Combined, yet separate: cocktails of carriers (not drugs) for actinium-225 α-particle therapy of solid tumors expressing moderate-to-low levels of targetable markers.

Alpha-particle radionuclide-antibody conjugates are being clinically evaluated against solid tumors even when they moderately express the targeted markers. At this limit of lower tumor-absorbed doses, to maintain efficacy, the few(er) intratumorally delivered alpha-particles need to traverse/hit as many different cancer cells as possible. We complement antibody-radioconjugate therapies with a separate nanocarrier delivering a fraction of the same total injected radioactivity to tumor regions geographically different than those affected by targeting antibodies; these carrier-cocktails collectively distribute the alpha-particle emitters better. METHODS: The efficacy of actinium-225 delivered by our carrier-cocktails was assessed in vitro and on mice with orthotopic MDA-MB-436 and/or MDA-MB-231 triple-negative breast cancers and/or an ectopic BxPC3 pancreatic cancer. Cells/tumors were chosen to express low-to-moderate levels of HER1, as model antibody-targeted marker. RESULTS: Independent of cell line, antibody-radioconjugates were most lethal on cell monolayers. On spheroids, with radii greater than alpha-particles' range, carrier-cocktails improved killing efficacy (p < 0.0500). Treatment with carrier-cocktails decreased the MDA-MB-436 and MDA-MB-231 orthotopic tumor volumes by 73.7% and 72.1%, respectively, relative to treatment with antibody-radioconjugates alone, at same total injected radioactivity; these carrier-cocktails completely eliminated formation of spontaneous metastases vs. 50% and 25% elimination in mice treated with antibody-radioconjugates alone. In BxPC3 tumor-bearing mice, carrier-cocktails increased the median survival to 25-26 days (in male-female animals) vs. 20-21 days of mice treated with antibody-radioconjugates alone (vs. 17 days for non-treated animals). Survival with carrier-cocktail radiotherapy was further prolonged by pre-injecting low-dose, standard-of-care, gemcitabine (p = 0.0390). CONCLUSION: Tumor-agnostic carrier-cocktails significantly enhance the therapeutic efficacy of existing alpha-particle radionuclide-antibody treatments.

Lipoplexes' Structure, Preparation, and Role in Managing Different Diseases.

Lipid-based vectors are becoming promising alternatives to traditional therapies over the last 2 decades specially for managing life-threatening diseases like cancer. Cationic lipids are the most prevalent non-viral vectors utilized in gene delivery. The increasing number of clinical trials about lipoplex-based gene therapy demonstrates their potential as well-established technology that can provide robust gene transfection. In this regard, this review will summarize this important point. These vectors however have a modest transfection efficiency. This limitation can be partly addressed by using functional lipids that provide a plethora of options for investigating nucleic acid-lipid interactions as well as in vitro and in vivo nucleic acid delivery for biomedical applications. Despite their lower gene transfer efficiency, lipid-based vectors such as lipoplexes have several advantages over viral ones: they are less toxic and immunogenic, can be targeted, and are simple to produce on a large scale. Researchers are actively investigating the parameters that are essential for an effective lipoplex delivery method. These include factors that influence the structure, stability, internalization, and transfection of the lipoplex. Thorough understanding of the design principles will enable synthesis of customized lipoplex formulations for life-saving therapy.

Predicting response of micrometastases with MIRDcell V3: proof of principle with 225Ac-DOTA encapsulating liposomes that produce different activity distributions in tumor spheroids.

PURPOSE: The spatial distribution of radiopharmaceuticals within multicellular clusters is known to have a significant effect on their biological response. Most therapeutic radiopharmaceuticals distribute nonuniformly in tissues which makes predicting responses of micrometastases challenging. The work presented here analyzes published temporally dependent nonuniform activity distributions within tumor spheroids treated with actinium-225-DOTA encapsulating liposomes (225Ac-liposomes) and uses these data in MIRDcell V3.11 to calculate absorbed dose distributions and predict biological response. The predicted responses are compared with experimental responses. METHODS: Four types of liposomes were prepared having membranes with different combinations of release (R) and adhesion (A) properties. The combinations were R-A-, R-A+, R+A-, and R+A+. These afford different penetrating properties into tissue. The liposomes were loaded with either carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) or 225Ac. MDA-MB-231 spheroids were treated with the CFDA-SE-liposomes, harvested at different times, and the time-integrated CFDA-SE concentration at each radial position within the spheroid was determined. This was translated into mean 225Ac decays/cell versus radial position, uploaded to MIRDcell, and the surviving fraction of cells in spherical multicellular clusters was simulated. The MIRDcell-predicted surviving fractions were compared with experimental fractional-outgrowths of the spheroids following treatment with 225Ac-liposomes. RESULTS: The biological responses of the multicellular clusters treated with 225Ac-liposomes with physicochemical properties R+A+, R-A+, and R-A- were predicted by MIRDcell with statistically significant accuracy. The prediction for R+A- was not predicted accurately. CONCLUSION: In most instances, MIRDcell predicts responses of spheroids treated with 225Ac-liposomes that result in different tissue-penetrating profiles of the delivered radionuclides.

Transport-driven engineering of liposomes for delivery of α-particle radiotherapy to solid tumors: effect on inhibition of tumor progression and onset delay of spontaneous metastases.

PURPOSE: Highly cytotoxic α-particle radiotherapy delivered by tumor-selective nanocarriers is evaluated on metastatic Triple Negative Breast Cancer (TNBC). On vascularized tumors, the limited penetration of nanocarriers (<50-80 µm) combined with the short range of α-particles (40-100 µm) may, however, result in only partial tumor irradiation, compromising efficacy. Utilizing the α-particle emitter Actinium-225 (225Ac), we studied how the therapeutic potential of a general delivery strategy using nanometer-sized engineered liposomes was affected by two key transport-driven properties: (1) the release from liposomes, when in the tumor interstitium, of the highly diffusing 225Ac-DOTA that improves the uniformity of tumor irradiation by α-particles and (2) the adhesion of liposomes on the tumors' ECM that increases liposomes' time-integrated concentrations within tumors and, therefore, the tumor-delivered radioactivities. METHODS: On an orthotopic MDA-MB-231 TNBC murine model forming spontaneous metastases, we evaluated the maximum tolerated dose (MTD), biodistributions, and control of tumor growth and/or spreading after administration of 225Ac-DOTA-encapsulating liposomes, with different combinations of the two transport-driven properties. RESULTS: At 83% of MTD, 225Ac-DOTA-encapsulating liposomes with both properties (1) eliminated formation of spontaneous metastases and (2) best inhibited the progression of orthotopic xenografts, compared to liposomes lacking one or both properties. These findings were primarily affected by the extent of uniformity of the intratumoral microdistributions of 225Ac followed by the overall tumor uptake of radioactivity. At the MTD, long-term toxicities were not detected 9.5 months post administration. CONCLUSION: Our findings demonstrate the potential of a general, transport-driven strategy enabling more uniform and prolonged solid tumor irradiation by α-particles without cell-specific targeting.

Growth of Metastatic Triple-Negative Breast Cancer Is Inhibited by Deep Tumor-Penetrating and Slow Tumor-Clearing Chemotherapy: The Case of Tumor-Adhering Liposomes with Interstitial Drug Release.

The poor prognosis of triple-negative breast cancer (TNBC) is attributed largely to the lack of tumor-selective therapeutic modalities that effectively deliver lethal doses at the sites of metastatic disease. Tumor-selective drug delivery strategies that aim to improve uniformity in intratumoral drug microdistributions and to prolong exposure of these cancer cells to delivered therapeutics may improve therapeutic efficacy against established TNBC metastases. In this study, we present lipid carriers for selective (due to their nanometer size) tumor delivery, which are loaded with cisplatin and designed to exhibit the following properties when in the tumor interstitium: (1) interstitial drug release (for deeper tumor penetration of cisplatin) and/or (2) intratumoral/interstitial adhesion of the carriers to tumors' extracellular matrix (ECM)-not accompanied by cell internalization-for delayed tumor clearance of carriers prolonging cancer cell exposure to the cisplatin being released. We show that on large multicellular spheroids, used as surrogates of avascular solid tumor regions, greater growth inhibition was strongly correlated with spatially more uniform drug concentrations (due to interstitial drug release) and with longer exposure to the released drug (i.e., higher time-integrated drug concentrations enabled by slow clearing of adhesive nanoparticles). Lipid nanoparticles with both the release and adhesion properties were the most effective, followed by nanoparticles with only the releasing property and then by nanoparticles with only the adhering property. In vivo, cisplatin-loaded nanoparticles with releasing and/or adhering properties significantly inhibited the growth of spontaneous TNBC metastases compared to conventional liposomal cisplatin, and the efficacy of different property combinations followed the same trends as in spheroids. This study demonstrates the therapeutic potential of a general strategy to bypass treatment limitations of established TNBC metastases due to the lack of cell-targeting markers: aiming to optimize the temporal intratumoral drug microdistributions for more uniform and prolonged drug exposure.

Surface-functionalised polymeric nanoparticles for breast cancer treatment: processes and advances.

The World Health Organization (WHO) reported that of all the non-communicable diseases, cancer is considered the second cause of death worldwide. This has driven the big pharma companies to prioritise anticancer products in their pipeline. In addition, research has focused on exploration of new anticancer molecules and design of suitable dosage forms to achieve effective drug delivery to the tumour site. Nanotechnology is a valuable tool to build nano delivery systems with controlled and targeted drug release properties. Nanoparticles can be fabricated by robust, scalable and economic techniques using various polymers. Moreover, specific functional groups can be introduced to the surface of nanoparticles enabling targeting to a specific tissue; besides, they exhibit versatile drug release patterns according to the rate of polymer degradation. This review outlines the processes and advances in surface functionalisation of nanoparticles employed for treatment of breast cancer. The therapeutic molecules, the polymers used to fabricate nanoparticles, the techniques used to prepare the nanoparticles have been reviewed with a focus on the processes employed to functionalise these nanoparticles with suitable ligands to target different types of breast cancer.

State-of-the-art drug delivery system to target the lymphatics.

PRIMARY OBJECTIVE: The primary objective of the review is to assess the potential of lymphatic-targeted drug delivery systems, with a particular emphasis on their role in tumour therapy and vaccination efficacy. REASON FOR LYMPHATIC TARGETING: The lymphatic system's crucial functions in maintaining bodily equilibrium, regulating metabolism, and orchestrating immune responses make it an ideal target for drug delivery. Lymph nodes, being primary sites for tumour metastasis, underscore the importance of targeting the lymphatic system for effective treatment. OUTCOME: Nanotechnologies and innovative biomaterials have facilitated the development of lymphatic-targeted drug carriers, leveraging endogenous macromolecules to enhance drug delivery efficiency. Various systems such as liposomes, micelles, inorganic nanomaterials, hydrogels, and nano-capsules demonstrate significant potential for delivering drugs to the lymphatic system. CONCLUSION: Understanding the physiological functions of the lymphatic system and its involvement in diseases underscores the promise of targeted drug delivery in improving treatment outcomes. The strategic targeting of the lymphatic system presents opportunities to enhance patient prognosis and advance therapeutic interventions across various medical contexts, indicating the importance of ongoing research and development in this area.

Harnessing DNA origami's therapeutic potential for revolutionizing cardiovascular disease treatment: A comprehensive review.

DNA origami is a cutting-edge nanotechnology approach that creates precise and detailed 2D and 3D nanostructures. The crucial feature of DNA origami is how it is created, which enables precise control over its size and shape. Biocompatibility, targetability, programmability, and stability are further advantages that make it a potentially beneficial technique for a variety of applications. The preclinical studies of sophisticated programmable nanomedicines and nanodevices that can precisely respond to particular disease-associated triggers and microenvironments have been made possible by recent developments in DNA origami. These stimuli, which are endogenous to the targeted disorders, include protein upregulation, pH, redox status, and small chemicals. Oncology has traditionally been the focus of the majority of past and current research on this subject. Therefore, in this comprehensive review, we delve into the intricate world of DNA origami, exploring its defining features and capabilities. This review covers the fundamental characteristics of DNA origami, targeting DNA origami to cells, cellular uptake, and subcellular localization. Throughout the review, we emphasised on elucidating the imperative for such a therapeutic platform, especially in addressing the complexities of cardiovascular disease (CVD). Moreover, we explore the vast potential inherent in DNA origami technology, envisioning its promising role in the realm of CVD treatment and beyond.