A new modality of drug targeting to tumors has been proposed. The ligand-mediated approach, that already increases the therapeutic index of the drug, can still be optimized by the encapsulation of the drug into sonosensitive nanoparticles. In this work, an endogenous ligand, estrone, was used to synthesize doxorubicin-encapsulating liposomes for estrogen receptor (ER)-positive breast cancer therapy with cyanuric chloride (2,4,6 trichloro-1,3,5 triazine) being used as a linking molecule to attach 3-OH group of estrone to the surface of liposomes. Then, drug release from liposomes was studied using ultrasound waves as a triggering mechanism with different frequencies and power densities. In addition, drug uptake by two cell lines ER-positive (MCF-7) and ER-negative (MDA-MB-231) was assessed, with the former cell line being examined later to study the synergetic effect of the receptor mediator targeting and ultrasound trigger. The sizes of the liposomes loaded with calcein (as a doxorubicin model drug) were determined by dynamic light scattering, and they were characterized as large unilamellar vesicles (LUVs). The release from the prepared liposomes triggered by ultrasound (US) waves at low frequency (20 kHz) and high frequency (1.07 and 3.24 MHz), at several power densities, was determined by monitoring the changes in calcein fluorescence, using a spectrofluorometer. Increasing power densities showed a significant effect on release at high frequencies and during the first two US pulses at low frequency. The echogenicity of the liposomes was proven and characterized at different power densities and frequencies. To confirm the viability of the carrier as a doxorubicin carrier, doxorubicin-encapsulating liposomes were prepared using the ammonium sulfate transmembrane gradient method. The liposomes were LUVs and were US-sensitive, exhibiting similar behavior to calcein-encapsulating liposomes. The calcein uptake by an ER + cell line (MCF-7) was compared with the uptake by an ER-cell line (MDA-MB-231). The MCF-7 uptake was significantly higher than the MDA-MB-231 uptake, which proved the targeting potential of estrone-conjugated liposomes. The exposure to low-frequency ultrasound (LFUS) revealed a statistically significant uptake of calcein compared to uptake without ultrasound. The described drug delivery (DD) system, comprising a new echogenic liposomal formulation, promises a non-immunogenic and site-specific biomedical approach to ER-positive breast cancer therapy.

Semicrystalline polymers are ubiquitous, yet despite their fundamental and industrial importance, the theory of homogeneous nucleation from a melt remains a subject of debate. A key component of the controversy is that polymer crystallization is a non-equilibrium process, making it difficult to distinguish between effects that are purely kinetic and those that arise from the underlying thermodynamics. Due to computational cost constraints, simulations of polymer crystallization typically employ non-equilibrium molecular dynamics techniques with large degrees of undercooling that further exacerbate the coupling between thermodynamics and kinetics. In a departure from this approach, in this study, we isolate the near-equilibrium nucleation behavior of a simple model of a melt of short, semiflexible oligomers. We employ several Monte Carlo methods and compute a phase diagram in the temperature–density plane along with two-dimensional free energy landscapes (FELs) that characterize the nucleation behavior. The phase diagram shows the existence of ordered nematic and crystalline phases in addition to the disordered melt phase. The minimum free energy path in the FEL for the melt–crystal transition shows a cooperative transition, where nematic order and monomer positional order move in tandem as the system crystallizes. This near-equilibrium phase transition mechanism broadly agrees with recent evidence that polymer stiffness plays an important role in crystallization but differs in the specifics of the mechanism from several recent theories. We conclude that the computation of multidimensional FELs for models that are larger and more fine-grained will be important for evaluating and refining theories of homogeneous nucleation for polymer crystallization.

While the process by which a polymer crystal nucleates from the melt has been extensively studied via molecular simulation, differences in polymer models and simulated crystallization conditions have led to contradictory results. We make steps to resolve this controversy by computing low-temperature phase diagrams of oligomer melts using Wang Landau Monte Carlo simulations. Two qualitatively different crystallization mechanisms are possible depending on the local bending stiffness potential. Polymers with a discrete bending potential crystallize via a single-step mechanism, whereas polymers with a continuous bending potential can crystallize via a two-step mechanism that includes an intermediate nematic phase. Other model differences can be quantitatively accounted for using an effective volume fraction and a temperature scaled by the bending stiffness. These results suggest that at least two universality classes of nucleation exist for melts and that local chain stiffness is a key determining factor in the mechanism of nucleation.