Radiotherapy reimagined: Integrating nanomedicines into radiotherapy clinical trials.

Radioenhancing nanoparticles (NPs) are being evaluated in ongoing clinical trials for various cancers including head and neck, lung, esophagus, pancreas, prostate, and soft tissue sarcoma. Supported by decades of preclinical investigation and recent randomized trial data establishing clinical activity, these agents are poised to influence future multimodality treatment paradigms involving radiotherapy. Although the physical interactions between NPs and ionizing radiation are well characterized, less is known about how these agents modify the tumor microenvironment, particularly regarding tumor immunogenicity. In this review, we describe the key multidisciplinary considerations related to radiation, surgery, immunology, and pathology for designing radioenhancing NP clinical trials. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Preclinical data on co-delivery of temozolomide and talazoparib by fucodain-coated nanoscale metal organic frameworks for colorectal cancer chemoradiation.

Nanoparticle characterization and in vitro data on the effects of combined PARP inhibition and DNA damage by chemoradiation are shown. This data accompanies the research article "Fucoidan-coated nanoparticles target radiation-induced P-selectin to enhance chemoradiotherapy in murine colorectal cancer" (DuRoss et al., 2021) Additional characterization of the physiochemical properties of nanoscale metal organic frameworks (nMOFs) comprised of hafnium and 1,4-dicarboxybenzene (Hf-BDC) loaded with temozolomide (TMZ) and talazoparib (Tal) are presented. Toxicity data of the drug-loaded nMOF coated with fucoidan (TT@Hf-BDC-Fuco) in colorectal cancer cells, CT-26, from alamarBlue-based chemoradiation experiments are shown. Experimental methods for the nanoparticle characterization and cell-based assays of the nMOF formulation are presented.

Fucoidan-coated nanoparticles target radiation-induced P-selectin to enhance chemoradiotherapy in murine colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer-related death for both men and women, highlighting the need for new treatment strategies. Advanced disease is often treated with a combination of radiation and cytotoxic agents, such as DNA damage repair inhibitors and DNA damaging agents. To optimize the therapeutic window of these multimodal therapies, advanced nanomaterials have been investigated to deliver sensitizing agents or enhance local radiation dose deposition. In this study, we demonstrate the feasibility of employing an inflammation targeting nanoscale metal-organic framework (nMOF) platform to enhance CRC treatment. This novel formulation incorporates a fucoidan surface coating to preferentially target P-selectin, which is over-expressed or translocated in irradiated tumors. Using this radiation stimulated delivery strategy, a combination PARP inhibitor (talazoparib) and chemotherapeutic (temozolomide) drug-loaded hafnium and 1,4-dicarboxybenzene (Hf-BDC) nMOF was evaluated both in vitro and in vivo. Significantly, these drug-loaded P-selectin targeted nMOFs (TT@Hf-BDC-Fuco) show improved tumoral accumulation over multiple controls and subsequently enhanced therapeutic effects. The integrated radiation and nanoformulation treatment demonstrated improved tumor control (reduced volume, density, and growth rate) and increased survival in a syngeneic CRC mouse model. Overall, the data from this study support the continued investigation of radiation-priming for targeted drug delivery and further consideration of nanomedicine strategies in the clinical management of advanced CRC.

Development of a Pemetrexed/Folic Acid Nanoformulation: Synthesis, Characterization, and Efficacy in a Murine Colorectal Cancer Model.

The folate analogue pemetrexed (PEM) is an approved therapeutic for non-small cell lung cancer and malignant pleural mesothelioma with the potential for broader application in combination therapies. Here, we report the development of a nanoformulation of PEM and its efficacy against the CT26 murine colorectal cancer cell line in vitro and in vivo. Utilizing layer-by-layer deposition, we integrate PEM, along with folic acid (FA), onto a fluorescent polystyrene nanoparticle (NP) substrate. The final nanoformulation (PEM/FA-NP) has a size of ∼40 nm and a zeta potential of approximately -20 mV. Cell uptake studies indicated increased uptake in vitro for the PEM/FA-NP compared to the uncoated NP, likely due to the presence of PEM and FA. Viability studies were performed to determine the potency of the PEM/FA-NP formulation against CT26 cells. Syngeneic CT26 tumors in BALB/c mice showed reduced growth when treated once daily (2.1 mg/kg PEM) for 3 days with PEM/FA-NP versus the vehicle (uncoated) control, with no observable signs of systemic toxicity associated with the nanoformulation. Although the current study size is limited (n = 4 animals for each group), the overall performance and biocompatibility of the PEM/FA-NP observed suggest that further optimization and larger-scale studies may be warranted for this novel formulation.

Formulation of Folate-Modified Raltitrexed-Loaded Nanoparticles for Colorectal Cancer Theranostics.

Multifunctional nanoparticles (NPs) that enable the imaging of drug delivery and facilitate cancer cell uptake are potentially powerful tools in tailoring oncologic treatments. Here we report the development of a layer-by-layer (LbL) formulation of folic acid (FA) and folate antimetabolites that have been well-established for enhanced tumor uptake and as potent chemotherapeutics, respectively. To investigate the uptake of LbL coated NPs, we deposited raltitrexed (RTX) or combined RTX-FA on fluorescent polystyrene NPs. The performance of these NP formulations was evaluated with CT26 murine colorectal cancer (CRC) cells in vitro and in vivo to examine both uptake and cytotoxicity against CRC. Fluorescence microscopy and flow cytometry indicated an increased accumulation of the coated NP formulations versus bare NPs. Ex vivo near-infrared (NIR) fluorescence imaging of major organs suggested the majority of NPs accumulated in the liver, which is typical of a majority of NP formulations. Imaging of the CRC tumors alone showed a higher average fluorescence from NPs accumulated in animals treated with the coated NPs, with the majority of RTX NP-treated animals showing the consistently-highest mean tumoral accumulation. Overall, these results contribute to the development of LbL formulations in CRC theranostic applications.

Inverse-micelle synthesis of doxorubicin-loaded alginate/chitosan nanoparticles and in vitro assessment of breast cancer cytotoxicity.

Naturally-derived polysaccharides, such as alginate and chitosan, can be assembled to form nanocarriers for the delivery of therapeutic agents. Here we exploit the electrostatic complexation of alginate/chitosan in a water-in-oil (w/o) emulsion process to produce doxorubicin (DOX)-loaded nanoparticles (~80 nm) with exceptional spherical morphology and uniformity. This robust synthetic route utilizes an aqueous phase dispersed in a cyclohexane/dodecylamine organic phase and is capable of encapsulating DOX in the nanoparticle solution. The uptake and efficacy of this novel formulation was evaluated in a murine breast cancer cell line, 4T1, with comparable 72 h IC50 values of the nanoparticle solution (0.15 µg/mL) and free DOX (0.13 µg/mL). Overall, the favorable performance, physiochemical properties, and their facile production support these nanocarriers as promising platform for the delivery of aqueous soluble drugs.

Integrating nanomedicine into clinical radiotherapy regimens.

While the advancement of clinical radiotherapy was driven by technological innovations throughout the 20th century, continued improvement relies on rational combination therapies derived from biological insights. In this review, we highlight the importance of combination radiotherapy in the era of precision medicine. Specifically, we survey and summarize the areas of research where improved understanding in cancer biology will propel the field of radiotherapy forward by allowing integration of novel nanotechnology-based treatments.

Micellar Formulation of Talazoparib and Buparlisib for Enhanced DNA Damage in Breast Cancer Chemoradiotherapy.

Chemoradiation is an effective combined modality therapeutic approach that utilizes principles of spatial cooperation to combat the adaptability associated with cancer and to potentially expand the therapeutic window. Optimal therapeutic efficacy requires intelligent selection and refinement of radiosynergistic pharmaceutical agents, enhanced delivery methods, and temporal consideration. Here, a monodisperse sub-20 nm mixed poloxamer micelle (MPM) system was developed to deliver hydrophobic drugs intravenously, in tandem with ionizing radiation. This report demonstrates in vitro synergy and enhanced radiosensitivity when two molecularly targeted DNA repair inhibitors, talazoparib and buparlisib, are encapsulated and combined with radiation in a 4T1 murine breast cancer model. Evaluation of in vivo biodistribution and toxicity exhibited no reduction in particle accumulation upon radiation and a lack of both acute and chronic toxicities. In vivo efficacy studies suggested the promise of combining talazoparib, buparlisib, and radiation to enhance survival and control tumor growth. Tissue analysis suggests enhanced DNA damage leading to apoptosis, thus increasing efficacy. These findings highlight the challenges associated with utilizing clinically relevant inclusion criteria and treatment protocols because complete tumor regression and extended survival were masked by an aggressively metastasizing model. As with clinical treatment regimens, the findings here establish a need for further optimization of this multimodal platform.

Nanoalginates via Inverse-Micelle Synthesis: Doxorubicin-Encapsulation and Breast Cancer Cytotoxicity.

Crosslinked-biopolymer nanoparticles provide a convenient platform for therapeutic encapsulation and delivery. Here, we present a robust inverse-micelle process to load water-soluble drugs into a calcium-crosslinked alginate matrix. The utility of the resulting nanoalginate (NALG) carriers was assessed by a doxorubicin (DOX) formulation (NALG-DOX) and evaluating its potency on breast cancer cells (4T1). This facile synthesis process produced doxorubicin-containing particles of ~ 83 nm by hydrodynamic size and zeta potential ~ 7.2 mV. The cyclohexane/dodecylamine microemulsion yielded uniform and spherical nanoparticles as observed by electron microscopy. The uptake of the drug from the NALG-DOX formulation in 4T1 cells was observed by fluorescence microscopy employing doxorubicin's inherent fluorescence. Therapeutic efficacy of the NALG-DOX against 4T1 cells was demonstrated qualitatively through a LIVE/DEAD fluorescence assay and quantitatively via cell viability assay (Alamar Blue). In addition, IC50 values were determined, with encapsulated doxorubicin having a slightly higher value. No toxicity of the empty NALG carrier was observed. Overall, these results demonstrate the utility of this synthesis process for encapsulation of hydrophilic therapeutics and NALG to function as a drug carrier.

Biodistribution and Toxicity of Micellar Platinum Nanoparticles in Mice via Intravenous Administration.

Platinum nanoparticles (PtNPs) have shown promise as diagnostic and therapeutic agents due to their unique physiochemical properties. However, critical parameters, such as toxicity and accumulation at both desired and other tissues, remain a significant concern in the clinical translation of these nanomaterials. Here, we examine the cytotoxicity, biodistribution, and effect on clearance organ function of an intravenously administered polyethylene glycol (PEG) -ylated PtNP construct. We synthesized hydrophobic PtNPs and assembled them into aqueous micelles with the lipid-polymer conjugate 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-PEG (PtNP: DSPE-PEG, ~70 nm). This construct was well tolerated in mice receiving up to 15 mg platinum per kg body weight with no observed loss in weight, plasma chemistry within normal healthy ranges, and normal histopathology of organs after three weeks. Platinum quantification studies (inductively-coupled plasma mass spectroscopy (ICP-MS)) were also performed to assess biodistribution of PtNPs. The findings of this study are consistent with the in vivo accumulation of metal nanomaterials and further highlight the need to address clearance when designing nanomaterials for medical applications.