Functional Poly(ε-caprolactone)/Poly(ethylene glycol) Copolymers with Complex Topologies for Doxorubicin Delivery to a Proteinase-Rich Tumor Environment

Abstract

Doxorubicin (DOX)-loaded polymer nanoparticles based on poly(ethylene glycol)-poly(ε-caprolactone) copolymers with a complex macromolecular topology are proposed to tackle the matrix metalloproteinase (MMP)-rich tumor environment. Linear, 4-arm comb-like copolymers and 4-arm brush block copolymers were synthesized through a combination of ring opening polymerization and atom transfer radical polymerization, in order to control the molar mass distribution, the arm/brush architecture, as well as the final size and DOX loading of self-assembled nanoparticles obtained by nanoprecipitation. The optimized nanocarriers were conjugated with penetrating low molecular weight protamine peptides coupled to a polyanionic inhibitory domain cleavable by matrix metalloproteinase-2 (MMP2). DOX-loaded, MMP2-activable nanocarriers were evaluated in the context of glioblastoma (GBM), a brain tumor characterized by remarkable and relevant MMP2 expression. Uptake and cytotoxicity in patient-derived GBM cells correlated with the level of MMP2 enzymatic activity in a dose-and time-dependent manner. No effects were observed in nontumoral endothelial cells that do not express MMP2. Results demonstrated that, by tuning polymer topology and peptide sequence, nanoparticle self-assembly, DOX encapsulation, and delivery can be optimized for the development of an advanced treatment for MMP2-overexpressing tumors.

Peptide‐conjugated Nanoparticle Platforms for Targeted Delivery, Imaging, and Biosensing Applications

“…Furthermore, the labile ester bond in the prodrug released free drug in the tumor environment leading to the inhibition of the growth of the tumors. In different studies, CPPs were conjugated to mesoporous silica NPs, [60] polymer NPs,, [61–63] gold nanorods, [64] hepatitis B virus‐like NPs,, [65] and silver NPs [66] for drug delivery applications. The use of targeting and cell penetrating peptides together with NP formulations in different biomedical applications were discussed in some other recent reviews in details, and we refer the readers to these papers [67–69] …”

How Precise are Nanomedicines in Overcoming the Blood–Brain Barrier? A Comprehensive Review of the Literature

“… [ 113 ] 4. Brain Cancer Doxorubicin-loaded poly copolymer Pulmonary Delivery Transport, absorption, and endocytosis via receptors Possible economically viable and effective treatment [ 114 ] 5. Epilepsy stroke LDL -Cholesterol Conjugates Nasal, Oral Parenteral, rectal, and respiratory Absorption Site-specific administration improves thrombolysis [ 115 ] 6.…”