Two diverse carriers are better than one: A case study in α-particle therapy for prostate specific membrane antigen-expressing prostate cancers.

Partial and/or heterogeneous irradiation of established (i.e., large, vascularized) tumors by α-particles that exhibit only a 4-5 cell-diameter range in tissue, limits the therapeutic effect, since regions not being hit by the high energy α-particles are likely not to be killed.

Combination of Carriers with Complementary Intratumoral Microdistributions of Delivered -Particles May Realize the Promise for Ac in Large, Solid Tumors.

α-particle radiotherapy has already been shown to be impervious to most resistance mechanisms. However, in established (i.e.

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 (Ac), 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 Ac-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.

Daptomycin-Induced Lipid Phases on Model Lipid Bilayers: Effect of Lipid Type and of Lipid Leaflet Order on Membrane Permeability.

Daptomycin's bacterial membrane activity is partly due to the defects of lipid-packing at the boundaries of daptomycin-induced, separated lipid phases, which are rich in phosphatidylglycerol (PG). On model membranes, the permeability of phase boundaries is strongly dependent on the extent of saturation of the lipid acyl tails, which affect the lipids' ability to pack within these boundaries, and on the cross-leaflet registration of these boundaries. Using vesicles with asymmetric lipid leaflet compositions, we evaluated the role of headgroup type and/or extent of acyl-tail saturation on daptomycin-induced membrane permeability.

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.

Interstitial Release of Cisplatin from Triggerable Liposomes Enhances Efficacy against Triple Negative Breast Cancer Solid Tumor Analogues.

Liposomal cisplatin, a promising triple negative breast cancer treatment modality, has been shown to decrease toxicities associated with cisplatin's free agent form. However, the heterogeneous intratumoral distributions of the liposomes themselves, combined with limited release of cisplatin from them contribute to limited penetration of cisplatin within tumors reducing efficacy. This study uses pH-responsive liposomes designed to release cisplatin within the acidic tumor interstitium (7.