Here, we report a new modification of doxorubicin based on an amphiphilic stearoylspermine anchor, enabling loading into liposomal membranes. Doxorubicin is coupled with stearoylspermine through an acid-labile hydrazone linker to ensure the release of the drug in the acidic interstitium of tumors. Using ATR-FTIR spectroscopy (Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy), the mechanism of interaction of doxorubicin with the anionic liposomal membrane was studied: incorporation of stearoyl chains leads to an increase in local microfluidity, and the amino groups of spermine interact with the phosphate groups of lipids. To stabilize liposomes against aggregation, we applied the copolymer PEG-chitosan as a coating: complex formation leads to charge neutralization, and the liposomes grow in size. According to MTT tests and confocal microscopy for cell lines A459 and Caco-2, PEG-chitosan-coated liposomes are as effective as neutral liposomes but are much more stable.