Amine‐Functionalized Amphiphilic Polyester‐Based Nanocarriers for Drug Delivery and Mitochondria Targeting in Cancer Cells

Cationic polymeric nanoaggregates having widespread applications in the biological domain majorly suffer from their non‐degradable nature, leading to cytotoxicity and bioaccumulation. Herein, we have synthesized an amphiphilic polyester, P1 through a facile condensation polymerization reaction between an activated pentafluorophenyl diester, A1 with three different functionalized diols, B1 , B2 , and B3 , where B1 is a biotin‐functionalized diol that imparts selectivity toward cancerous cells, while B2 is a naphthalene monoimide moiety that induces fluorescent property to P1 , and B3 is a tertiary amine‐functionalized PEGylated diol featuring pH‐induced charge modulation property. P1 is capable of forming neutral micellar nanoaggregates in aqueous medium under physiological conditions and can acquire a positive surface‐charge by virtue of the quaternization of the amine group at mildly acidic pH, mimicking the cancerous extracellular microenvironment. These biotin‐functionalized nanoaggregates are nontoxic and exhibit higher cellular uptake in cancerous HeLa cells compared to the non‐cancerous NIH 3T3 cells. The acquired surface charge in cancerous microenvironment enabled higher cellular uptake of P1 nanoaggregates along with mitochondria‐targeting ability, driven by the mitochondrial negative membrane potential. Additionally, the hydrophobic nature of the nanoaggregate core allowed encapsulation of the chemotherapeutic drug doxorubicin for their successful intracellular delivery upon the degradation of the polyester linkages.