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A library of amphiphilic monomethoxypolyethylene glycol (mPEG) terminating polyaminoacid co-polymers able to self-assemble into colloidal systems was screened for the delivery and controlled release of doxorubicin (Doxo). mPEG-Glu/Leu random co-polymers were generated by Ring Opening Polymerization from 5 kDa mPEG-NH 2 macroinitiator using 16:0:1, 8:8:1, 6:10:1, 4:12:1 γ-benzyl glutamic acid carboxy anhydride monomer/leucine N-carboxy anhydride monomer/PEG molar ratios. Glutamic acid was selected for chemical conjugation of Doxo, while leucine units were introduced in the composition of the polyaminoacid block as spacer between adjacent glutamic repeating units to minimize the steric hindrance that could impede the Doxo conjugation and to promote the polymer self-assembly by virtue of the aminoacid hydrophobicity. The benzyl ester protecting the γ-carboxyl group of glutamic acid was quantitatively displaced with hydrazine to yield mPEG 5kDa -b-(hydGlu m -r-Leu n ). Doxo was conjugated to the diblock co-polymers through pH-sensitive hydrazone bond. The Doxo derivatized co-polymers obtained with a 16:0:1, 8:8:1, 6:10:1 Glu/Leu/PEG ratios self-assembled into 30-40 nm spherical nanoparticles with neutral zeta-potential and CMC in the range of 4-7 μM. At pH 5.5, mimicking endosome environment, the carriers containing leucine showed a faster Doxo release than at pH 7.4, mimicking the blood conditions. Doxo-loaded colloidal formulations showed a dose dependent cytotoxicity on two cancer cell lines, CT26 murine colorectal carcinoma and 4T1 murine mammary carcinoma with IC 50 slightly higher than those of free Doxo. The carrier assembled with the polymer containing 6:10:1 hydGlu/Leu/PEG molar ratio {mPEG 5kDa -b-[(Doxo-hydGlu) 6 -r-Leu 10 ]} was selected for subsequent in vitro and in vivo investigations. Confocal imaging on CT26 cell line showed that intracellular fate of the carrier involves a lysosomal trafficking pathway. The intratumor or intravenous injection to CT26 and 4T1 subcutaneous tumor bearing mice yielded higher antitumor activity compared to free Doxo. Furthermore, mPEG 5kDa -b-[(Doxo-hydGlu) 6 -r-Leu 10 ] displayed a better safety profile when compared to commercially available Caelyx®., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A Passerini three-component polymerization was performed for the synthesis of amphiphilic star-shaped block copolymers with hydrophobic cores and hydrophilic coronae. The degree of polymerization of the hydrophobic core was varied from 5 to 10 repeating units, and the side chain ends were conjugated by performing a Passerini-3CR with PEG-isocyanide and PEG-aldehyde (950 g/mol). The resulting amphiphilic star-shaped block copolymers contained thioether groups, which could be oxidized to sulfones in order to further tune the polarity of the polymer chains. The ability of the amphiphilic copolymers to act as unimolecular micellar encapsulants was tested with the water-insoluble dye Orange II, the water-soluble dye Para Red and the macrolide antibiotic azithromycin. The results showed that the new copolymers were able to retain drug cargo at pH levels corresponding to circulating blood and selectively release therapeutically effective doses of antibiotic as measured by bacterial cell kill. The polymers were also well-tolerated by differentiated THP-1 macrophages in the absence of encapsulated drugs.

Among various types of stimuli‐responsive drug delivery systems, reduction‐responsive polymers have attracted great interest. In general, these systems have high stability in systemic circulation, however, they can respond quickly to differences in the concentrations of reducing species in specific physiological sites associated with a pathology. This is a particularly relevant strategy to target diseases in which hypoxic regions are present, as polymers which are sensitive to in‐situ expressed antioxidant species can, through a local response, release a therapeutic at high concentration in the targeted site, and thus, improve the selectivity and efficacy of the treatment. At the same time, such reduction‐responsive materials can also decrease the toxicity and side effects of certain drugs. To date, polymers containing disulfide linkages are the most investigated of the class of reduction‐responsive nanocarriers, however, other groups such as selenide and diselenide have also been used for the same purpose. In this review article, we discussed the rationale behind the development of reduction‐responsive polymers as drug delivery systems and highlight examples of recent progress. We include the most popular design methods to generate reduction‐responsive polymeric carriers and their applications in cancer therapy, and question what areas may still need to be explored in a field with already a very large number of research articles. Finally, we consider the main challenges associated with the clinical translation of these nanocarriers and the future perspectives in this area. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseNanotechnology Approaches to Biology > Nanoscale Systems in BiologyTherapeutic Approaches and Drug Discovery > Emerging Technologies [ABSTRACT FROM AUTHOR]