin into niche cells restores bone marrow niches to rejuvenate HSCs for chemotherapy-induced myelosuppression

BackgroundUp to 80 % of chemotherapeutic drugs induce myelosuppression in patients. Chemotherapy not only impairs of hematopoietic stem cells (HSCs) but also damages bone marrow niches (vascular and endosteal). Current treatments for myelosuppression overlook these chemotherapy-induced damages to bone marrow niches and the critical role of niche restoration on hematopoietic regeneration. Ginsenoside protopanaxatriol (PPT) protects vascular endothelium from injury, while icariin (ICA) promotes osteogenic differentiation. The combination of PPT and ICA aims to restore damaged vascular and endosteal niches, thus rejuvenating HSCs for treating myelosuppression. PurposeThis study aims to develop effective, bone marrow niche-directed PPT/ICA therapies for treating chemotherapy-induced myelosuppression. Methods3D cell spheroids were used to investigate the effects of PPT/ICA on cell-cell interactions in vascular niches, osteogenesis, and extracellular matrix (ECM) secretion in endosteal niches. In vitro mimic niche models were designed to access the drug combination's efficacy in rejuvenating and mobilizing in HSCs within bone marrow niches. The delivery capability of PPT/ICA to key niche cell types (mesenchymal stromal cells (MSCs), endothelial cells (ECs), and osteoblasts (OBs)) via nanocarriers has been determined. DSS6 peptide-modified nanoparticles (DSS6-NPs) were prepared for specific co-delivery of PPT/ICA into key niche cell populations in vivo. ResultsPPT can prevent vascular niche injury by restoring vascular EC cell-cell adhesion and the intercellular interactions between ECs and MSCs in 5-fluorouracil (5-FU)-damaged cell spheroids. ICA repaired 5-FU-damaged endosteal niches by promoting osteogenesis and ECM secretion. The combination of PPT and ICA restores key HSC niche factor gene expressions, normalizing HSC differentiation and mobilization. The in vitro cellular uptake efficiency of nanocarriers in a mimic niche is positively correlated with their in vivo delivery into bone marrow niche cells. DSS6-NPs greatly enhance the delivery of PPT/ICA into MSCs and OBs within bone marrow niches. Co-loading of PPT/ICA into DSS6-NPs effectively repairs damaged bone marrow niches and promotes HSC rejuvenation in vivo. ConclusionThe combination of PPT and ICA effectively prevents injury to the vascular and endosteal niches, thereby promoting hematopoietic regeneration in the bone marrow. This study provides novel niche-directed PPT/ICA therapies for managing chemotherapy-induced myelosuppression.

Hybrid cell membranes camouflaged copper-loaded nano-prodrug for tumor angiogenesis inhibition and cell cuproptosis

The establishment of hybrid cell membrane-camouflaged nanotherapeutics is crucial to preserve and impart their biological functionality inherited from the source cells. In this study, one side relies on the intrinsic affinity between the intracellular domain of Band 3 in the red blood cells membrane (Rm) and P4.2 peptide-modified nanoparticles (Rm-Que/Cu), promoting the self-assembly coupling-driven encapsulation of Rm on the surface of nanodrugs. On the other side, it involves integrating the bioengineered cell membrane with high Del-1 expression (Dm) with Rm-Que/Cu to form RDm-Que/Cu, targeting the role of integrin αvβ3 on tumor neovascularization and endothelial cells (ECs). This approach simultaneously integrates the multi-functions, including self-assembly encapsulation, targeted drug delivery, and on-demand drug release. Both in vitro and in vivo experimental results confirmed that RDm-Que/Cu were able to disrupt the cellular copper homeostasis, inhibit tumor angiogenesis, and induce cuproptosis. This discovery provides a feasible platform for the biomedical application of hybrid cell membrane-camouflaged biomimetic nanotechnology.

Role of Functionalized Peptides in Nanomedicine for Effective Cancer Therapy.

Peptide-functionalized nanomedicine, which addresses the challenges of specificity and efficacy in drug delivery, is emerging as a pivotal approach for cancer therapy. Globally, cancer remains a leading cause of mortality, and conventional treatments, such as chemotherapy, often lack precision and cause adverse effects. The integration of peptides into nanomedicine offers a promising solution for enhancing the targeting and delivery of therapeutic agents. This review focuses on the three primary applications of peptides: cancer cell-targeting ligands, building blocks for self-assembling nanostructures, and elements of stimuli-responsive systems. Nanoparticles modified with peptides improved targeting of cancer cells, minimized damage to healthy tissues, and optimized drug delivery. The versatility of self-assembled peptide structures makes them an innovative vehicle for drug delivery by leveraging their biocompatibility and diverse nanoarchitectures. In particular, the mechanism of cell death induced by self-assembled structures offers a novel approach to cancer therapy. In addition, peptides in stimuli-responsive systems enable precise drug release in response to specific conditions in the tumor microenvironment. The use of peptides in nanomedicine not only augments the efficacy and safety of cancer treatments but also suggests new research directions. In this review, we introduce systems and functionalization methods using peptides or peptide-modified nanoparticles to overcome challenges in the treatment of specific cancers, including breast cancer, lung cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, skin cancer, glioma, osteosarcoma, and cervical cancer.

Albumin Nanoparticles Surface Decorated with a Tumor-Homing Peptide Help in Selective Killing of Triple-Negative Breast Cancer Cells.

In this article, we describe a method of delivery of doxorubicin using a novel tumor-homing peptide-based albumin nanoparticle system to triple-negative breast cancer cells (TNBC). The absence and reduced expression of the hormone (estrogen, progesterone) and HER2 (human epidermal growth factor 2) receptors, respectively, render TNBC patients nonsusceptible to different available targeted therapies. These peptide-modified nanoparticles could be taken up by TNBC cells more effectively than their bare counterparts. The drug-loaded peptide-modified nanoparticles achieved an optimal but crucial balance between cell killing in cancerous cells and cell survival in the noncancerous ones. This appears to be because of different routes of entry and subsequent fate of the bare and peptide-modified nanoparticles in cancerous and noncancerous cells. In a TNBC mouse model, the peptide-modified system fared better than the free drug in mounting an antitumor response while not being toxic systemically.

Light-activated arginine-rich peptide-modified nanoparticles for deep-penetrating chemo-photo-immunotherapy of solid tumor

Light-activated arginine-rich peptide-modified nanoparticles for deep-penetrating chemo-photo-immunotherapy of solid tumor

The trajectory patterns of single HIV-1 virus-like particle in live CD4 cells: A real time three-dimensional multi-resolution microscopy study using encapsulated nonblinking giant quantum dot.

The exploration of virology knowledge was limited by the optical technology for the observation of virus. Previously, a three-dimensional multi-resolution real-time microscope system (3D-MRM) was developed to observe the uptake of HIV-1-tat peptide-modified nanoparticles in cell membrane. In this study, we labeled HIV-1 virus-like particles (VLPs) with passivated giant quantum dots (gQDs) and recorded their interactive trajectories with human Jurkat CD4 cells through 3D-MRM. The labeled of gQDs of the HIV-1 VLPs in sucrose-gradient purified viral lysates was first confirmed by Cryo-electronic microscopy and Western blot assay. After the infection with CD4 cells, the gQD-labeled VLPs were visualized and their extracellular and intracellular trajectories were recorded by 3D-MRM. A total of 208 prime trajectories was identified and classified into three distinct patterns: cell-free random diffusion pattern, directional movement pattern and cell-associated movement pattern, with distributions and mean durations were 72.6%/87.6s, 9.1%/402.7sand 18.3%/68.7s, respectively. Further analysis of the spatial-temporal relationship between VLP trajectories and CD4 cells revealed the three stages of interactions: (1) cell-associated (extracellular) diffusion stage, (2) cell membrane surfing stage and (3) intracellular directional movement stage. A complete trajectory of HIV-1 VLP interacting with CD4 cells was presented in animation. This encapsulating method could increase the accuracy for the observation of HIV-1-CD4 cell interaction in real time and three dimensions.

Spontaneously Right-Side-Out-Orientated Coupling-Driven ROS-Sensitive Nanoparticles on Cell Membrane Inner Leaflet for Efficient Renovation in Vascular Endothelial Injury.

Biomimetic cell membrane camouflaged technology has drawn extensive attention as a feasible and efficient way to realize the biological functions of nanoparticles from the parent cells. As the burgeoning nanotherapeutic, the right-side-out orientation self-assembly and pathological dependent "on-demand" cargo release of cell membrane camouflaged nanocarriers remarkably limit further development for practical applications. In the present study, a spontaneously right-side-out-orientated coupling-driven ROS-sensitive nanotherapeutic has been constructed for target endothelial cells (ECs) repair through the synergistic effects of spontaneously right-side-out-orientated camouflaging. This condition results from the specific affinity between the intracellular domain of key transmembrane receptors band 3 on cell membrane inner leaflet and the corresponding P4.2 peptide-modified nanoparticles without the additional coextrusion. The "on-demand" cargo release results from the pathological ROS-cleavable prodrug. Particularly, the red blood cell camouflaged nanotherapeutics (RBC-LVTNPs) can enhance target drug delivery through low oscillatory shear stress (LSS) blood flow in the injured ECs lesion. Both in vitro and in vivo results collectively confirm that RBC-LVTNPs can restore the damaged ECs and function with the recovered vascular permeability and low inflammation microenvironment. The findings provide a powerful and universal approach for developing the biomimetic cell membrane camouflaged nanotechnology.

Recent Trends in Nanomedicine-Based Strategies to Overcome Multidrug Resistance in Tumors.

Simple SummaryCancer chemotherapy results in poor treatment response due to increased tumor resistance. There is a need to develop novel nanoparticle-based strategies to overcome resistance and improve therapeutic response. Nanomedicine-based strategies include the nanoparticle-/liposome-based delivery of drugs and siRNA to downregulate the genes causing resistance and the use of natural substances such as chemosensitizers to improve response to therapy.Cancer is the leading cause of economic and health burden worldwide. The commonly used approaches for the treatment of cancer are chemotherapy, radiotherapy, and surgery. Chemotherapy frequently results in undesirable side effects, and cancer cells may develop resistance. Combating drug resistance is a challenging task in cancer treatment. Drug resistance may be intrinsic or acquired and can be due to genetic factors, growth factors, the increased efflux of drugs, DNA repair, and the metabolism of xenobiotics. The strategies used to combat drug resistance include the nanomedicine-based targeted delivery of drugs and genes using different nanocarriers such as gold nanoparticles, peptide-modified nanoparticles, as well as biomimetic and responsive nanoparticles that help to deliver payload at targeted tumor sites and overcome resistance. Gene therapy in combination with chemotherapy aids in this respect. siRNA and miRNA alone or in combination with chemotherapy improve therapeutic response in tumor cells. Some natural substances, such as curcumin, quercetin, tocotrienol, parthenolide, naringin, and cyclosporin-A are also helpful in combating the drug resistance of cancer cells. This manuscript summarizes the mechanism of drug resistance and nanoparticle-based strategies used to combat it.

Retro-inversion follicle-stimulating hormone peptide-modified nanoparticles for delivery of PDK2 shRNA against chemoresistant ovarian cancer by switching glycolysis to oxidative phosphorylation

BackgroundMost ovarian cancers are diagnosed at advanced stages characterized by abdominal dissemination and frequently exhibit chemoresistance. Pyruvate dehydrogenase kinase 2 (PDK2) regulates the switch between glycolysis and oxidative phosphorylation and contributes to tumor progression and chemoresistance. Here, we investigated the effects of PDK2 blockade on metabolic reprogramming and cisplatin sensitivity and evaluated the in vivo antitumor effects of PDK2 shRNA in chemoresistant ovarian cancer using retro-inverso follicle-stimulating hormone peptide-modified nanoparticle as carriers.MethodsThe expression of PDK2 was detected by immunohistochemistry, Western blot and real-time PCR. Cell proliferation and apoptosis were detected using CCK-8 and flow cytometry. Cell migration was detected by Transwell assay. Seahorse Analyzer was used to evaluate metabolic changes. The cisplatin-resistant ovarian cancer cells A2780cp were used to establish the mouse model of peritoneal metastatic ovarian cancer.ResultsA higher expression level of PDK2 was observed in chemoresistant ovarian cancer tissues and cell lines and was associated with shorter progression-free survival. PDK2 knockdown inhibited proliferation and migration and promoted apoptosis of both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. Cisplatin sensitivity was increased even in cisplatin-resistant ovarian cancer cells. Mechanistically, PDK2 knockdown resulted in an increased oxygen consumption rate and decreased extracellular acidification rate, along with reduced lactate production, increased PDHC activity and increased levels of electron transport chain complexes III and V. The metabolism switched from glycolysis to oxidative phosphorylation. Finally, to specifically and effectively deliver PDK2 shRNA in vivo, we formulated a targeted delivery system containing retro-inverso follicle-stimulating hormone peptide as a targeting moiety and polyethylene glycol–polyethylenimine copolymers as carriers. The nanoparticle complex significantly suppressed tumor growth and peritoneal metastasis of cisplatin-resistant ovarian cancer without obvious toxicities.ConclusionsOur findings showed the link between metabolic reprogramming and chemoresistance in ovarian cancer and provided an effective targeting strategy for switching metabolic pathways in cancer therapy.

Use of peptide-modified nanoparticles as a bacterial cell targeting agent for enhanced antibacterial activity and other biomedical applications

Bacterial pathogens have posed a serious threat to human health because they are difficult to be eliminated inside cells. Here, an effective design of poly(lactic-co-glycolic) (PLGA) nanoparticles (NPs) modified with antimicrobial peptides and loaded with gentamicin (Gen) was reported with enhanced antibacterial activity and cellular internalization ability. The results showed that the drug loading capacity and encapsulation efficiency of OVTp12-modified NPs were 7.55 % and 81.3 %, respectively. We observed that OVTp12 and OVTp12-modified NPs significantly increased the interaction with Staphylococcus aureus cells. Moreover, OVTp12-modified NPs showed an effective inhibitory effect on S. aureus with low cytotoxicity. The results of cell internalization indicated that OVTp12-modified NPs were markedly higher than that of unmodified nanoparticles when incubated with MC3T3-E1 cells. In conclusion, the bacterial cell-targeting ability of this antimicrobial peptide provides advantages for the treatment of intracellular bacterial infections.

Hepatotropic Peptides Grafted onto Maleimide-Decorated Nanoparticles: Preparation, Characterization and In Vitro Uptake by Human HepaRG Hepatoma Cells.

We recently demonstrated the strong tropism of George Baker (GB) Virus A (GBVA10-9) and Plasmodium circumsporozoite protein (CPB) derived synthetic peptides towards hepatoma cells. In a first approach, these peptides were covalently bound to poly(benzyl malate) (PMLABe73) and poly(ethylene glycol)-block-PMLABe73 (PEG62-b-PMLABe73) (co)polymers, and corresponding peptide-decorated nanoparticles (NPs) were prepared by nanoprecipitation. We showed that peptide enhanced NPs internalization by hepatoma cells. In the present work, we set up a second strategy to functionalize NPs prepared from PMLABe73 derivates. First, maleimide-functionalized PMLABe73 (Mal-PMLABe73) and PEG62-b-PMLABe73 (Mal-PEG62-b-PMLABe73) were synthesized and corresponding NPs were prepared by nanoprecipitation. Then, peptides (GBVA10-9, CPB and their scramble controls GBVA10-9scr and CPBscr) with a thiol group were engrafted onto the NPs’ maleimide groups using the Michael addition to obtain peptide functionalized NPs by post-formulation procedure. These peptide-modified NPs varied in diameter and dispersity depending on the considered peptides and/or (co)polymers but kept their spherical shape. The peptide-functionalized NPs were more efficiently internalized by HepaRG hepatoma cells than native and maleimide-NPs with various levels relying on the peptide’s nature and the presence of PEG. We also observed important differences in internalization of NPs functionalized by the maleimide-thiol-peptide reaction compared to that of NPs prepared from peptide-functionalized PMLABe73 derivatives.

Peptide-Modified Nanoparticles for Tumor Targeting and Molecular Imaging.

Nanoparticles hold great promise in tumor targeting and molecular imaging because they can co-deliver therapeutic drugs and imaging agents to the tumor site with a single entity. Nanoparticles modified with ligands against moieties overexpressed on tumor tissues have gained increasing attention due to their active targeting mechanisms. Peptides are well suited for nanoparticle targeting modifications because they are small, easy to synthesize and typically non-immunogenic. Herein, we review the peptide-modified nanoparticles used for tumor targeting therapy and molecular imaging based on the classification of peptide-targeting ligands. The development of targeting peptides and nanoparticles will also be discussed.

Pharmacokinetic Analysis of Peptide-Modified Nanoparticles with Engineered Physicochemical Properties in a Mouse Model of Traumatic Brain Injury

Peptides are used to control the pharmacokinetic profiles of nanoparticles due to their ability to influence tissue accumulation and cellular interactions. However, beyond the study of specific peptides, there is a lack of understanding of how peptide physicochemical properties affect nanoparticle pharmacokinetics, particularly in the context of traumatic brain injury (TBI). We engineered nanoparticle surfaces with peptides that possess a range of physicochemical properties and evaluated their distribution after two routes of administration: direct injection into a healthy mouse brain and systemic delivery in a mouse model of TBI. In both administration routes, we found that peptide-modified nanoparticle pharmacokinetics were influenced by the charge characteristics of the peptide. When peptide-modified nanoparticles are delivered directly into the brain, nanoparticles modified with positively charged peptides displayed restricted distribution from the injection site compared to nanoparticles modified with neutral, zwitterionic, or negatively charged peptides. After intravenous administration in a TBI mouse model, positively charged peptide-modified nanoparticles accumulated more in off-target organs, including the heart, lung, and kidneys, than zwitterionic, neutral, or negatively charged peptide-modified nanoparticles. The increase in off-target organ accumulation of positively charged peptide-modified nanoparticles was concomitant with a relative decrease in accumulation in the injured brain compared to zwitterionic, neutral, or negatively charged peptide-modified nanoparticles. Understanding how nanoparticle pharmacokinetics are influenced by the physicochemical properties of peptides presented on the nanoparticle surface is relevant to the development of nanoparticle-based TBI therapeutics and broadly applicable to nanotherapeutic design, including synthetic nanoparticles and viruses.Graphical abstract

Chitosan-based nanoparticle co-delivery of docetaxel and curcumin ameliorates anti-tumor chemoimmunotherapy in lung cancer

The application of traditional chemotherapy drugs for lung cancer has obvious limitations, such as toxic side effects, uncontrolled drug-release, poor bioavailability, and drug-resistance. Thus, to address the limitations of free drugs and improve treatment effects, we developed novel T7 peptide-modified nanoparticles (T7-CMCS-BAPE, CBT) based on carboxymethyl chitosan (CMCS), which is capable of targeted binding to the transferrin receptor (TfR) expressed on lung cancer cells and precisely regulating drug-release according to the pH value and reactive oxygen species (ROS) level. The results showed that the drug-loading content of docetaxel (DTX) and curcumin (CUR) was approximately 7.82% and 6.48%, respectively. Good biosafety was obtained even when the concentration was as high as 500 μg/mL. More importantly, the T7-CMCS-BAPE-DTX/CUR (CBT-DC) complexes exhibited better in vitro and in vivo anti-tumor effects than DTX monotherapy and other nanocarriers loaded with DTX and CUR alone. Furthermore, we determined that CBT-DC can ameliorate the immunosuppressive micro-environment to promote the inhibition of tumor growth. Collectively, the current findings help lay the foundation for combinatorial lung cancer treatment.

Interactions of Cell-Penetrating Peptide-Modified Nanoparticles with Cells Evaluated Using Single Particle Tracking.

Cell-penetrating peptides (CPPs) are known to interact with cell membranes and by doing so enhance cellular interaction and subsequent cellular internalization of nanoparticles. Yet, the early events of membrane interactions are still not elucidated, which is the aim of the present work. Surface conjugation of polymeric nanoparticles with cationic CPPs of different architecture (short, long linear, and branched) influences the surface properties, especially the charge of the nanoparticles, and therefore provides the possibility of increased electrostatic interactions between nanoparticles with the cell membrane. In this study, the physicochemical properties of CPP-tagged poly(lactic-co-glycolic acid) (PLGA) nanoparticles were characterized, and nanoparticle-cell interactions were investigated in HeLa cells. With the commonly applied methods of flow cytometry as well as confocal laser scanning microscopy, low and similar levels of nanoparticle association were detected for the PLGA and CPP-tagged PLGA nanoparticles with the cell membrane. However, single particle tracking of CPP-tagged PLGA nanoparticles allowed direct observation of the interactions of individual nanoparticles with cells and consequently elucidated the impact that the CPP architecture on the nanoparticle surface can have. Interestingly, the results revealed that nanoparticles with the branched CPP architecture on the surface displayed decreased diffusion modes likely due to increased interactions with the cell membrane when compared to the other nanoparticles investigated. It is anticipated that single particle approaches like the one used here can be widely employed to reveal currently unresolved characteristics of nanoparticle-cell interaction and aid in the design of improved surface-modified nanoparticles for efficient delivery of therapeutics.

A bolt-like-blocking nanovalve on mesoporous silica nanoparticles for controlled release

A novel bolt-like-blocking nanovalve based on mesoporous silica nanoparticles (MSNs) has developed as a drug carrier, using the modified short peptide as a support and the delivery drug as a bridge for fulfilling the blocking process. The peptide-modified nanoparticle MSN-S-S-NAC-Trp combined with the loaded drug can be used as a carrier with no leakage and be triggered for release by appropriate GSH. The peptide-modified nanoparticles have showed no obvious cytotoxicity and can be internalized into L929 cells; moreover, the doxorubicin loaded nanoparticles incubated with HeLa cells have showed GSH-responsive capability and induced cell apoptosis. Since the chain of the modified peptide on the surface of MSN is not long enough to block the channel via self-assembly process, a bolt-like-blocking model is proposed.

Dual Peptide-Modified Nanoparticles Improve Combination Chemotherapy of Etoposide and siPIK3CA Against Drug-Resistant Small Cell Lung Carcinoma.

Small cell lung carcinoma (SCLC) is a highly aggressive form of malignancy with rapid recurrence and poor prognosis. The dual peptide-modified nanoparticles (NPs) for improving chemotherapy against drug-resistant small cell lung carcinoma cells has been developed. In this study, the SCLC targeting ligand, antagonist G peptide (AG), and cell-penetrating peptide, TAT, modified NPs were used to encapsulate both anticancer drugs etoposide (ETP) and PIK3CA small-interfering RNA (siPIK3CA). The ETP@NPs and siRNA@NPs had particle size 201.0 ± 1.9–206.5 ± 0.7 nm and 155.3 ± 12.4–169.1 ± 11.2 nm, respectively. The lyophilized ETP@NPs and siRNA@NPs maintained their particle size and zeta potential during 28-day storage without severe aggregation or dissociation. Either ETP@NPs or siRNA@NPs significantly reduced the IC50 of drugs by 2.5–5.5 folds and 2.4–3.9 folds, respectively, as compared to free ETP and siRNA/PEI nanocomplex in drug-resistant CD133(+) H69 cells. Herein, the IC50 of dual-peptide modified ETP@NPs and siRNA@NPs were prominently lower than single-peptide modified NPs. The synergistic effect (CI < 1) was further observed in co-treatment of ETP and siPIK3CA particularly delivered by dual-peptide modified NPs.

PEG-coated nanoparticles detachable in acidic microenvironments for the tumor-directed delivery of chemo- and gene therapies for head and neck cancer.

Background: Head and neck cancer (HNC) is a major cause of morbidity and mortality and has a poor treatment outcome. Irinotecan, a topoisomerase-I inhibitor, induces cell death by decreasing the religation of double-strand DNA. However, epithelial-mesenchymal transition (EMT), therapy resistance, and systemic toxicity caused by available antineoplastic agents hinder the efficacy and safety of HNC treatment. Chemotherapy combined with gene therapy shows potential application in circumventing therapy resistance and EMT. miR-200 exerts a remarkable suppressing effect on EMT-associated genes. Herein, liposomes and solid lipid nanoparticles (SLNs) modified with a pH-sensitive, self-destructive polyethylene glycol (PEG) shell and different peptides were designed as irinotecan and miR-200 nanovectors to enhance tumor-specific accumulation. These peptides included one ligand targeting the angiogenic tumor neovasculature, one mitochondrion-directed apoptosis-inducing peptide, and one cell-penetrating peptide (CPP) with high potency and selectivity toward cancer cells.Methods: Physicochemical characterization, cytotoxicity analysis, cellular uptake, regulation mechanisms, and in vivo studies on miR-200- and irinotecan-incorporated nanoparticles were performed to identify the potential antitumor efficacy and biosafety issues involved in HNC treatment and to elucidate the underlying signaling pathways.Results: We found that the cleavable PEG layer responded to low extracellular pH, and that the CPP and targeting peptides were exposed to improve the uptake and release of miR-200 and irinotecan into HNC human tongue squamous carcinoma (SAS) cells. The apoptosis of SAS cells treated with the combinatorial therapy was significantly induced by regulating various pathways, such as the Wnt/β-catenin, MDR, and EMT pathways. The therapeutic efficacy and safety of the proposed co-treatment outperformed the commercially available Onivyde and other formulations used in a SAS tumor-bearing mouse model in this study.Conclusion: Chemotherapy and gene therapy co-treatment involving pH-sensitive and targeting peptide-modified nanoparticles may be an innovative strategy for HNC treatment.

Abstract A100: Tumor-targeted and pH-shiftable nanoparticles to encapsulate oxaliplatin and microRNA for colorectal cancer therapy

Abstract Colorectal cancer is a popular cancer type all over the world. Among various treatment regimen, oxaliplatin (Oxa) is approved in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFOX) as the first-line therapy for colorectal cancer of metastatic or advanced stage. MicroRNAs (miRs) may target genes critical for regulating tumor proliferation and invasion. Among different miRs, miR-c has been proved to induce apoptosis, inhibit proliferation and epithelial-mesenchymal transition of cancer cells. Peptide-modified nanoparticles, which are capable of increasing cellular uptake and targeting to specific receptors, are well suitable for delivering Oxa and miR. Moreover, coating pH-sensitive polymers to the outer layer of peptide-modified nanoparticles may enhance specific targeting to the acidic tumor sites. Physicochemical characterization, cellular uptake, cytotoxicity, migration assay, and western blotting studies of these nanoparticle formulations have been performed. Our results indicated that these pH-sensitive and peptide-modified nanoparticles displayed a narrow size distribution. The cellular uptake of peptide-modified nanoparticles was found to be greater than that of naked nanoparticles. Besides, the cellular uptake of pH-sensitive nanoparticles was significantly increased at pH 6.0 compared to that at pH 7.4, suggesting the successful pH-responsive property of these delivery systems. Furthermore, the combined treatment of miR-c and Oxa by peptide-modified nanoparticles increased the cytotoxicity of Oxa to colorectal cancer cells. We demonstrated that the upregulation of apoptosis pathway and the downregulation of β-catenin pathway were accounted for the efficient antitumor effect. In conclusion, the delivery of miR-c and Oxa in pH-sensitive and peptide-modified nanoparticles may provide a novel and potential strategy for colorectal cancer treatment. Citation Format: Yu-Li Lo, Y.C. Chen, C.H. Chang, W.H. Tseng, C.S. Wang. Tumor-targeted and pH-shiftable nanoparticles to encapsulate oxaliplatin and microRNA for colorectal cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A100. doi:10.1158/1535-7163.TARG-19-A100

PH-Responsive PEG-Shedding and Targeting Peptide-Modified Nanoparticles for Dual-Delivery of Irinotecan and microRNA to Enhance Tumor-Specific Therapy.

Irinotecan is one of the main chemotherapeutic agents for colorectal cancer (CRC). MicroRNA-200 (miR-200) has been reported to inhibit metastasis in cancer cells. Herein, pH-sensitive and peptide-modified liposomes and solid lipid nanoparticles (SLN) are designed for encapsulation of irinotecan and miR-200, respectively. These peptides include one cell-penetrating peptide, one ligand targeted to tumor neovasculature undergoing angiogenesis, and one mitochondria-targeting peptide. The peptide-modified nanoparticles are further coated with a pH-sensitive PEG-lipid derivative with an imine bond. These specially-designed nanoparticles exhibit pH-responsive release, internalization, and intracellular distribution in acidic pH of colon cancer HCT116 cells. These nanoparticles display low toxicity to blood and noncancerous intestinal cells. Delivery of miR-200 by SLN further increases the cytotoxicity of irinotecan-loaded liposomes against CRC cells by triggering apoptosis and suppressing RAS/β-catenin/ZEB/multiple drug resistance (MDR) pathways. Using CRC-bearing mice, the in vivo results further indicate that irinotecan and miR-200 in pH-responsive targeting nanoparticles exhibit positive therapeutic outcomes by inhibiting colorectal tumor growth and reducing systemic toxicity. Overall, successful delivery of miR and chemotherapy by multifunctional nanoparticles may modulate β-catenin/MDR/apoptosis/metastasis signaling pathways and induce programmed cancer cell death. Thus, these pH-responsive targeting nanoparticles may provide a potential regimen for effective treatment of colorectal cancer.