Retention In Tumor Tissue Research Articles

Abstract 6050: Targeting KRAS G12D mutant tumors with the PROTAC degrader RP03707

Abstract RAS oncogene mutations are prevalent in approximately 19% of cancer patients, with the most frequent alteration occurring in codon 12 of the KRAS gene, resulting in a variety of G12X oncoproteins. Recent advances in drug discovery have yielded several KRAS G12C inhibitors currently in clinical use, benefiting a subset of patients. However, addressing the high-prevalence G12D mutation remains a substantial unmet medical need. Targeted protein degradation using PROTAC molecules offers a promising approach for treating KRAS G12D-associated tumors, potentially providing superior efficacy and mitigating the development of resistance, a challenge frequently observed with KRAS G12C inhibitors in clinical settings. In the present study, we report a PROTAC compound RP03707 that efficiently induces the degradation of the KRAS G12D mutant protein and inhibits tumor growth. Treatment of AsPc-1 cells with RP03707 results in significant degradation of the KRAS G12D protein, with a DC50 value in the sub-nanomolar range. Within 24 hours, the compound eliminates over 90% of G12D proteins and effectively suppresses downstream cellular MAPK signaling. Additional in vitro experiments demonstrate that RP03707 inhibits cell proliferation in multiple KRAS G12D mutant cell lines, surpassing the anti-tumor efficacy of enzyme inhibitors. In a mouse GP2d xenograft tumor model, a single intravenous administration of RP03707 at 10 mpk results in excellent compound penetration and retention in tumor tissues, followed by 90% reduction of G12D protein levels for 7 days. Profound inhibition of tumor growth is observed not only in mouse GP2d xenograft but also in other mouse KRAS G12D tumor models, even when the compound is administered in low and infrequent doses. Moreover, RP03707 exhibits high selectivity for degrading the KRAS G12D protein and possesses favorable drug-like properties. RP03707, therefore, meets the criteria for advancing into drug development and represents a valuable therapeutic option for treating KRAS G12D-associated tumors. Citation Format: Xiang Ji, Huanping Li, Gang Wu, Qiguo Zhang, Xiaolin He, Yanpeng Wu, Bing Zong, Xiaojin Xu, Chao Liang, Beibei Wang, Yuwei Zhang, Qingyao Hu, Jiaxin Zhou, Weihui Guo, Bing Bai, Lin Wang, Jinchao Ai, Leduo Zhang, Honggui Zhou, Shihao Sun, Yijie Wang, Youhong Wang, Qiming Fan, Dawei Chen, Tianlun Zhou, Jiasheng Lu. Targeting KRAS G12D mutant tumors with the PROTAC degrader RP03707 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6050.

Promotion of tumor angiogenesis and growth induced by low-dose antineoplastic agents via bone-marrow-derived cells in tumor tissues.

More research is needed to solidify the basis for reasonable metronomic chemotherapy regimens due to the inconsistent clinical outcomes from studies on metronomic chemotherapy with antineoplastic agents, along with signs of a nonlinear dose-response relationship at low doses. The present study therefore explored the dose-response relationships of representative antineoplastic agents in low dose ranges and their underlying mechanisms. Cyclophosphamide (CPA) and 5-fluorouracil (5-Fu) were employed to observe the effects of the frequent administration of low-dose antineoplastic agents on tumor growth, tumor angiogenesis, and bone-marrow-derived cell (BMDC) mobilization in mouse models. The effects of antineoplastic agents on tumor and endothelial cell functions with or without BMDCs were analyzed in vitro. Tumor growth and metastasis were significantly promoted after the administration of CPA or 5-Fu at certain low dose ranges, and were accompanied by enhanced tumor angiogenesis and proangiogenic factor expression in tumor tissues, increased proangiogenic BMDC release in the circulating blood, and augmented proangiogenic BMDC retention in tumor tissues. Low concentrations of CPA or 5-Fu were found to significantly promote tumor cell migration and invasion, and enhance BMDC adhesion to endothelial cells in vitro. These results suggest that there are risks in empirical metronomic chemotherapy using low-dose antineoplastic agents and the optimal dosage and administration schedule of antineoplastic agents need to be determined through further research.

Strategies to prolong drug retention in solid tumors by aggregating Endo-CMC nanoparticles

Developing a highly effective nano-drug delivery system with sufficient drug permeability and retention in tumors is still a major challenge for oncotherapy. Herein, a tumor microenvironment responsive, aggregable nanocarriers embedded hydrogel (Endo-CMC@hydrogel) was developed to inhibit the tumoral angiogenesis and hypoxia for enhanced radiotherapy. The antiangiogenic drug (recombinant human endostatin, Endo) loaded carboxymethyl chitosan nanoparticles (Endo-CMC NPs) was wrapped by 3D hydrogel to comprise the Endo-CMC@hydrogel. After peritumoral injection, the Endo-CMC NPs were released, invaded deeply into the solid tumor, and cross-linked with intratumoral calcium ions. The cross-linking process enabled these Endo-CMC NPs to form larger particles, leading to long retention in tumor tissue to minimize premature clearance. This Endo-CMC@hydrogel, integrating the abilities of good tumoral penetration, long retention of anti-drug, and alleviation of hypoxia in tumor tissue, greatly improved the therapeutic effect of radiotherapy. This work provides a proof-of-concept of tumor microenvironment-responding and an aggregable nano-drug delivery system as promising antitumor drug carriers for effective tumor therapy.

Abstract 6339: BCA101, a novel tumor-targeted bifunctional fusion antibody simultaneously inhibiting EGFR and TGF-β signaling with potential for durable tumor growth inhibition

Abstract Introduction: The suboptimal clinical efficacy EGFR-targeting therapeutics is attributed to both tumor intrinsic and tumor microenvironment (TME) derived acquired (extrinsic) resistance mechanisms. Intrinsic factors include activation of other receptor tyrosine kinases and key extrinsic resistance mechanism include the enhanced secretion of immunosuppressive factors such as IL-10 and TGF-β1. Here, we describe a first-in-class bifunctional monoclonal antibody fusion designed to simultaneously target EGFR and sequester TGF-β in the TME. Experimental Procedures: Functional activity of BCA101 was evaluated in multiple in vitro assays such as ELISA, inhibition of proliferation, antibody-dependent cellular toxicity, SMAD-reporter assay. Neutralization of TGF-β by BCA101 was demonstrated by epithelial-to-mesenchymal transition and tumor cell/immune cell co-culture assays. BCA101 tumor targeting was evaluated in a whole animal imaging study and efficacy studies were performed in nude xenograft models while combination studies with immune checkpoint inhibitors were performed in B16-EGFR syngeneic models. Results: BCA101 is an anti-EGFR IgG1 monoclonal antibody linked to an extracellular domain of human TGF-βRII. The TGF-β “trap” fused to light chain in BCA101 did not sterically interfere with its ability to bind EGFR, inhibit cell proliferation, or mediate antibody-dependent cellular cytotoxicity in vitro. BCA101 increased production of proinflammatory cytokines and key markers associated with T and NK cell activation, while suppressing VEGF secretion. Additionally, BCA101 inhibited differentiation of naïve CD4+ T cells to inducible T-regulatory (iTreg) cells when compared to cetuximab. In vivo, biodistribution studies showed that BCA101 localized to tumor tissues in xenograft mouse models, with comparable kinetics as cetuximab. TGF-β in tumors was neutralized to about 90% in animals dosed with 10 mg/kg of BCA101 compared to 54% in animals dosed with equimolar TGF-βRII-Fc. BCA101 had longer tumor tissue retention compared to cetuximab, further confirming improved tumor localization. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response post dose cessation as compared to cetuximab. In FaDu xenografts, BCA101 displayed early and durable response to cetuximab/cetuximab plus TGF-βRII-Fc combination. The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR expressing syngeneic mouse and in humanized HuNOG-EXL mice bearing human PC-3 xenograft models. Conclusion: These results support clinical development of BCA101, either as a monotherapy or in combination with immune checkpoint therapy. Citation Format: Srinivas Reddy Boreddy, Reshmi Nair, Prashant Kumar Pandey, Anshu Kuriakose, Arindam Banerjee, Chaitali Dey, Madhukara A R, Bhadravathi Marigowda Shivakumar, Hanumant Kulkarni, Milind Sagar, Prashantha Kumar M. V, Shiv Ram Krishn, Jaya Bhatnagar, Moni Abhram Kuriakose, Ram Bhupal Reddy, Amritha Suresh, Praveen Reddy Moole, Usha Bughani, Seng-Lai Tan, Pradip Nair, Rachel Salazar. BCA101, a novel tumor-targeted bifunctional fusion antibody simultaneously inhibiting EGFR and TGF-β signaling with potential for durable tumor growth inhibition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6339.

Bibliometric and visualized analysis of the application of nanotechnology in glioma.

Background: Glioma is the most prevalent malignant tumor in the central nervous system (CNS). Due to its highly invasive characteristics and the existence of the blood–brain barrier (BBB), the early diagnosis and treatment of glioma remains a major challenge in cancer. With the flourishing development of nanotechnology, targeted nano-therapy for glioma has become a hot topic of current research by using the characteristics of nanoparticles (NPs), such as it is easier to pass the blood–brain barrier, degradable, and aids controllable release of drugs in the brain. The purpose of this study is to visualize the scientific achievements and research trends of the application of nanotechnology in glioma. Methods: We searched the literature related to glioma nanotechnology on the Web of Science (WOS). The bibliometric and visual analysis was performed mainly using CiteSpace, VOSviewer, and R software, for countries/regions, authors, journals, references, and keywords associated with the field. Results: A total of 3,290 publications from 2012 to June 2022 were searched, and 2,041 works of literature were finally obtained according to the search criteria, the number of publications increasing year by year, with an average growth rate (AGR) of 15.22% from 2012 to 2021. China published 694 (20.99%), followed by the United States (480, 20.70%). The institution with the highest number of publications is Fudan Univ (111, 13.16%), and 80% of the top ten institutions belong to China. HUILE GAO (30) and XINGUO JIANG (30) both published the largest number of research studies. STUPP R (412) was the most cited author, followed by GAO HL (224). The degree of collaboration (DC) among countries/regions, research institutions, and authors is 23.37%, 86.23%, and 99.22%, respectively. International Journal of Nanomedicine published the largest number of publications (81), followed by Biomaterials (73). Biomaterials (1,420) was the most cited journal, followed by J Control Release (1,300). The high frequency of keywords was drug delivery (487), followed by nanoparticle (450), which indicates that nanoparticles (NPs) as a carrier for drug delivery is a hot topic of current research and a direction of continuous development. Conclusion: In recent years, nanotechnology has attracted much attention in the medical field. Cooperation and communication between countries/regions and institutions need to be strengthened in future research to promote the development of nanomedicine. Nanotherapeutic drug delivery systems (NDDS) can enhance drug penetration and retention in tumor tissues, improve drug targeting, and reduce the toxic side effects of drugs, which has great potential for the treatment of glioma and has become the focus of current research and future research trends in the treatment of glioma.

CASTING: A Potent Supramolecular Strategy to Cytosolically Deliver STING Agonist for Cancer Immunotherapy and SARS-CoV-2 Vaccination

CASTING: A Potent Supramolecular Strategy to Cytosolically Deliver STING Agonist for Cancer Immunotherapy and SARS-CoV-2 Vaccination

An Injectable Nanocomposite Hydrogel Improves Tumor Penetration and Cancer Treatment Efficacy

Hydrogel as a local drug depot can increase drug concentration at the tumor site. However, conventional drug-loaded hydrogel is typically formed by direct dissolution of drug molecules inside the hydrogel, which usually suffers from limited drug retention and poor tumor penetration. In this study, a nanocomposite hydrogel consisting of oxaliplatin (OXA)-conjugated G5 polyamidoamine (G5-OXA) and oxidized dextran (Dex-CHO) is constructed to improve local drug delivery. The OXA-containing nanocomposite hydrogel (denoted as PDO gel) is injectable and could maintain in vivo up to more than three weeks, which increases drug retention in tumor tissues. More interestingly, G5-OXA released from the PDO gel show potent tumor penetration mainly through an active transcytosis process. In vivo antitumor studies in an orthotopic 4T1 tumor model show that PDO gel significantly inhibits primary tumor growth as well as the metastasis. In addition, the PDO gel can also activate the immunosuppressive tumor microenvironment through immunogenic cell death effect, and further improves therapeutic efficacy with the combination of PD-1 antibody. These results demonstrate that the nanocomposite hydrogel can simultaneously enhance the retention and penetration of chemotherapeutic drugs via the combination of both advantages of hydrogel and nanoparticles, which provides new insights for the design of local drug delivery systems. Statement of significanceHydrogel represents an important class of local drug delivery depot. However, conventional drug-loaded hydrogel is usually achieved by direct dissolution of small drug molecules inside the hydrogel, which typically suffers from limited drug retention and poor tumor penetration. Herein, we developed a nanocomposite hydrogel, which could gradually degrade and release drug-conjugated small nanoparticles (∼ 6 nm) for improved tumor penetration through the combination of an active transcytosis process and a passive diffusion process. This nanocomposite hydrogel system improved tumor penetration and retention of drug in primary tumors as well as the drug deposition in lymph nodes, which significantly suppressed tumor growth and metastasis.

Atomically Precise Water-Soluble Graphene Quantum Dot for Cancer Sonodynamic Therapy.

Although water‐soluble graphene quantum dots (GQDs) have shown various promising bio‐applications due to their intriguing optical and chemical properties, the large heterogeneity in compositions, sizes, and shapes of these GQDs hampers the better understanding of their structure‐properties correlation and further uses in terms of large‐scale manufacturing practices and safety concerns. It is shown here that a water‐soluble atomically‐precise GQD (WAGQD‐C96) is synthesized and exhibits a deep‐red emission and excellent sonodynamic sensitization. By decorating sterically hindered water‐soluble functional groups, WAGQD‐C96 can be monodispersed in water without further aggregation. The deep‐red emission of WAGQD‐C96 facilitates the tracking of its bio‐process, showing a good cell‐uptake and long‐time retention in tumor tissue. Compared to traditional molecular sonosensitizers, WAGQD‐C96 generates superior reactive oxygen species and demonstrates excellent tumor inhibition potency as an anti‐cancer sonosensitizer in in vivo studies. A good biosafety of WAGQD‐C96 is validated in both in vitro and in vivo assays.

HSA-MnO2-131I Combined Imaging and Treatment of Anaplastic Thyroid Carcinoma.

Purpose Compelling evidence suggests that nanoparticles (NPs) play a crucial role in cancer therapy. NPs templated with human serum albumin (HSA) has good retention in tumors. Manganese dioxide (MnO2) has been used to enhance the effect of radiotherapy. In this study, synthesized NPs using HSA-MnO2 labeled 131I to perform both imaging and therapy for anaplastic thyroid carcinoma (ATC). Method HSA-MnO2 was synthesized via HSA using a simple biomineralization method, and then labeled with Na131I by the chloramine T method. The cytotoxicity and biosafety of HSA-MnO2 were evaluated by the MTT test. The proliferation-inhibiting effect of HSA-MnO2-131I was evaluated in papillary thyroid cancer cell lines (K1, BCPAP, and KTC) and anaplastic thyroid carcinoma cell lines (Cal62, THJ16T, and ARO). For further translational application in medicine, we established a model of transplantable subcutaneously tumors in BALB\\c-nu mice to assess the anti-tumor effect of HSA-MnO2-131I. The imaging effects of NPs were evaluated by MRI and SPECT/CT. Results The MTT test proved that the HSA-MnO2 had low toxicity. HSA-MnO2-131I significantly inhibited the proliferation of PTC and ATC cell lines. In addition, the results unveiled that HSA-MnO2-131I exhibited dual-modality MR/SPECT imaging for thyroid cancer visualization. In particular, HSA-MnO2-131I had an enhanced T1 signal in MR. Using SPECT/CT, we observed that HSA-MnO2-131I had good retention in tumor tissue, which was helpful for the diagnosis and treatment of tumor. In vivo assays indicated that the NPs led to a reduction in radioresistance in the tumor hypoxic microenvironment. Conclusion The nanomaterial had a simple synthesis method, good water solubility and biosafety, and good retention in tumor tissue. Hence, it could be used for SPECT/CT and MR dual mode imaging and therapy with radioiodine of tumor cells. The experimental results provided a feasible solution for combining radiotherapy and dual-model imaging by NPs for cancer diagnosis and treatment.

A Novel Boron Lipid to Modify Liposomal Surfaces for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a cancer treatment with clinically demonstrated efficacy using boronophenylalanine (BPA) and sodium mercaptododecaborate (BSH). However, tumor tissue selectivity of BSH and retention of BPA in tumor cells is a constant problem. To ensure boron accumulation and retention in tumor tissues, we designed a novel polyethylene glycol (PEG)-based boron-containing lipid (PBL) and examined the potency of delivery of boron using novel PBL-containing liposomes, facilitated by the enhanced permeability and retention (EPR) effect. PBL was synthesized by the reaction of distearoylphosphoethanolamine and BSH linked by PEG with Michael addition while liposomes modified using PBL were prepared from the mixed lipid at a constant molar ratio. In this manner, novel boron liposomes featuring BSH in the liposomal surfaces, instead of being encapsulated in the inner aqueous phase or incorporated in the lipid bilayer membrane, were prepared. These PBL liposomes also carry additional payload capacity for more boron compounds (or anticancer agents) in their inner aqueous phase. The findings demonstrated that PBL liposomes are promising candidates to effect suitable boron accumulation for BNCT.

CXCR6 by increasing retention of memory CD8+ T cells in the ovarian tumor microenvironment promotes immunosurveillance and control of ovarian cancer

PurposeResident memory CD8 T cells, owing to their ability to reside and persist in peripheral tissues, impart adaptive sentinel activity and amplify local immune response, and have beneficial implications for...

Indocyanine green–guided nephron-sparing surgery for pediatric renal tumors

BackgroundIndocyanine green (ICG), a water-soluble tricarbocyanine fluorophore, is being increasingly used for tumor localization based on its passive intra-tumoral accumulation due to enhanced permeability and retention in tumor tissue. Therefore, we hypothesized that ICG can provide contrast to facilitate accurate, real-time recognition of renal tumors at the time of nephron-sparing surgery in children. MethodsThis retrospective study examined the feasibility of ICG in guiding nephron-sparing surgery for pediatric renal tumors. ResultsWe reviewed the medical records of 8 pediatric patients with renal tumors in 12 kidneys. Intraoperative localization of tumor with near infrared guidance was successful in all 12 kidneys. However, we consistently found an inverse pattern of near infrared signal in which the normal kidney demonstrated increased fluorescent signal relative to the kidney tumor. ConclusionsFluorescence-guided renal tumor delineation is unique because it has an inverse pattern of near infrared signal in which the normal kidney demonstrates increased signal relative to the adjacent tumor. Nevertheless fluorescence-guided distinguishing of renal tumor from surrounding normal kidney is feasible.

Bioevaluation of glucose-modified liposomes as a potential drug delivery system for cancer treatment using 177-Lu radiotracking

Liposomes are promising drug's delivery systems due to decreased toxicity of the liposome-encapsulated drug, but wider clinical application requires their more efficient tumor targeting with uptake, controlled drug release and higher shelf life. The unique metabolic characteristics of cancer cells based on higher demand for energy and therefore increased glucose utilization were exploited in the design of glucose modified liposomes (GML) with the aim to provide increased tumor targeting via glucose transporters and increased ability of drug delivery into tumor cells. Tumor accumulating potential of GML and non-glucose liposomes (NGL) were investigated on CT26 and LS174T tumor-bearing mice by simple and reliable radiotracer method using 177Lu as radioactive marker. Both liposomes, GML and NGL were radiolabeled in high radiolabeling yield, showing high in vitro stability in biological media, as the main prerequisite for the biodistribution studies. Tumors displayed significantly better accumulation of 177Lu-GML with the maximum uptake 6 h post-injection (5.8 ± 0.2%/g in LS174T tumor and 5.1 ± 0.5%/g in CT26 tumor), compared to negligible uptake of 177Lu-NGL (0.6 ± 0.1%/g in LS174T tumor and 0.9 ± 0.2%/g in CT26 tumor). Results of comparative biodistribution studies of 177Lu-NGL and 177Lu-GML indicate that increased accumulation of GML is enabled by glucose transporters and subsequent endocytosis, resulting in their prolonged retention in tumor tissues (up to 72 h). Direct radiolabeling of liposomes with 177Lu may be used not only for biodistribution studies using radiotracking, but also for cancer treatment.

Novel biomimetic nanostructured lipid carriers for cancer therapy: preparation, characterization, and in vitro/in vivo evaluation

Nanostructured lipid carriers (NLC) have become a research hotspot, wherein cancer-targeting effects are enhanced and side effects of chemotherapy are overcome. Usually, accelerated blood clearance (ABC) occurs after repeated injections, without changing the immunologic profile, despite PEGylation which prolongs the circulation function. To overcome these problems, we designed a red blood cell-membrane-coated NLC (RBCm-NLC), which was round-like, with a particle size of 60.33 ± 3.04 nm and a core-shell structure. Its stability was good, the drug paclitaxel (PTX) release from RBCm-PTX-NLC was less than 30% at pH7.4 and pH6.5, and the integrity of RBC membrane surface protein was maintained before and after preparation. Additionally, in vitro assays showed that, with the RBCm coating, the cellular uptake of the NLC by cancer cells was significantly enhanced. RBCm-NLC can avoid recognition by macrophage cells and prolong circulation time in vivo. In S180 tumor-bearing mice, the DiR-labeled RBCm-NLC group showed a stronger fluorescence signal and longer retention in tumor tissues, indicating a prompt tumor-targeting effect and extended blood circulation. Importantly, RBCm-PTX-NLC enhanced the antitumor effect and extended the survival period significantly in vivo. In summary, biomimetic NLC offered a novel strategy for drug delivery in cancer therapy.

Targeting of Cisplatin-Resistant Melanoma Using a Multivalent Ligand Presenting an Elastin-like Polypeptide.

Acquired drug resistance is a common occurrence and the main cause of melanoma treatment failure. Melanoma cells frequently developed resistance against cisplatin during chemotherapy, and thus, targeting delivery systems have been devised to decrease drug resistance, increase therapeutic efficacy, and reduce side effects. We genetically engineered a macromolecular carrier using the recursive directional ligation method that specifically targets cisplatin-resistant (Cis-R) melanoma. This carrier is composed of an elastin-like polypeptide (ELP) and multiple copies of Cis-R melanoma-targeting ligands (M-peptide). The designed M16E108 contains 16 targeting ligands incorporated within an ELP and has an ideal thermal phase transition at 39 °C. When treated to melanoma cells, M16E108 specifically accumulated in Cis-R B16F10 melanoma cells and accumulated to a lesser extent in parental B16F10 cells. Consistently, M16E108 exhibited efficient homing and longer retention in tumor tissues in Cis-R melanoma-bearing mice than in parental B16F10 melanoma-bearing mice. Thus, M16E108 was found to display considerable potential as a novel agent that specifically targets cisplatin-resistant melanoma.

Physical Properties of Nanoparticles That Result in Improved Cancer Targeting

The therapeutic efficacy of drugs is dependent upon the ability of a drug to reach its target, and drug penetration into tumors is limited by abnormal vasculature and high interstitial pressure. Chemotherapy is the most common systemic treatment for cancer but can cause undesirable adverse effects, including toxicity to the bone marrow and gastrointestinal system. Therefore, nanotechnology-based drug delivery systems have been developed to reduce the adverse effects of traditional chemotherapy by enhancing the penetration and selective drug retention in tumor tissues. A thorough knowledge of the physical properties (e.g., size, surface charge, shape, and mechanical strength) and chemical attributes of nanoparticles is crucial to facilitate the application of nanotechnology to biomedical applications. This review provides a summary of how the attributes of nanoparticles can be exploited to improve therapeutic efficacy. An ideal nanoparticle is proposed at the end of this review in order to guide future development of nanoparticles for improved drug targeting in vivo.

Heptamethine Cyanine Dye Mediated Drug Delivery: Hype or Hope.

This review covers the application of heptamethine cyanine dye (HMCD) mediated drug delivery. A relatively small number of HMCDs possess tumor targeting abilities, and this has spurred interest from research groups to explore them as drug delivery systems. Their tumor selectivity is primarily attributed to their uptake by certain isoforms of organic anion transporting polypeptides (OATPs) which are overexpressed in cancer tissues, although there are other possible mechanisms for the observed selectivity still under investigation. This specificity is confirmed using various cancer cell lines and is accompanied by moderate cytotoxicity. Their retention in tumor tissue is facilitated by the formation of albumin adducts as revealed by published mechanistic studies. HMCDs are also organelle selective dyes with specificity toward mitochondria and lysosomes, and with absorption and emission in the near-infrared region. This makes them valuable tools for biomedical imaging, especially in the field of fluorescence-guided tumor surgery. Furthermore, conjugating antitumor agents to HMCDs is providing novel drugs that await clinical testing. HMCD development as theranostic agents with dual tumor targeting and treatment capability signals a new approach to overcome drug resistance (mediated through evasion of efflux pumps) and systemic toxicity, the two parameters which have long plagued drug discovery.

Evaluation of a Novel Boron-Containing α-D-Mannopyranoside for BNCT.

Boron neutron capture therapy (BNCT) is a unique anticancer technology that has demonstrated its efficacy in numerous phase I/II clinical trials with boronophenylalanine (BPA) and sodium borocaptate (BSH) used as 10B delivery agents. However, continuous drug administration at high concentrations is needed to maintain sufficient 10B concentration within tumors. To address the issue of 10B accumulation and retention in tumor tissue, we developed MMT1242, a novel boron-containing α-d-mannopyranoside. We evaluated the uptake, intracellular distribution, and retention of MMT1242 in cultured cells and analyzed biodistribution, tumor-to-normal tissue ratio and toxicity in vivo. Fluorescence imaging using nitrobenzoxadiazole (NBD)-labeled MMT1242 and inductively coupled mass spectrometry (ICP-MS) were performed. The effectiveness of BNCT using MMT1242 was assessed in animal irradiation studies at the Kyoto University Research Reactor. MMT1242 showed a high uptake and broad intracellular distribution in vitro, longer tumor retention compared to BSH and BPA, and adequate tumor-to-normal tissue accumulation ratio and low toxicity in vivo. A neutron irradiation study with MMT1242 in a subcutaneous murine tumor model revealed a significant tumor inhibiting effect if injected 24 h before irradiation. We therefore report that 10B-MMT1242 is a candidate for further clinical BNCT studies.

Electrostatic driven transport enhances penetration of positively charged peptide surfaces through tumor extracellular matrix

Drug carriers achieve poor and heterogeneous distribution within solid tumors due to limited transport through the tumor extracellular matrix (ECM). The tumor ECM forms a net negatively charged network that interacts with and hinders the transport of molecules in part due to electrostatic interactions. Traditionally, the surfaces of drug delivery systems are passivated to minimize these interactions, but the mechanism of how charge interactions impact transport and penetration within the tumor microenvironment (TME) is not well understood. Here, we used T7 bacteriophage as a model biological nanoparticle to display peptides of different charges on its surface and elucidate how charge-based binding drives transport, uptake, and retention within tumor tissue. In contrast to current studies with neutrally charged surfaces, we discovered that a positively charged peptide displayed on T7 enhanced its penetration through a tumor-like ECM when compared to neutrally and negatively charged peptides. The positively charged peptide displayed on T7 facilitated weak and reversible binding with the TME to achieve Donnan partitioning and deep penetration into ex vivo tumor tissue. Additionally, the positively charged peptide-presenting T7 has a high number of intra-tissue binding sites in the TME (~4 µM) that enables almost 100% retention in the tumor tissue for up to 24 h. These results, coupled with transport studies of systematically mutated T7, show that electrostatic interactions can be responsible for uptake and retention of the positively charged peptide-presenting T7 within the net negatively charged TME. Statement of significanceThe TME selectively hinders the transport of drugs and drug delivery systems due to their size, shape, and intermolecular interactions. Typically, the focus in drug delivery has been to develop delivery systems smaller than the pore size of the tumor ECM and/or develop inert surface coatings that have negligible interactions with the tumor ECM for diffusive transport. While there is an association of the surface charge of carriers with their transport through the tumor ECM, the mechanism of charge-driven transport is poorly understood. In this work, we elucidate the mechanism and find that interestingly, particles with a weakly positive surface charge interact with the net negatively charged tumor ECM to significantly improve their uptake, penetration, and retention in tumor tissue.

Peptide 18-4/chlorin e6-conjugated polyhedral oligomeric silsesquioxane nanoparticles for targeted photodynamic therapy of breast cancer

Chlorin e6 (Ce6), with its high phototoxic potential, has wide applications in photodynamic therapy (PDT) for many human diseases. However, poor cancer cell localization of Ce6 has limited its direct application for PDT. Here, we developed cancer-targeting peptide p 18-4/chlorin e6 (Ce6)-conjugated polyhedral oligomeric silsesquioxane (PPC) nanoparticles for improving the targeting ability of Ce6 to breast cancer cells, thereby enhancing PDT efficacy. The synthesized PPC nanoparticles exhibited a spherical shape with an average diameter of 127.2 ± 11.3 nm in aqueous solution. Compared with free Ce6, the immobilization of p 18-4 enhanced the in vitro cellular uptake and targeting ability of PPC nanoparticles in breast cancer cell line MDA-MB-231. In addition, the intracellular uptake of PPC nanoparticles in MDA-MB-231 cells was dramatically increased compared with other cancer cells, indicating an obvious targeting ability of PPC nanoparticles on breast cancer cells. Upon light irradiation, PPC nanoparticles revealed significantly improved phototoxicity to MDA-MB-231 cells, mainly due to apoptotic cell death. In vivo PDT study suggested that PPC nanoparticles exhibited increased retention in tumor tissues and effectively inhibited the growth of MDA-MB-231 tumors in a target-specific manner. Overall, these results indicate that PPC nanoparticles are highly effective PDT agents for breast cancer therapy.