Tumor Targeting Efficiency Research Articles

Enhancing therapeutic efficacy of photothermal therapy using poloxamer-reduced graphene oxide and mesenchymal stem cells

Due to their heat-generating property based on exogenous energy irradiation, reduced graphene oxide particles (RGOs) have been widely used for photothermal cancer therapy. They show high absorbance for the near-infrared wavelength that is suitable for in vivo experimentation. However, enhancing the tumor-targeting efficiency and avoiding the self-aggregation of RGO to maximize the photothermal effect remain challenging. We demonstrated here that human mesenchymal stem cells (hMSCs) can deliver poloxamer conjugated RGOs (pRGOs) to target tumors. Self-aggregation limits cellular uptake and induces treatment of high particle concentrations for the photothermal effect. However, compared to RGOs, pRGOs did not show any self-aggregation. pRGOs-laden hMSCs injected intravenously to tumor-bearing mice led to significantly enhanced tumor-targeting efficiency and higher heat generation than injections of RGOs following exogenous laser irradiation. This work shows that the tumor tropism of hMSC can be applied for increased tumor-targeting efficiency with small amounts of particles. Taken together, the results indicate that combining hMSCs with pRGOs could increase the therapeutic effect in photothermal cancer therapy in a synergistic manner.

Immunomodulatory Lipocomplex Functionalized with Photosensitizer-Embedded Cancer Cell Membrane Inhibits Tumor Growth and Metastasis.

Liposomes are clinically used as drug carriers for cancer therapy; however, unwanted leakage of the encapsulated anticancer drug and poor tumor-targeting efficiency of liposomes may generate toxic side effects on healthy cells and lead to failure of tumor eradication. To overcome these limitations, we functionalized liposomes with a photosensitizer (KillerRed, KR)-embedded cancer cell membrane (CCM). A lipid adjuvant was also embedded in the lipocomplex to promote the anticancer immune response. KR proteins were expressed on CCM and did not leak from the lipocomplex. Owing to the homotypic affinity of the CCM for the source cancer cells, the lipocomplex exhibited a 3.3-fold higher cancer-targeting efficiency in vivo than a control liposome. The liposome functionalized with KR-embedded CCM and lipid adjuvant generated cytotoxic reactive oxygen species in photodynamic therapy and effectively induced anticancer immune responses, inhibiting primary tumor growth and lung metastasis in homotypic tumor-bearing mice. Taken together, the lipocomplex technology may improve liposome-based cancer therapy.

Carrier-Enhanced Anticancer Efficacy of Sunitinib-Loaded Green Tea-Based Micellar Nanocomplex beyond Tumor-Targeted Delivery.

Although a few nanomedicines have been approved for clinical use in cancer treatment, that recognizes improved patient safety through targeted delivery, their improved efficacy over conventional drugs has remained marginal. One of the typical drawbacks of nanocarriers for cancer therapy is a low drug-loading capacity that leads to insufficient efficacy and requires an increase in dosage and/or frequency of administration, which in turn increases carrier toxicity. In contrast, elevating drug-loading would cause the risk of nanocarrier instability, resulting in low efficacy and off-target toxicity. This intractable drug-to-carrier ratio has imposed constraints on the design and development of nanocarriers. However, if the nanocarrier has intrinsic therapeutic effects, the efficacy would be synergistically augmented with less concern for the drug-to-carrier ratio. Sunitinib-loaded micellar nanocomplex (SU-MNC) was formed using poly(ethylene glycol)-conjugated epigallocatechin-3-O-gallate (PEG-EGCG) as such a carrier. SU-MNC specifically inhibited the vascular endothelial growth factor-induced proliferation of endothelial cells, exhibiting minimal cytotoxicity to normal renal cells. SU-MNC showed enhanced anticancer effects and less toxicity than SU administered orally/intravenously on human renal cell carcinoma-xenografted mice, demonstrating more efficient effects on anti-angiogenesis, apoptosis induction, and proliferation inhibition against tumors. In comparison, a conventional nanocarrier, SU-loaded polymeric micelle (SU-PM) comprised of PEG-b-poly(lactic acid) (PEG-PLA) copolymer, only reduced toxicity with no elevated efficacy, despite comparable drug-loading and tumor-targeting efficiency to SU-MNC. Improved efficacy of SU-MNC was ascribed to the carrier-drug synergies with the high-performance carrier of PEG-EGCG besides tumor-targeted delivery.

Low density lipoprotein-inspired nanostructured lipid nanoparticles containing pro-doxorubicin to enhance tumor-targeted therapeutic efficiency

Inefficient tumor accumulation and controlling drug release at the tumor site are two major obstacles limiting the antitumor efficacy of nanoparticle delivery systems. Inspired by the biological structure and function of low-density lipoprotein (LDL), a pH-sensitive ApoB-100/Oleic acid-DOX/NLC (AODN) nanoparticle based on nanostructured lipid carrier (NLC) was prepared in this study. The biological composition of ApoB-containing NLC nanoparticles is similar to that of LDL, which can effectively increase the cycle time and targeting efficiency of nanoparticles. Meantime, the doxorubicin prodrug strategy was used to increase the drug loading of the nanoparticles and achieve drug-sensitive release. In vitro results indicated that AODN nanoparticles can cause more drugs to be phagocytosed by LDL receptor-mediated endocytosis, thus showing high cytotoxicity in 4T1 cells. In vivo experiments have shown that pH-sensitive AODN nanoparticles can cause more drugs to accumulate in the tumor site, reducing systemic toxicity and effectively inhibiting orthotopic breast cancer. These data provide strong evidence that the strategy of combining bionics and prodrug technology provides a new approach to improving the efficiency of chemotherapy drugs in cancer treatment. Statement of SignificanceInefficient tumor accumulation and controlling drug release at the tumor site are two major obstacles limiting the antitumor efficacy of nanoparticle delivery systems. Inspired by low density lipoprotein, a pH-sensitive ApoB-100/oleic acid-DOX/NLC (AODN) nanoparticle based on nanostructured lipid carrier (NLC) was prepared. Its biological composition is similar to that of LDL, which can effectively increase the cycle time and targeting efficiency of drugs. Then, the doxorubicin prodrug strategy was used to increase the drug loading of the nanoparticles and achieve drug-sensitive release. AODN nanoparticles can effectively inhibit tumor by effectively accumulating at tumor site and controlling release. The strategy of combining bionics and prodrug technology provides a new approach to improving the efficiency of chemotherapy drugs in cancer treatment.

Doxorubicin and siRNA-PD-L1 co-delivery with T7 modified ROS-sensitive nanoparticles for tumor chemoimmunotherapy

Tumor cells avoid immunosurveillance during the tumorigenesis, metastasis and recurrence periods thanks to the overexpressed immunosuppressive molecules on their surface. For instance, the programmed cell death 1 ligand (PD-L1) binds with the T-cells’ programmed cell death receptor 1 (PD-1) impairing the anti-tumor activity of the host T cells. In this study, a new reactive oxygen species (ROS) responsive nanoparticle (NP), modified with the HAIYPRH (T7) peptide, was developed for the co-delivery of siRNA-PD-L1 and doxorubicin (Dox). These NPs can block the inhibitory signal responding to T cells and enhance cytotoxicity of Dox against tumor cells. The T7 modification binds to the overexpressed transferrin receptor on tumor cells facilitating its cellular uptake. Dox rapid release is then triggered by the high tumor cells cytoplasmic concentration of ROS, leading to cell apoptosis. Our results demonstrated these NPs exhibited a T7-mediated cellular uptake and an intracellular ROS-triggered payloads release in vitro. They also suggested an improved in vivo 4T1 tumor targeting efficiency and chemoimmunotherapy. Most notably, the co-delivery system exhibited a significantly enhanced antitumor effect over Dox-only loaded NPs following prompting the proliferation of T cells by siRNA-PD-L1. In conclusion, these ROS-responsive NPs provided a promising strategy to combine siRNA-PD-L1 immunotherapy and Dox chemotherapy.

Vinblastine-Loaded Nanoparticles with Enhanced Tumor-Targeting Efficiency and Decreasing Toxicity: Developed by One-Step Molecular Imprinting Process.

Molecularly imprinted polymers have exhibited good performance as carriers on drug loading and sustained release. In this paper, vinblastine (VBL)-loaded polymeric nanoparticles (VBL-NPs) were prepared by a one-step molecular imprinting process, avoiding the waste and incomplete removal of the template, and evaluated as targeting carriers for VBL delivery after modification. Using acryloyl amino acid comonomers and disulfide cross-linkers, VBL-NPs were synthesized and then conjugated with poly(ethylene glycol)-folate. The dynamic size of the obtained VBL-NPs-PEG-FA was 258.3 nm (PDI = 0.250), and the encapsulation efficiency was 45.82 ± 1.45%. The nanoparticles of VBL-NPs-PEG-FA were able to completely release VBL during 48 h under a mimic tumor intracellular condition (pH 4.5, 10 mM glutathione (GSH)), displaying significant redox responsiveness, whereas the release rates were much slower in the mimic body liquid (pH 7.4, 2 μM GSH) and tumor extracellular environment (pH 6.5, 2 μM GSH). Furthermore, the carriers NPs-PEG-FA, prepared without VBL, showed satisfactory intrinsic hemocompatibility, cellular compatibility, and tumor-targeting properties: they could rapidly and efficiently accumulate to folate receptor positive Hela cells and then internalized via receptor-mediated endocytosis, and the retention in tumor tissues could last for over 48 h. Interestingly, VBL-NPs-PEG-FA could evidently increase the accumulation of VBL in tumor tissues while decreasing the distribution of VBL in organs, exert similar anticancer efficacy against Hela tumors in the xenograft model of nude mice to VBL injection, and significantly improve the abnormality of liver and spleen observed in VBL injection. VBL-NPs-PEG-FA has the potential to be the delivery carrier for VBL by enhancing the tumor-targeting efficacy of VBL and decreasing toxicity to normal tissues.

Characterization and bioactivity of self-assembled anti-angiogenic chondroitin sulfate-ES2-AF nanoparticle conjugate.

BackgroundIn the past few years, significant progress has been made in inhibiting neovascularization at the tumor site, cutting off the nutrient supply of the tumor, and inhibiting tumor growth and metastasis. However, many proteins/peptides have the disadvantage of poor stability, short half-life, and uncertain targeting ability. Chemical modification can be used to overcome these disadvantages; many polyethylene glycol-modified proteins/peptides have been approved by US FDA. The purpose of this study was to obtain a novel anti-angiogenic chondroitin sulfate (CS)-peptide nanoparticle conjugate with efficient anti-neovascularization and tumor targeting ability and an acceptable half-life.Materials and methodsThe CS-ES2-AF nanoparticle conjugate was synthesized and characterized using 1H-nuclear magnetic resonance spectroscopy, transmission electron microscopy, and particle size and zeta potential analyzer. The anti-angiogenic ability was studied using MTT, migration, tube formation, and chick chorioallantoic membrane assays. The targeting ability of CS-ES2-AF was studied by ELISA, surface plasmon resonance, and bioimaging. The pharmacokinetics was also studied.ResultsThe CS-ES2-AF could self-assemble into stable nanoparticles in aqueous solution, which significantly enhances its anti-neovascularization activity, tumor targeting more explicit, and prolongs its half-life.ConclusionCS is an effective protein/peptide modifier, and CS-ES2-AF displayed good potential in tumor targeting therapy.

Functionalized docetaxel-loaded lipid-based-nanosuspensions to enhance antitumor efficacy in vivo.

Purpose: To further enhance the antitumor efficacy through targeted delivery, DTX loaded lipid-based-nanosuspensions (DTX-LNS) were prepared and functionalized by PEGylation or NGR modification to develop DSPE-PEG2000 modified DTX-LNS (P-DTX-LNS) or DSPE-PEG2000-NGR modified DTX-LNS (N-DTX-LNS), respectively.Methods: Based on our previous work, functionalized DTX-LNS including P-DTX-LNS and N-DTX-LNS were prepared using thin-film hydration, and then characterized. Release behavior, stability in vitro, cytotoxicity and cellular uptake of functionalized LNS were observed. To demonstrate tumor targeting efficiency of functionalized DTX-LNS, in vivo real-time and ex vivo imaging study were conducted. Furthermore, therapeutic efficacy in vivo was evaluated in an H22-bearing mice model.Results: Functionalized DTX-LNS 100–110 nm in diameter were successfully prepared and exhibited good stability under various conditions. In vitro release studies demonstrated that DTX was released from functionalized DTX-LNS steadily and reached approximately 95% at 48 hrs. Functionalized DTX-LNS showed dose-dependent cytotoxicity and time-dependent internalization in human hepatocellular liver carcinoma cells (HepG2) cells. In vivo real-time and ex vivo imaging results indicated that tumor targeting efficiencies of P-DiR-LNS and N-DiR-LNS were 29.9% and 34.3%, respectively. Moreover, evaluations of in vivo antitumor efficacy indicated that functionalized DTX-LNS effectively inhibited tumor growth with low toxicity.Conclusion: The functionalized LNS exhibited suitable particle size, nearly spherical structure, enough drug loading and great potentials for large-scale production. The results in vitro and in vivo demonstrated that functionalized LNS could realize tumor targeting and antitumor efficacy. Consequently, functionalized DTX-LNS could be expected to be used for tumor targeting therapy.

Dendritic polylysine based ανβ3 integrin targeted probe for near-infrared fluorescent imaging of glioma.

The difficulty in identifying tumor tissues from healthy brain tissues is a major challenge for the accurate resection of glioma in clinical practice. Many efforts have been made to develop targeting probes to precisely visualize and resect glioma. However, most of these probes are hindered by non-degradation, intolerable toxicity, complicated and costly preparation procedures. In this work, we report an ανβ3 integrin-targeted near-infrared (NIR) fluorescent probe DP-RGD for detection of glioma. Considering its well-defined structure, good biodegradability, and biocompatibility, dendritic polylysine (DP) is selected as the carrier which is conjugated with a glioma-targeting ligand c(RGDyK) and NIR fluorescent dye IR783. The diameter of the targeted probe DP-RGD can be well controlled in a range of 10-20 nm. Cytotoxicity and histological analysis demonstrated that the probe possesses good biocompatibility. NIR fluorescent imaging studies indicated that this probe possessed high tumor targeting efficiency and precisely visualized the glioma xenograft with a high tumor to normal tissue signal ratio. Above all, the ανβ3 integrin-targeted probe DP-RGD shows great promise for noninvasively and precisely visualizing glioma and holds the possibility for NIR fluorescent imaging-guided glioma resection.

Enhanced anti-tumor activity of the Multi-Leu peptide PACE4 inhibitor transformed into an albumin-bound tumor-targeting prodrug

The proprotein convertase PACE4 has been validated as a potential target to develop new therapeutic interventions in prostate cancer (PCa). So far, the most effective compound blocking the activity of this enzyme has been designed based on the structure of a small peptide Ac-LLLLRVKR-NH2 known as the Multi-Leu (ML) peptide. Optimization of this scaffold led to the synthesis of compound C23 (Ac-[DLeu]LLLRVK-amidinobenzylamide) with a potent in vivo inhibitory effect on the tumor growth. However, further developments of PACE4 inhibitors may require additional improvements to counter their rapid renal clearance and to increase their tumor targeting efficiency. Herein, we explored the transformation of the ML-peptide into an albumin-binding prodrug containing a tumor specific release mechanism based on the prostate-specific antigen. Our data confirms that intravenous treatment using the ML-peptide alone has little effect on tumor growth, whereas by using the ML-prodrug in LNCaP xenograft-bearing mice it was significantly reduced. Additionally, excellent in vivo stability and tumor-targeting efficiency was demonstrated using a radiolabelled version of this compound. Taken together, these results provide a solid foundation for further development of targeted PACE4 inhibition in PCa.

Core-matched nanoassemblies for targeted co-delivery of chemotherapy and photosensitizer to treat drug-resistant cancer

Emergence of drug resistance in tumors causes therapeutic failure or tumor relapse. Combination of chemotherapy and photodynamic therapy holds significant promise to treat drug-resistant tumors. However, stubborn hydrophobicity of photosensitizer (PS), low encapsulation efficiency and leaking problem of PS in organic carrier, and disparate physicochemical properties of PS and chemotherapeutics make the combination unachievable. Thus how to efficiently co-deliver the two functional agents to enable photo-chemotherapy seems to be one of the key challenges. Here, core-matched technology (CMT) was developed to realize efficient co-delivery of PS and chemotherapeutics, in which PS verteporfin (VP), tumor angiogenesis-targeting iNGR peptide and poly(lactic acid) (PLA) were respectively pre-modified with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and the conjugates self-assembled into iNGR-modified and VP conjugated nanoassemblies (iNGR-VP-NA) with chemotherapeutic agent docetaxel (DTX) loaded in the hydrophobic core. The obtained iNGR-VP-NA-DTX was characterized by mean size of 166.0 ± 9.2 nm and morphology of uniformly spherical shape. In vitro, with the assistance of laser, iNGR-VP-NA-DTX exhibited higher cellular uptake, stronger cytotoxicity in HUVEC cells, drug-resistant HCT-15 tumor cells and more effective inhibition of tube formation than iNGR-VP-NA-DTX without laser or VP-NA-DTX with laser. After intravenously injected into mice, through the near-infrared light emitted by VP, iNGR-VP-NA exhibited improved accumulation compared to VP-NA in drug-resistant HCT-15 tumor. Besides, iNGR-VP-NA-DTX with laser enhanced inhibition of angiogenesis and induced severe apoptosis and necrosis in tumor tissues along with minimal impact to normal areas. These evidences demonstrated that iNGR-VP-NA-DTX was of great potential to treat drug-resistant tumors via efficient angiogenesis-targeted photo-chemotherapy. Statement of SignificanceCombination of chemotherapy and photodynamic therapy is thought to be a potential approach to treat drug-resistant cancer. However, it is difficult to realize optimized photo-chemotherapy in one nano-system. Here, iNGR-modified nanoassemblies is created based on core-matched nanotechnology to realize targeted photo-chemotherapy. In this study, the improved co-loading of chemotherapy and photosensitizer in the nanoassemblies exerted a synergistic anti-tumor effect and the decoration with iNGR enhanced tumor-targeting efficiency. In the presence of laser irradiation, the nanoassemblies exhibited enhanced and targeted anti-tumor efficacy in drug-resistant HCT-15 tumor both in vitro and in vivo.

ASSESSMENT OF CANCER TARGETING POTENTIAL OF DOXORUBICIN CONJUGATED WITH SURFACE FUNCTIONALIZED MULTI-WALLED CARBON NANOTUBES

Our main aim in the present investigation was to assess the cancer targeting potential of doxorubicin conjugated with folic acid (FA), ethylene di-amine (EDA) and surface F- MWCNTs (FA-EDA-MWCNTs- DOX) conjugate employing on MCF-7 (breast cancer cell line) for efficient tumor targeting. We developed a highly effective novel targeted drug delivery based on DOX-conjugated with the surface of F-MWCNTs by using nucleophilic substitution reaction mechanism and evaluated in facile strategy for cancer treatment. The in vitro drug release study shows that the percentage of drug release under an acidic condition pH-5.4 is higher than that under normal physiological conditions. The FA-EDAMWCNTs- DOX nano-conjugate affords higher efficacy in tumor growth suppression due to its stealth nature and most preferentially taken up by cultured MCF-7 cells through receptor-mediated endocytosis mechanism. Fourier Transform Infrared Spectroscopy (FTIR), UV-Visible Spectroscopy, Nuclear Magnetic Resonance Spectroscopy (NMR) and Scanning Electron Microscopy (SEM) measurements clearly confirmed the functionalization & conjugation steps. The results concluded that developed watersoluble nano-conjugate might emerge as “safe and effective” nano-medicine in cancer treatment by minimizing the side effects with generally regarded as a safe prominence.

A Highly Efficient Tumor‐Targeting Nanoprobe with a Novel Cell Membrane Permeability Mechanism

Efficient tumor targeting has been a great challenge in the clinic for a very long time. The traditional targeting methods based on enhanced permeability and retention (EPR) effects show only an ≈5% targeting rate. To solve this problem, a new graphene-based tumor cell nuclear targeting fluorescent nanoprobe (GTTN), with a new tumor-targeting mechanism, is developed. GTTN is a graphene-like single-crystalline structure amphiphilic fluorescent probe with a periphery that is functionalized by sulfonic and hydroxyl groups. This probe has the characteristic of specific tumor cell targeting, as it can directly cross the cell membrane and specifically target to the tumor cell nucleus by the changed permeability of the tumor cell membranes in the tumor tissue. This new targeting mechanism is named the cell membrane permeability targeting (CMPT) mechanism, which is very different from the EPR effect. These probes can recognize tumor tissue at a very early stage and track the invasion and metastasis of tumor cells at the single cell level. The tumor-targeting rate is improved from less than 5% to more than 50%. This achievement in efficient and accurate tumor cell targeting will speed up the arrival of a new era of tumor diagnosis and treatment.

Enzyme-responsive multifunctional peptide coating of gold nanorods improves tumor targeting and photothermal therapy efficacy

It is well known that stealth coating effectively extends the circulation lifetime of nanomaterials in blood, which favors systemic delivery but also limits their cellular internalization and in turn prevents efficient tumor-targeting and accumulation. In this study, we address this dilemma by developing an enzyme-responsive zwitterionic stealth peptide coating capable of responding to matrix metalloproteinase-9 (MMP-9) which is overexpressed in tumor microenvironment. The peptide consists of a cell-penetrating Tat sequence, an MMP-9 cleavable sequence, and a zwitterionic antifouling sequence. Using this coating to protect photothermal gold nanorods (AuNRs), we found that responsive AuNRs showed both satisfactory systemic circulation lifetime and significantly enhanced cellular uptake in tumors, resulting in clearly improved photothermal therapeutic efficacy in mouse models. These results suggest that multifunctional peptide coated AuNRs sensitive to MMP-9 are promising nanomaterials, conferring both extended systemic circulation and enhanced tumor tissue accumulation, for more specific and efficient tumor therapy. Statement of significanceIt is well known that stealth coating effectively extends the circulation lifetime of nanomaterials in blood, which favors systemic delivery but also limits their cellular internalization and in turn prevents efficient tumor-targeting and accumulation. In this study, we address this dilemma by developing an enzyme-responsive zwitterionic stealth peptide coating capable of responding to matrix metalloproteinase-9 (MMP-9) which is overexpressed in tumor microenvironment. The peptide consists of a cell-penetrating Tat sequence, an MMP-9 cleavable sequence, and a zwitterionic antifouling sequence. Using this coating to protect photothermal gold nanorods (AuNRs), we found that responsive AuNRs showed both satisfactory systemic circulation lifetime and significantly enhanced cellular uptake in tumors, resulting in clearly improved photothermal therapeutic efficacy in mouse models.

Rod in Tube: A Novel Nanoplatform for Highly Effective Chemo-Photothermal Combination Therapy toward Breast Cancer.

Gold nanorods (GNRs) and doxorubicin (DOX) were loaded into the lumen of halloysite nanotubes (HNTs) via a rapid synthesis process (2 min) and physical adsorption. The targeting molecules of folic acid (FA) are then conjugated to HNTs via reactions with bovine serum albumin (BSA). The formation of GNRs in HNTs was verified by different techniques. Au-HNT-DOX@BSA-FA shows a maximum temperature of 26.8 °C rising after 8 min of 808 nm laser irradiation under 0.8 W cm-2. The functionalized HNTs exhibited stronger chemotherapeutic effect under laser irradiation as the laser could promote the release of DOX and temperature rising. Au-HNT-DOX@BSA-FA-treated MCF-7 cells exhibited a survival rate of 7.4% after laser irradiation. Au-HNT-DOX@BSA-FA treatment does not induce obvious toxicity in blood biochemistry, liver, and kidney function in normal mice. In vivo chemo-photothermal treatment toward 4T1-bearing mice suggested that Au-HNT-DOX@BSA-FA exhibited remarkable tumor-targeted efficiency and good controlled release effect for DOX. Also, the nanoparticles exhibited a rapid photothermal performance and an ability to inhibit the growth of tumors. Because of the synergistic effect of chemical-photothermal therapy, the toxicity of DOX to normal tissues was reduced on the premise of ensuring the same curative effect with a low dosage of 0.32 mg kg-1. This novel chemo-photothermal therapy nanoplatform provided a safe, rapid, effective, and cheap choice for the treatment of breast tumors both in vitro and in vivo.

Engineering Tumor-Targeting Nanoparticles as Vehicles for Precision Nanomedicine.

As a nascent and emerging field that holds great potential for precision oncology, nanotechnology has been envisioned to improve drug delivery and imaging capabilities through precise and efficient tumor targeting, safely sparing healthy normal tissue. In the clinic, nanoparticle formulations such as the first-generation Abraxane® in breast cancer, Doxil® for sarcoma, and Onivyde® for metastatic pancreatic cancer, have shown advancement in drug delivery while improving safety profiles. However, effective accumulation of nanoparticles at the tumor site is sub-optimal due to biological barriers that must be overcome. Nanoparticle delivery and retention can be altered through systematic design considerations in order to enhance passive accumulation or active targeting to the tumor site. In tumor niches where passive targeting is possible, modifications in the size and charge of nanoparticles play a role in their tissue accumulation. For niches in which active targeting is required, precision oncology research has identified targetable biomarkers, with which nanoparticle design can be altered through bioconjugation using antibodies, peptides, or small molecule agonists and antagonists. This review is structured to provide a better understanding of nanoparticle engineering design principles with emphasis on overcoming tumor-specific biological barriers.

Versatile and Finely Tuned Albumin Nanoplatform based on Click Chemistry.

Albumin is one of the most attractive nanoplatforms for targeted imaging and drug delivery due to its biocompatibility and long circulation half-life. However, previously reported albumin-based nanoplatforms have shown inconsistent blood circulation half-life according to the modified methods, and the affecting factors were not well evaluated, which could hamper the clinical translation of albumin-based nanoplatforms. Herein, we developed a finely tuned click-chemistry based albumin nanoplatform (CAN) with a longer circulation half-life and an efficient tumor targeting ability.Methods: CAN was synthesized in two steps. First, albumin was conjugated with ADIBO-NHS (albumin-ADIBO) by reacting albumin with various molar ratios of ADIBO. The number of attached ADIBO moieties was determined using matrix-assisted laser desorption ionization time of flight (MALDI-TOF). Second, the desired modalities including azide-functionalized chelator, a fluorescence dye, and folate were incorporated into albumin-ADIBO using strain-promoted alkyne-azide cycloaddition reaction (SPAAC reaction). The biodistribution and targeting efficiency of functionalized CANs were demonstrated in mice.Results: The degree of functionalization (DOF) and resulting in vivo biodistribution was controlled precisely using the click chemistry approach. Specifically, the numbers of attached azadibenzocyclooctyne (ADIBO) moieties on albumin, the DOF, were optimized by reacting albumin with varying molar ratios of ADIBO with a high reproducibility. Furthermore, we developed a simple and efficient method to estimate the DOF using UV-visible spectrophotometry (UV-vis), which was further validated by matrix-assisted laser desorption ionization time of flight (MALDI-TOF). The biodistribution of CAN could be controlled by DOF, and CAN with an optimized DOF showed a long circulation half-life (> 18 h). CAN was further functionalized using a simple click chemistry reaction with an azide functionalized chelator, a fluorescence dye, and folate. 64Cu- and folate-labeled CAN (64Cu-CAN-FA) showed effective and specific folate receptor targeting in vivo, with an over two-fold higher uptake than the liver at 24 h post-injection.Conclusions: Our development from the precisely controlled DOF demonstrates that an optimized CAN can be used as a multifunctional nanoplatform to obtain a longer half-life with radioisotopes and ligands, and provides an effective method for the development of albumin-based tumor theranostic agents.

Enhanced blood-brain-barrier penetrability and tumor-targeting efficiency by peptide-functionalized poly(amidoamine) dendrimer for the therapy of gliomas.

Glioblastoma is one of the most common primary tumor types of central nervous system (CNS) with high malignance and lethality. Although many treatment options are currently available, the therapy of brain cancers remains challenging because of blood-brain-barrier (BBB) which prevents most of the chemotherapeutics into the CNS. In this work, a poly(amidoamine) dendrimer-based carrier was fabricated and modified with angiopep-2 (Ang2) peptide that has been demonstrated to bind to low density lipoprotein receptor-relative protein-1 (LRP1) on the endothelial cells of BBB and could therefore induce BBB penetration of the carrier. To improve tumor-targeting effect towards the glioma sites, the dendrimer was simultaneously functionalized with an epidermal growth factor receptor (EGFR)-targeting peptide (EP-1) which was screened from a “one-bead one-compound” (OBOC) combinatorial library. EP-1 peptide was demonstrated to have high affinity and specificity to EGFR at both the molecular and cellular levels. The dual-targeting dendrimer exhibited outstanding BBB penetrability and glioma targeting efficiency both in vitro and in vivo, which strikingly enhanced the anti-gliomas effect of the drugs and prolonged the survival of gliomas-bearing mice. These results show the potential of the dual-targeting dendrimer-based carrier in the therapy of gliomas through enhancing BBB penetrability and tumor targeting.

Dual functional matrix metalloproteinase-responsive curcumin-loaded nanoparticles for tumor-targeted treatment

The limitations of anticancer drugs, including poor tumor targeting and weak uptake efficiency, are important factors affecting tumor therapy. According to characteristics of the tumor microenvironment, in this study, we aimed to synthesize matrix metalloproteinase (MMP)-responsive curcumin (Cur)-loaded nanoparticles (Cur-P-NPs) based on amphiphilic block copolymer (MePEG-peptide-PET-PCL) with MMP-cleavable peptide (GPLGIAGQ) and penetrating peptide (r9), modified to improve tumor targeting and cellular uptake. The average size of Cur-P-NPs was 176.9 nm, with a zeta potential of 8.1 mV, and they showed drug entrapment efficiency and a loading capacity of 87.07% ± 0.63% and 7.44% ± 0.16%, respectively. Furthermore, Cur release from Cur-P-NPs was sustained for 144 h at pH 7.4, and the release rate was accelerated under enzyme reaction condition. The MTT assay demonstrated that free P-NPs had favorable biosafety, and the anti-proliferative activity of Cur-P-NPs was positively correlated with Cur concentration in MCF-7 cells. Additionally, the results of cellular uptake, in vivo pharmacokinetics, and biodistribution showed that Cur-P-NPs had a good effect on cellular uptake and tumor targeting, resulting in the best bioavailability in tumor therapy. Therefore, Cur-P-NPs, as a promising drug delivery system, might lead to a new and efficient route for targeted therapy in clinical practice.

Co-delivery of VEGF siRNA and Etoposide for Enhanced Anti-angiogenesis and Anti-proliferation Effect via Multi-functional Nanoparticles for Orthotopic Non-Small Cell Lung Cancer Treatment

Targeting tumor angiogenesis pathway via VEGF siRNA (siVEGF) has shown great potential in treating highly malignant and metastatic non-small cell lung cancer (NSCLC). However, anti-angiogenic monotherapy lacked sufficient antitumor efficacy which suffered from malignant tumor proliferation. Therefore, the combined application of siVEGF and chemotherapeutic agents for simultaneous targeting of tumor proliferation and angiogenesis has been a research hotspot to explore a promising NSCLC therapy regimen.Methods: We designed, for the first time, a rational therapy strategy via intelligently co-delivering siVEGF and chemotherapeutics etoposide (ETO) by multi-functional nanoparticles (NPs) directed against the orthotopic NSCLC. These NPs consisted of cationic liposomes loaded with siVEGF and ETO and then coated with versatile polymer PEGylated histidine-grafted chitosan-lipoic acid (PHCL). We then comprehensively evaluated the anti-angiogenic and anti-proliferation efficiency in the in vitro tumor cell model and in bioluminescent orthotopic lung tumor bearing mice model.Results: The NPs co-delivering siVEGF and ETO exhibited tailor-made surface charge reversal features in mimicking tumor extracellular environment with improved internal tumor penetration capacity and higher cellular internalization. Furthermore, these NPs with flexible particles size triggered by intracellular acidic environment and redox environment showed pinpointed and sharp intracellular cargo release guaranteeing adequate active drug concentration in tumor cells. Enhanced VEGF gene expression silencing efficacy and improved tumor cell anti-proliferation effect were demonstrated in vitro. In addition, the PHCL layer improved the stability of these NPs in neutral environment allowing enhanced orthotopic lung tumor targeting efficiency in vivo. The combined therapy by siVEGF and ETO co-delivered NPs for orthotopic NSCLC simultaneously inhibited tumor proliferation and tumor angiogenesis resulting in more significant suppression of tumor growth and metastasis than monotherapy.Conclusion: Combined application of siVEGF and ETO by the multi-functional NPs with excellent and on-demand properties exhibited the desired antitumor effect on the orthotopic lung tumor. Our work has significant potential in promoting combined anti-angiogenesis therapy and chemotherapy regimen for clinical NSCLC treatment.