Remotely Phototriggered, Transferrin-Targeted Polymeric Nanoparticles for the Treatment of Breast Cancer.

Triple-negative breast cancer (TNBC) has the worst prognosis among all subtypes of breast cancer. Currently, no targeted treatment has been approved for TNBC. The goal of this study was to design a remotely triggered, targeted therapy for TNBC using polymeric nanoparticles and light. Active targeting of TNBC was achieved by conjugating the nanoparticles to a peptide (hTf) that binds to the transferrin receptor, which is overexpressed in TNBC. Photodynamic therapy (PDT) was explored for TNBC treatment by remotely triggering benzoporphyrin derivative monoacid (BPD), a photosensitizer, using near-infrared light. In this study, we investigated the use of actively targeting polymeric nanoparticles for PDT against TNBC using in vitro imaging and cytotoxicity studies. Fluorescence imaging confirmed that the BPD-loaded nanoparticles showed greater fluorescence in TNBC cells compared to free BPD, but more importantly, actively targeted nanoparticles displayed stronger fluorescence compared to passively targeted nanoparticles. Moreover, fluorescence imaging following competition with empty targeted nanoparticles validated the specificity of the targeted nanoparticles for TNBC cells. The PDT killing results were in line with the fluorescence imaging results, where actively targeting nanoparticles exhibited the highest phototriggered cytotoxicity in TNBC cells, making them an attractive nanoplatform for TNBC treatment.

Co-Administered Polymeric Nano-Antidotes for Improved Photo-Triggered Response in Glioblastoma.

Polymer-based nanoparticles (NPs) are useful vehicles in treating glioblastoma because of their favorable characteristics such as small size and ability to cross the blood⁻brain barrier, as well as reduced immunogenicity and side effects. The use of a photosensitizer drug such as Verteporfin (BPD), in combination with a pan-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), Cediranib (CED), encapsulated in NPs will provide the medical field with new research on the possible ways to treat glioblastoma. Concomitant administration of BPD and CED NPs have the potential to induce dual photocytotoxic and cytostatic effects in U87 MG cells by (1) remotely triggering BPD through photodynamic therapy by irradiating laser at 690 nm and subsequent production of reactive oxygen species and (2) inhibiting cell proliferation by VEGFR interference and growth factor signaling mechanisms which may allow for longer progression free survival in patients and fewer systemic side effects. The specific aims of this research were to synthesize, characterize and assess cell viability and drug interactions for polyethylene-glycolated (PEGylated) polymeric based CED and BPD NPs which were less than 100 nm in size for enhanced permeation and retention effects. Synergistic effects were found using the co-administered therapies compared to the individual drugs. The major goal of this research was to investigate a new combination of photodynamic-chemotherapy drugs in nano-formulation for increased efficacy in glioblastoma treatment at reduced concentrations of therapeutics for enhanced drug delivery in vitro.

Targeting Strategies for the Combination Treatment of Cancer Using Drug Delivery Systems.

Cancer cells have characteristics of acquired and intrinsic resistances to chemotherapy treatment-due to the hostile tumor microenvironment-that create a significant challenge for effective therapeutic regimens. Multidrug resistance, collateral toxicity to normal cells, and detrimental systemic side effects present significant obstacles, necessitating alternative and safer treatment strategies. Traditional administration of chemotherapeutics has demonstrated minimal success due to the non-specificity of action, uptake and rapid clearance by the immune system, and subsequent metabolic alteration and poor tumor penetration. Nanomedicine can provide a more effective approach to targeting cancer by focusing on the vascular, tissue, and cellular characteristics that are unique to solid tumors. Targeted methods of treatment using nanoparticles can decrease the likelihood of resistant clonal populations of cancerous cells. Dual encapsulation of chemotherapeutic drug allows simultaneous targeting of more than one characteristic of the tumor. Several first-generation, non-targeted nanomedicines have received clinical approval starting with Doxil® in 1995. However, more than two decades later, second-generation or targeted nanomedicines have yet to be approved for treatment despite promising results in pre-clinical studies. This review highlights recent studies using targeted nanoparticles for cancer treatment focusing on approaches that target either the tumor vasculature (referred to as 'vascular targeting'), the tumor microenvironment ('tissue targeting') or the individual cancer cells ('cellular targeting'). Recent studies combining these different targeting methods are also discussed in this review. Finally, this review summarizes some of the reasons for the lack of clinical success in the field of targeted nanomedicines.

Targeting Cancer using Polymeric Nanoparticle mediated Combination Chemotherapy.

Cancer forms exhibiting poor prognosis have been extensively researched for therapeutic solutions. One of the conventional modes of treatment, chemotherapy shows inadequacy in its methodology due to imminent side-effects and acquired drug-resistance by cancer cells. However, advancements in nanotechnology have opened new frontiers to significantly alleviate collateral damage caused by current treatments via innovative delivery techniques, eliminating pitfalls encountered in conventional treatments. Properties like reduced drug-clearance and increased dose efficacy by the enhanced permeability and retention effect deem nanoparticles suitable for this application. Optimization of size, surface charge and surface modifications have provided nanoparticles with stealth properties capable of evading immune responses, thus deeming them as excellent carriers of chemotherapeutic agents. Biocompatible and biodegradable forms of polymers enhance the bioavailability of chemotherapeutic agents, and permit a sustained and time-dependent release of drugs which is a characteristic of their composition, thereby providing a controlled therapeutic approach. Studies conducted in vitro and animal models have also demonstrated a synergism in cytotoxicity given the mechanism of action of anticancer drugs when administered in combination providing promising results. Combination therapy has also shown implications in overcoming multiple-drug resistance, which can however be subdued by the adaptable nature of tumor microenvironment. Surface modifications with targeting moieties can therefore feasibly increase nanoparticle uptake by specific receptor-ligand interactions, increasing dose efficacy which can seemingly overcome drug-resistance. This article reviews recent trends and investigations in employing polymeric nanoparticles for effectively delivering combination chemotherapy, and modifications in delivery parameters enhancing dose efficacy, thus validating the potential in this approach for anticancer treatment.