Non-targeted Nanoparticles Research Articles

Chondroitin sulfate-functionalized polymeric nanoparticles for colon cancer-targeted chemotherapy.

Targeted delivery of chemotherapeutic drugs to tumors is a major challenge in colon cancer chemotherapy. To overcome this bottleneck, we loaded camptothecin (CPT) into polymeric nanoparticles (NPs), and further functionalized their surface with chondroitin sulfate (CS). The resulting CS-CPT-NPs had a desirable hydrodynamic diameter (289 nm), narrow particle size distribution (polydispersity index = 0.192) and neutral surface charge. Furthermore, in vitro experiments revealed that the surface functionalization of CS endowed NPs with the capacity of colon cancer-targeted drug delivery, and significantly improved the anti-colon cancer activities and pro-apoptosis effects against colon cancer cells. Strikingly, treatment of colon tumor-bearing mice with different NPs clearly indicated that CS-CPT-NPs showed much better therapeutic outcomes than non-targeted NPs and no systemic toxicity. Taken together, these results demonstrated the promising potential of CS-CPT-NP as an effective drug delivery system for colon cancer-targeted chemotherapy.

Enhanced antiproliferative effect of resveratrol in head and neck squamous cell carcinoma using GE11 peptide conjugated liposome.

The present study describes the preparation of a dodecapeptide YHWYGYTPQNVI (GE11)-conjugated liposome bound with polyethylene glycol to enhance the therapeutic effect of resveratrol (RSV) in head and neck cancer cells. The results indicated that (RSV)-loaded GE11-conjugated liposomes (RSV-GL) exhibited a high entrapment efficiency of >95%, with an active drug loading level of 19.5% w/w. Release kinetics revealed that RSV was released in a slow and sustained manner from the RSV-GL and RSV-loaded liposome (RSV-L) nanoparticulate systems. The epidermal growth factor receptor (EGFR)-overexpressing squamous cell carcinoma HN cells specifically internalized GE11 surface-conjugated liposome in a manner that was markedly increased compared with that of the non-targeted carrier. Consistently, RSV-GL exhibited a significantly increased cytotoxic effect compared with that of the non-targeted nanoparticles. Notably, RSV-GL induced significantly increased proportions of early (~60%) and late (~10%) apoptotic cells in head and neck cancer cell populations. To the best of our knowledge, the application and development of EGFR-targeted peptide-conjugated liposome system for RSV delivery has not been studied previously in the treatment of head and neck cancer. In addition, RSV-GL exhibited the greatest antitumor efficacy compared with any other group. RSV-GL exhibited a 2-fold decrease in tumor volume compared with the free RSV and a 3-fold decrease in volume compared with the control. Overall, the nanomedicine strategy described in the present study may potentially advance the chemotherapy-based treatment of head and neck cancer, with promising applications in other EGFR-overexpressing tumors.

Effectiveness and Safety of a Nontargeted Boost for a CXCR4-Targeted Magnetic Hyperthermia Treatment of Cancer Cells

We investigate the effectiveness and safety of a novel magnetic hyperthermia (MHT) protocol, whereby a pretreatment with nontargeted magnetic nanoparticles (MNPs) is used to boost the subsequent ir...

Tri-block copolymer nanoparticles modified with folic acid for temozolomide delivery in glioblastoma.

In the present study, Folic Acid (FA) ligand was used to functionalize Temozolomide-loaded Poly (ethylene Glycol)-Poly (Butylene Adipate)-Poly (ethylene Glycol)-coated magnetite nanoparticles (TMZ-SPION-PEG-PBA-PEG) for targeted chemotherapy of glioma cells. Four types of nanoparticles were synthesized with the hydrodynamic diameters of 24-49 nm. Using MTT, Prussian blue, and ICP-OES assays, the cytotoxicity effect and cellular uptake of nanoparticles were evaluated in C6 cancer cells and OLN-93 normal cells. Moreover, in vitro anti-tumor efficacy of nanoparticles was evaluated through colony formation, quantitative real-time PCR, and flow cytometry analysis. As compared to OLN-93 cells TMZ-SPION-PEG-PBA-PEG-FA nanoparticles showed an increase in the cytotoxicity of the loaded TMZ in C6 cells within 24 and 48 h treatment (P < 0.0001), while such effect was not observed in the case of non-targeting nanoparticles. The colony formation, flow cytometry, and real-time PCR assays showed that TMZ-SPION-PEG-PBA-PEG-FA led to the enhancement of inhibitory effects to C6 cells compared to TMZ alone (P < 0.05). These results suggested that TMZ-SPION-PEG-PBA-PEG-FA could effectively slow down cell proliferation, due to the targeting effect and the high accumulation of TMZ in C6 cells via an FA-receptor mediated endocytosis. In conclusion, TMZ-loaded magnetite FA-conjugated PEG-PBA-PEG NPs could be used as a targeted drug delivery system for targeted therapy of brain glioma.

111In-Labeled Glycoprotein Nonmetastatic b (GPNMB) Targeted Gemini Surfactant-Based Nanoparticles against Melanoma: In Vitro Characterization and in Vivo Evaluation in Melanoma Mouse Xenograft Model.

Melanoma is a devastating form of skin cancer with high tendency to metastasis. This work addresses the development of new targeted nanoparticles that can be used for single-photon emission computed tomography (SPECT) imaging of melanoma. Melanoma-specific glycoprotein nonmetastatic b (GPNMB) antigen targeted and nontargeted gemini nanoparticles were prepared, characterized, and radiolabeled with 111In. 111In-labeled nanoparticles were composed of gemini surfactant grafted with monoclonal antibody Fab fragment that targeted GPNMB. Specific uptake of GPNMB-Fab was studied in six melanoma cell lines using flow cytometry. In vitro cellular uptake and internalization were studied using flow cytometry, confocal laser scanning microscopy, and radiometric techniques. Specific uptake of anti-GPNMB targeted nanoparticles was observed in GPNMB expressing cells, which was higher than low expressing or control cells. In vitro studies showed that conjugation of GPNMB targeted nanoparticles led to enhanced intracellular uptake of the nanodelivery system, which is critical for drug delivery. In vivo distribution of the nanoparticles was studied by microSPECT/CT imaging and ex vivo biodistribution. Tumor uptake was significantly higher ( p < 0.05) in nontargeted nanoparticles (5.47 ± 0.46%IA/cc) compared to GPNMB targeted nanoparticles (1.87 ± 0.27% ID/cc), which might be attributed to the high spleen uptake of the targeted formulation. These findings demonstrated that the radiolabeled gemini nanoparticles are promising for image-guided radiotherapy of melanoma. Formulation optimization is needed to improved tumor uptake and in vivo intracellular delivery for radiotherapeutic applications.

Lipid-polymer nanoparticles with CD133 aptamers for targeted delivery of all-trans retinoic acid to osteosarcoma initiating cells

Osteosarcoma, a common type of bone cancer in children, and represents an aggressive and fetal cancer worldwide. Osteosarcoma initiating cells are considered to be a subpopulation of cancer cells which contribute to the progression, recurrence, metastasis and multi-drug resistance of osteosarcoma. CD133 is considered to be one marker for osteosarcoma initiating cells. All-trans retinoic acid (ATRA), an active metabolite of vitamin A under the family retinoid, is an up-and-coming drug which was able to effectively treat various cancer initiating cells. Nevertheless, there have been no research that reported the activity of ATRA against osteosarcoma initiating cells. In this research, we hereby examined the potential activity of ATRA in osteosarcoma initiating cells, and developed lipid-polymer nanoparticles with CD133 aptamers for targeted ATRA delivery to osteosarcoma initiating cells. Using the cytotoxicity assay, colony formation assay, tumorsphere formation assay and flow cytometry, the therapeutic effect of ATRA and ATRA-loaded lipid-polymer nanoparticles conjugated with CD133 aptamers (ATRA-PLNP-CD133) against osteosarcoma initiating cells were investigated. The results showed that ATRA exerted potent activity towards osteosarcoma initiating cells. ATRA-PLNP-CD133, which showed a size of 129.9 nm and a sustained release of ATRA during 144 h, was demonstrated to efficiently and specifically promote the ATRA delivery to osteosarcoma initiating cells, and achieve superior therapeutic efficacy in osteosarcoma compared with ATRA and non-targeted nanoparticles. This is the first report of the therapeutic efficacy of ATRA towards osteosarcoma initiating cells, and the increased ATRA delivery by nanoparticles to osteosarcoma initiating cells using CD133 aptamers. ATRA-PLNP-CD133 represent an up-and coming approach for the therapy of osteosarcoma initiating cells.

Nanoparticle Binding to Urokinase Receptor on Cancer Cell Surface Triggers Nanoparticle Disintegration and Cargo Release.

Cancer cell expresses abundant surface receptors. These receptors are important targets for cancer treatment and imaging applications. Our goal here is to develop nanoparticles with cargo loading and tumor targeting capability.Methods: A peptide targeting at cancer cell surface receptor (urokinase receptor, uPAR) was expressed in fusion with albumin (diameter of ~7 nm), and the fusion protein was assembled into nanoparticles with diameter of 40 nm, either in the presence or absence of cargo molecules, by a novel preparation method. An important feature of this method is that the nanoparticles were stabilized by hydrophobic interaction of the fusion protein and no covalent linking agent was used in the preparation. The stability, the cargo release, in vitro and in vivo properties of such formed nanoparticles were characterized by transmission electron microscopy, dynamic light scattering, gel shift assay, laser scanning confocal microscopy and 3D fluorescent molecular tomography.Results: The nanoparticles were stable for more than two weeks in aqueous buffer, even in the buffer containing 10% fetal bovine serum. Interestingly, in the presence of urokinase receptor, the uPAR-targeting nanoparticle disintegrated into 7.5 nm fragments and released its cargo, but not the non-targeting nanoparticles made from albumin by the same preparation method. Such nanoparticles also showed higher uptake and cytotoxicity to the receptor-expressing cancer cells in vitro and higher tumor accumulation in xenografted tumor-bearing mice in vivo compared to the non-targeting nanoparticles.Conclusion: Our results demonstrate a new function of cell surface receptor as a responsive trigger to disassemble nanoparticles, besides its common use to enrich targeting agents. Such nanoparticles were thus named receptor-responsive nanoparticles (RRNP).

A comparative analysis of EGFR-targeting antibodies for gold nanoparticle CT imaging of lung cancer.

Computed tomography (CT) is the standard imaging test used for the screening and assessment of suspected lung cancer, but distinguishing malignant from benign nodules by CT is an ongoing challenge. Consequently, a large number of avoidable invasive procedures are performed on patients with benign nodules in order to exclude malignancy. Improving cancer discrimination by non-invasive imaging could reduce the need for invasive diagnostics. In this work we focus on developing a gold nanoparticle contrast agent that targets the epidermal growth factor receptor (EGFR), which is expressed on the cell surface of most lung adenocarcinomas. Three different contrast agents were compared for their tumor targeting effectiveness: non-targeted nanoparticles, nanoparticles conjugated with full-sized anti-EGFR antibodies (cetuximab), and nanoparticles conjugated with a single-domain llama-derived anti-EGFR antibody, which is smaller than the cetuximab, but has a lower binding affinity. Nanoparticle targeting effectiveness was evaluated in vitro by EGFR-binding assays and in cell culture with A431 cells, which highly express EGFR. In vivo CT imaging performance was evaluated in both C57BL/6 mice and in nude mice with A431 subcutaneous tumors. The cetuximab nanoparticles had a significantly shorter blood residence time than either the non-targeted or the single-domain antibody nanoparticles. All of the nanoparticle contrast agents demonstrated tumor accumulation; however, the cetuximab-targeted group had significantly higher tumor gold accumulation than the other two groups, which were statistically indistinguishable from one another. In this study we found that the relative binding affinity of the targeting ligands had more of an effect on tumor accumulation than the circulation half life of the nanoparticles. This study provides useful insight into targeted nanoparticle design and demonstrates that nanoparticle contrast agents can be used to detect tumor receptor overexpression. Combining receptor status data with traditional imaging characteristics has the potential for better differentiation of malignant lung tumors from benign lesions.

Integrin αvβ3-Targeted [64Cu]CuS Nanoparticles for PET/CT Imaging and Photothermal Ablation Therapy.

Copper sulfide (CuS) nanoparticles have been considered one of the most clinical relevant nanosystems because of their straightforward chemistry, small particle size, low toxicity, and intrinsic theranostic characteristics. In our previous studies, radioactive [64Cu]CuS nanoparticles were successfully developed to be used as efficient radiotracers for positron emission tomography and for photothermal ablation therapy of cancer cells using near-infrared laser irradiation. However, the major challenge of CuS nanoparticles as a theranostic platform is the lack of a means for effective targeted delivery to the tumor site. To overcome this challenge, we designed and synthesized angiogenesis-targeting [64Cu]CuS nanoparticles, which are coupled with cyclic RGDfK peptide [c(RGDfK)] through polyethylene glycol (PEG) linkers using click chemistry. In assessing their tumor-targeting efficacy, we found that the tumor uptakes of [64Cu]CuS-PEG-c(RGDfK) nanoparticles at 24 h after intravenous injection were significantly greater (8.6% ± 1.4% injected dose/gram of tissue) than those of nontargeted [64Cu]CuS-PEG nanoparticles (4.3% ± 1.2% injected dose/gram of tissue, p < 0.05). Irradiation of tumors in mice administered [64Cu]CuS-PEG-c(RGDfK) nanoparticles induced 98.7% necrotic areas. In contrast, irradiation of tumors in mice administered nontargeted CuS-PEG nanoparticles induced 59% necrotic areas ( p < 0.05). The angiogenesis-targeting [64Cu]CuS nanoparticles may serve as a promising platform for image-guided ablation therapy with high efficacy and minimal side effects in future clinical translation of this novel class of multifunctional nanomaterials.

Method of establishing breast cancer brain metastases affects brain uptake and efficacy of targeted, therapeutic nanoparticles.

HER2‐targeted therapies effectively control systemic disease, but their efficacy against brain metastases is hindered by their low penetration of the blood‐brain and blood‐tumor barriers (BBB and BTB). We investigate brain uptake and antitumor efficacy of transferrin receptor (TfR)‐targeted, therapeutic nanoparticles designed to transcytose the BBB/BTB in three murine models. Two known models involving intracranial (IC) or intracardiac (ICD) injection of human breast cancer cells were employed, as was a third model developed here involving intravenous (IV) injection of the cells to form whole‐body tumors that eventually metastasize to the brain. We show the method of establishing brain metastases significantly affects therapeutic BBB/BTB penetration. Free drug accumulates and delays growth in IC‐ and ICD‐formed brain tumors, while non‐targeted nanoparticles show uptake and inhibition only in IC‐established metastases. TfR‐targeted nanoparticles accumulate and significantly delay growth in all three models, suggesting the IV model maintains a more intact BBB/BTB than the other models.

Radiolabeled Molecular Imaging Probes for the In Vivo Evaluation of Cellulose Nanocrystals for Biomedical Applications.

Cellulose nanocrystals (CNCs) have remarkable potential to improve the delivery of diagnostic and therapeutic agents to tumors; however, the in vivo studies on CNC biodistribution are still limited. We developed CNC-based imaging probes for the in vitro and in vivo evaluation using two labeling strategies: site-specific hydrazone linkage to the terminal aldehyde of the CNC and nonsite-specific activation using 1,1'-carbonyldiimidazole (CDI). The in vivo behavior of unmodified CNC, DOTA-CNC (ald.), and DOTA-CNC (OH) was investigated in healthy and 4T1 breast cancer mouse models. They displayed good biocompatibility in cell models. Moreover, the biodistribution profile and SPECT/CT imaging confirmed that the accumulation of 111In-labeled DOTA-CNC (ald.) and 111In-DOTA-CNC (OH) was primarily in hepatic, splenic, and pulmonary ducts in accordance with the clearance of nontargeted nanoparticles. The developed CNC imaging probes can be used to obtain information with noninvasive imaging on the behavior in vivo to guide structural optimization for targeted delivery.

Evaluation of cellular and transcriptional targeting of breast cancer stem cells via anti-HER2 nanobody conjugated PAMAM dendrimers

According to the cancer stem cell (CSC) theory, a small subset of cells with stem cell-like characteristics is responsible for tumor initiation, progression, and recurrence. CD44+/CD24– phenotype is assumed to be one of the main characteristics of the breast CSCs. We developed an MDA-MB-231 cell line overexpressing cell surface HER2 antigen for the evaluation of targeting efficiency of anti-HER2 nanobody (Nb)-conjugated polyamidoamine (PAMAM) polyplexes. Apoptosis-inducing tBid gene under control of CXCR1 promoter was delivered by this nanoparticle. Cellular uptake study showed higher uptake of Nb-targeted PAMAM carriers compared to non-targeted nanoparticles after 6 h of incubation. Gene expression analysis showed a significant rise in the expression of tBid in both MDA-MB-231/HER2+ and MDA-MB-231 compared to the two other cell lines. The same effect was observed after transfection with Nb-conjugated polyplexes within MDA-MB-231/HER2+ cell line compared to non-conjugated PAMAM polyplexes. We confirmed the killing efficiency of the gene construct in both MDA-MB-231/HER2+ and MDA-MB-231 cell lines by caspase 3 activity assay. These findings suggest that imposing pre-entry and post-entry restrictions on tBid killer gene might be a promising approach to specifically target the breast CSCs.

Targeting lung cancer initiating cells by all-trans retinoic acid-loaded lipid-PLGA nanoparticles with CD133 aptamers.

Lung cancer initiating cells represent a specific subpopulation of lung cancer cells, which significantly contribute to the initiation, metastasis and recurrence of lung cancer. CD133, initially considered a marker of stem cells, is now considered as a marker for lung cancer initiating cells. All-trans retinoic acid (RA) has been demonstrated to cause the differentiation, inhibition of proliferation, and apoptosis of cancer cells and cancer initiating cells. However, there have been no reports on the activity of RA against lung cancer initiating cells. In the present study, the activity of RA against lung cancer initiating cells was investigated by determining the cytotoxicity, and performing a tumorsphere assay and flow cytometry-based analysis. In addition, to promote the therapeutic effect of RA in CD133+ lung cancer initiating cells, RA-loaded lipid poly(lactic-co-glycolic acid) (PLGA) nanoparticles with CD133 aptamers (RA-LPNPs-CD133) were developed. The activity of RA and RA-LPNPs-CD133 against lung cancer initiating cells was also investigated. RA-LPNPs-CD133 had a size of 129.9 nm, and exhibited sustained release of RA during the 144-h period. For the first time, to the best of our knowledge, the present study demonstrated that RA exerted potent activity towards CD133+ lung cancer initiating cells. The results also showed that RA-LPNPs-CD133 efficiently and specifically promoted the delivery of RA to CD133+ lung cancer initiating cells, exhibiting superior inhibitory effects against CD133+ lung cancer initiating cells compared with non-targeted nanoparticles and RA. To the best of our knowledge, the present study is the first to report the promotion of RA delivery via nanoparticles to lung cancer initiating cells and achievement of a superior inhibitory effect against lung cancer initiating cells by the utilization of CD133 aptamers. Therefore, RA-LPNPs-CD133 represents a promising tool for the elimination of lung cancer initiating cells.

Could FA-PG-SPIONs act as a hyperthermia sensitizing agent? An in vitro study

The therapeutic effect of polyglycerol coated iron oxide nanoparticles (PG-SPIONs, non-targeted nanoparticles) and folic acid-conjugated polyglycerol coated iron oxide nanoparticles (FA-PG-SPIONs, targeted nanoparticles) in combination with hyperthermia on viability of HeLa cells was investigated. It was observed that coated and uncoated SPIONs have spherical shapes with an average diameter of 17.9 ± 2.85 nm and 5.4 ± 0.75 nm, respectively. The penetration rate for cells treated with targeted nanoparticles was shown to be more than that of non-targeted nanoparticles. Moreover, it was revealed that the treatment of cells with ≥ 50 µg/ml FA-PG-SPIONs in combination with hyperthermia induced cytotoxicity in comparison to control cells. The results also showed that increasing the concentrations of targeted nanoparticles (FA-PG-SPIONs) and heating time would increase the value of thermal enhancement factor (TEF). In contrast, TEF values were not increased with increasing heating time and concentrations of non-targeted nanoparticles (PG-SPIONs). On the other hand, TEF values were increased with increasing concentrations and heating time so that the maximum TEF value was obtained at the highest concentration (FA-PG-SPION, 200 µg/ml) as well as the longest heating duration (60 min). Thus, it is concluded that FA-PG-SPIONs with concentrations ≥ 100 µg/ml could be introduced and used as hyperthermia sensitizing agents leading to enhanced cancer therapy efficiency.

All-trans retinoic acid-encapsulated, CD20 antibody-conjugated poly(lactic-co-glycolic acid) nanoparticles effectively target and eliminate melanoma-initiating cells in vitro.

PurposeMelanoma, which is initiated from melanocytes, is the most fatal type of skin cancer. Melanoma-initiating cells significantly contribute to the initiation, metastasis, and recurrence of melanoma, and CD20 is a marker of melanoma-initiating cells. All-trans retinoic acid (ATRA) has been demonstrated to induce differentiation, inhibit proliferation, and promote the apoptosis of cancer cells and cancer-initiating cells (CICs). However, there has been no report on ATRA activity against melanoma-initiating cells. In this study, we examined the activity of ATRA against melanoma-initiating cells and developed ATRA-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles, which were conjugated with a CD20 antibody (ATRA-PNP-CD20) for targeted delivery of ATRA to CD20+ melanoma-initiating cells.Materials and methodsThe effects of ATRA and ATRA-PNP-CD20 against melanoma-initiating cells were investigated using a cytotoxicity assay, tumorsphere formation assay, and flow cytometry.ResultsATRA-PNP-CD20 had a size of 126.9 nm and a negative zeta potential. The drug-loading capacity of ATRA-PNP-CD20 was 8.7%, and ATRA-PNP-CD20 displayed a sustained release of ATRA for 144 hours. The results showed that ATRA-PNP-CD20 could effectively and specifically deliver ATRA to CD20+ melanoma-initiating cells, achieving superior inhibitory effects against CD20+ melanoma-initiating cells compared with those of free ATRA and nontargeted nanoparticles. To the best of our knowledge, we report for the first time a potent activity of ATRA against CD20+ melanoma-initiating cells, targeted drug delivery of ATRA via nanoparticles to melanoma-initiating cells, and the achievement of a superior inhibitory effect against melanoma-initiating cells by using a CD20 antibody.ConclusionATRA-PNP-CD20 represents a promising tool for eliminating melanoma-initiating cells and shows a potential for the therapy of melanoma.

Targeting sialic acid residues on lung cancer cells by inhalable boronic acid-decorated albumin nanocomposites for combined chemo/herbal therapy

Etoposide (ETP), as a potential treatment for lung cancer, has limited application due to its poor solubility, and systemic side effects. In the current study, we propose inhalable boronate-targeted HSA nanocomposites for combined delivery of ETP and the herbal drug, berberine (BER) for localized therapy of lung cancer. First, ETP was pre-formulated as phospholipid complex (EPC) to enhance drug solubility and facilitate its encapsulation within the hydrophilic albumin nanoparticles (NPs). Second, EPC and BER were then co-loaded with high efficiency into HSA NPs as a synergistic therapy for lung cancer. The NPs displayed suitable size around 200 nm and sequential drug release pattern. Moreover, conjugation of aminophenylboronic acid (APBA) to HSA NPs resulted in enhanced cytotoxicity and internalization into A549 lung cancer cells, compared to non-targeted NPs or free drugs via binding to sialic acid residues over-expressed by cancer cells. Using mannitol as a spray-drying carrier, the developed inhalable nanocomposites demonstrated deep pulmonary deposition, confirmed by small MMAD (2.112 μm) and high FPF (77.86%). In vivo investigations in lung cancer animal models revealed the superior anti-tumor efficacy of the inhalable nanocomposites. Overall, the inhalable APBA-HSA nanocomposites offered an alternative strategy for systemic delivery of ETP and BER in lung cancer therapy.

Promoted delivery of salinomycin sodium to lung cancer cells by dual targeting PLGA hybrid nanoparticles.

As the leading cause of cancer-associated mortality worldwide, lung cancer is often associated with therapy failure and decreases in survival; these factors are often attributed to lung cancer-initiating cells (CICs). In addition, sufficient evidence has suggested that simultaneous targeting of CICs, together with cancer cells, is critical for the achievement of preferable therapeutic efficacy, due to the spontaneous conversion between CICs and cancer cells. Salinomycin sodium(SS) is an antibacterial therapeutic agent that exerts potent activity against CICs in various types of cancer, including lung cancer. The present study generated SS lipid-polymer hybrid nanoparticles(NPs) with cluster of differentiation(CD)133 and epidermal growth factor receptor (EGFR) antibodies (CD133/EGFRSSNPs) for the simultaneous treatment of lung CICs and cancer cells. The activity of CD133/EGFRSSNPs was analyzed using cytotoxicity and tumorsphere formation assays, flow cytometry, and an in vivo anticancer assay in mice bearing lung cancer xenografts. The results revealed that CD133/EGFRSSNPs effectively promoted SS delivery to lung CICs and cancer cells, achieving superior therapeutic effects compared with non-targeted NPs or NPs with a single antibody. Furthermore, CD133/EGFRSSNPs exhibited the best efficacy in inhibiting tumor growth compared with the control agents in lung cancer-bearing mice. In conclusion, CD133/EGFRSSNPs may be capable of efficiently targeting and treating lung CICs together with cancer cells, and may represent an effective treatment for lung cancer.

Abstract 4641: Improved chemotherapeutic delivery to brain metastases with targeted nanoparticles in preclinical breast cancer brain metastasis models

Abstract Brain metastases present an increasing challenge to long-term survival for HER2-amplified breast cancer patients. While HER2 targeted therapies effectively control systemic metastases, they are largely ineffective against brain metastases due to their inability to cross the blood-brain barrier. We have recently demonstrated that brain uptake of targeted nanoparticles can be increased by adding an acid-cleavable linkage between transferrin (Tf) and the nanoparticle core [1]. Our lab has also developed a method for assembling targeted nanoparticles by complexing diol-containing polymer-drug conjugates and boronic acid-containing targeting agents [2]. Here, we report the first efficacy results of targeted nanoparticles formed via this assembly strategy in a preclinical model of breast cancer brain metastasis. Female Rag2-/-;Il2rg-/- mice were intracranially injected with human HER2-amplified BT-474 breast cancer cells, and formation of brain tumors was monitored by MRI. Mice were randomized into four groups of six mice per group (targeted nanoparticle, non-targeted nanoparticle, free drug, and saline). Targeted and non-targeted nanoparticles were prepared by functionalizing nanoparticle cores consisting of a mucic acid polymer conjugate of camptothecin (CPT) with either Tf-PEG or methoxy-PEG, respectively, using boronic acid-diol chemistry. The different formulations were administered intravenously once per week for four weeks at a dose of 4 mg/kg (CPT basis), and tumor volume was measured weekly by MRI. Targeted nanoparticles significantly reduced tumor growth in mice bearing intracranially implanted tumors compared to saline, free drug, and non-targeted nanoparticle controls. However, free drug and non-targeted nanoparticles also reduced tumor growth compared to saline, albeit to a lesser extent. Taken together, the results are highly suggestive that there isn't a completely intact blood-brain or blood-tumor barrier, and furthermore that artificial transport pathways may be introduced following intracranial implantation. To overcome limitations of the intracranial injection model, female Rag2-/-;Il2rg-/- mice were intracardiacly or intravenously (tail vein) injected with human HER2-amplified BT-474 breast cancer cells, and formation of metastatic brain tumors was monitored by MRI. Unlike brain tumors from intracranially injected cells, brain tumors formed from intravenous cell injections were not affected by systemic doses of either lapatinib or trastuzumab. Current investigations involve collection of efficacy data for the different formulations in the intracardiac and intravenous models that may provide further insight into the blood-brain barrier integrity and nanoparticle delivery. [1] Clark, AJ, Davis, ME, PNAS, 112 (2015) 12486-12491. [2] Han, H, Davis, ME, Mol. Pharmaceutics, 10 (2013) 2558-2567. Citation Format: Emily A. Wyatt, Mark E. Davis. Improved chemotherapeutic delivery to brain metastases with targeted nanoparticles in preclinical breast cancer brain metastasis models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4641.

Folic acid-conjugated mesoporous silica nanoparticles for enhanced therapeutic efficacy of topotecan in retina cancers.

In this study, topotecan-loaded mesoporous silica nanoparticles were prepared and surface conjugated with folic acid (FTMN) to enhance the therapeutic efficacy of topotecan for the treatment of retinoblastoma (RB) cancers. The particles were nano-sized and exhibited a sustained release of drug in the physiological conditions. The folic acid-conjugated nanoformulations exhibited a remarkable uptake in RB cells compared to that of non-targeted nanoparticles. These results clearly indicate that receptor-mediated endocytosis is the mechanism of cellular internalization. The greater cellular uptake of FTMN resulted in significantly higher cytotoxic effect in Y79 cancer cells compared to that of other formulations. The results were well corroborated with the live/dead assay and nuclear fragmentation assay. FTMN consistently induced apoptosis of cancer cells with an efficiency of ~58%. Our results clearly showed that nanoparticulate encapsulation of TPT exhibited superior anticancer efficacy in Y79 cancer cells compared to that of free drug or non-targeted nanoparticles. As expected, FTMN exhibited a remarkable reduction in the overall tumor volume compared to any other group with less presence of tumor cells in histology staining. Overall, folic acid-conjugated nanoparticulate system could provide an effective platform for RB treatment.

Application of active targeting nanoparticle delivery system for chemotherapeutic drugs and traditional/herbal medicines in cancer therapy: a systematic review.

Patients treated with conventional cancer chemotherapy suffer from side effects of the drugs due to non-selective action of chemotherapeutic drugs to normal cells. Active targeting nanoparticles that are conjugated to targeting ligands on the surface of nanoparticles play an important role in improving drug selectivity to the cancer cell. Several chemotherapeutic drugs and traditional/herbal medicines reported for anticancer activities have been investigated for their selective delivery to cancer cells by active targeting nanoparticles. This systematic review summarizes reports on this application. Literature search was conducted through PubMed database search up to March 2017 using the terms nanoparticle, chemotherapy, traditional medicine, herbal medicine, natural medicine, natural compound, cancer treatment, and active targeting. Out of 695 published articles, 61 articles were included in the analysis based on the predefined inclusion and exclusion criteria. The targeting ligands included proteins/peptides, hyaluronic acid, folic acid, antibodies/antibody fragments, aptamer, and carbohydrates/polysaccharides. In vitro and in vivo studies suggest that active targeting nanoparticles increase selectivity in cellular uptake and/or cytotoxicity over the conventional chemotherapeutic drugs and non-targeted nanoparticle platform, particularly enhancement of drug efficacy and safety. However, clinical studies are required to confirm these findings.