There are several barriers that drug molecules encounter in body beginning from kidney filtration and reticulo-endothelial system (RES) clearance to cellular trafficking. Multifunctional nanocarriers have a great potential for the delivery of drugs by enhancing therapeutic activity of existing methodologies. A variety of nanocarriers are constructed by different material types, which have unique physicochemical properties for drug delivery applications. Micelles formed by amphiphilic polymers are one of the most important drug/nanocarrier formulation products, in which the core part is suitable for encapsulation of hydrophobic agent whereas the outer shell can be utilized for targeting the drug to the disease area. Micelles as self-assembled nanostructures may encounter difficulties in biodistribution of encapsulated drugs because they have a tendency to be dissociated in dilution or high ionic strength. Therefore, therapeutic efficiency is decreased and it requires high amount of drug to be administered to achieve more efficient result. To overcome this problem, covalently stabilized structures produced by cross-linking in core or shell part, which can prevent the micelle dissociation and regulate drug release, have been proposed. These systems can be designed as responsive systems in which cross-links are degradable or hydrolysable under specific conditions such as low pH or reductive environment. These are enhancing characteristics in drug delivery because their cleavage allows the release of bioactive agent encapsulated in the carrier at a certain site or time. This review describes the chemical methodologies for the preparation of cross-linked micelles, and reports an update of latest studies in literature.

Research on the conjugates of synthetic polyelectrolytes with antigenic molecules, such as proteins, peptides, or carbohydrates, is an attractive area due to their highly immunogenic character in comparison to classical adjuvants. For example, polyacrylic acid (PAA) is a weak polyelectrolyte and has been used in several biomedical applications such as immunological studies, drug delivery, and enzyme immobilization. However, to our knowledge, there are no studies that document immune-stimulant properties of PAA in Leishmania infection. Therefore, we aimed to develop a potential vaccine candidate against leishmaniasis by covalently conjugating PAA with an immunologically vital molecule of lipophosphoglycan (LPG) found in Leishmania parasites. In the study, LPG and PAA were conjugated by a multi-step procedure, and final products were analyzed with GPC and MALDI-TOF MS techniques. In cytotoxicity experiments, LPG-PAA conjugates did not indicate toxic effects on L929 and J774 murine macrophage cells. We assume that LPG-PAA conjugate can be a potential vaccine candidate, and will be immunologically characterized in further studies to prove its potential.

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Here, a targeted, dual‐pH responsive, and stable micelle nanocarrier is designed, which specifically selects an HER2 receptor on breast cancer cells. Intracellularly degradable and stabilized micelles are prepared by core cross‐linking via reversible addition−fragmentation chain‐transfer (RAFT) polymerization with an acid‐sensitive cross‐linker followed by the conjugation of maleimide–doxorubicin to the pyridyl disulfide‐modified micelles. Multifunctional nanocarriers are obtained by coupling HER2‐specific peptide. Formation of micelles, addition of peptide and doxorubicin (DOX) are confirmed structurally by spectroscopical techniques. Size and morphological characterization are performed by Zetasizer and transmission electron microscope (TEM). For the physicochemical verification of the synergistic acid‐triggered degradation induced by acetal and hydrazone bond degradation, Infrared spectroscopy and particle size measurements are used. Drug release studies show that DOX release is accelerated at acidic pH. DOX‐conjugated HER2‐specific peptide‐carrying nanocarriers significantly enhance cytotoxicity toward SKBR‐3 cells. More importantly, no selectivity toward MCF‐10A cells is observed compared to HER2(+) SKBR‐3 cells. Formulations cause apoptosis depending on Bax and Caspase‐3 and cell cycle arrest in G2 phase. This study shows a novel system for HER2‐targeted therapy of breast cancer with a multifunctional nanocarrier, which has higher stability, dual pH‐sensitivity, selectivity, and it can be an efficient way of targeted anticancer drug delivery.

In this study, we describe the synthesis and aqueous solution behavior of temperature-sensitive N-(3-sulfopropyl)-N-methacroyloxyethyl-N,N-dimethylammonium betaine (SBMA) homopolymers and core cross-linked micelles (CCMs) with an SBMA shell. Reversible addition–fragmentation chain transfer polymerization has been utilized to synthesize sulfobetaine homopolymers, followed by CCM formation during copolymerization in the presence of an acid-degradable cross-linker. First, SBMA homopolymers of varying chain lengths were synthesized, and it has been demonstrated that an increase in the chain length and concentration of the homopolymer resulted in an increase in the upper critical solution temperature (UCST). Besides, micelles showed concentration-dependent dual temperature-sensitive behavior with UCST and LCST transitions. Also, homopolymers and CCMs were characterized by FTIR, 1H-NMR, GPC, and TEM. Micelle formation and temperature sensitivity were also investigated by DLS. As a result, stabilized micelles were successfully prepared with the motivation of preventing premature drug release and achieving a pH- and temperature-controlled system. Due to their dual-responsive characteristics, the CCMs show promising potential to be used as smart drug carriers for controlled delivery.