Stimuli-Responsive Hybrid Nanocarriers As Antitumor Theranostics

Multifunctional nanomedicine holds great value in treating a diverse range of diseases.Efficient cargo loading in the nanocarrier together with on-demand release is essential to fulfil the mission of nanotechnology in biomedicine,which is particularly valid when the cargo potency is low.However,the cargo encapsulation in nanocarriers by traditional physical means is very poor;the drug loading is typically less than 5%?w/w?which limits their therapeutic effect and translation potential.Recently,manganese(Mn²⁺)was reported to be coprecipitated in lipid-calcium phosphate?LCP?nanocarriers to realize magnetic resonance imaging?MRI?.LCP is usually composed of an inorganic calcium phosphate core and an asymmetric lipid bilayer shell;the core and shell are united via the electrostatic interaction at the core-shell interface.Moreover,LCP inherently displays a triggered release characteristic;upon cellular uptake via endocytosis,the cargo in the core can be released post particle collapse within the acidic endosome/lysosome.Inspired by the structure of LCP,we postulated that manganese phosphate?MnP?nanoparticles could be used as an anchor to interfacially deposit negatively charged cargos by electrostatic interactions.The combination of large surface area of nanoparticles and electrostatic interactions would ensure a high loading without premature dose dumping.The acid-labile disintegration of MnP could enable intracellular on-demand release.Many drugs contain ionic groups?e.g.phosphonate?or can be easily engineered to obtain a phosphonate moiety,which means that this approach is robust and applicable to a large collection of drugs.The manganese dose can be readily manipulated by calcium doping;hence the ratio of imaging agents and drugs can be precisely regulated.In the current project,we employed a novel“drug encapsulation by imaging agents”approach to engineer high drug loading theranostic MRI nanomedicine with pH-triggered delivery properties.The cationic MnP core was coated with ionic drugs via interfacial electronic deposition,followed by lipid coating to generate a hierarchical hybrid nanocarrier.Camptothecin?CPT?was modified and used as the model drug.Such nanoplatform could surprisingly load camptothecin 16.9±3.0%?w/w?with decent serum stability.The nanocarrier displayed pH-dependent cargo release profiles due to the particle collapse at acidic conditions under which the r₁ relaxivity of magnetic resonance imaging?MRI?was 25.2 mM^-1s^-1?pH 5.0?.The nanocarrier could efficiently transport camptothecin into 4T1 cells with a half maximal inhibitory concentration of 5.4±0.3?M.Both in vivo MRI and fluorescence imaging analysis revealed that the nanocarrier could efficiently deliver the cargo to the tumor site.The anticancer efficacy of camptothecin-loaded nanocarrier was proved using the same 4T1tumor-bearing mice model coupled with the histological and apoptosis analysis.This work not only presented a novel drug encapsulation approach,but also provided a new theranostic hybrid nanoplatform which could realize MRI-guided delivery of hydrophobic agents.Such a nanoplatform also provides a strategy for combinational delivery of hydrophilic and hydrophobic agents,as well as small molecule drugs with genes.The current work created a method of electronic interfacial deposition for efficient hydrophobic drug loading in hybrid nanocarriers and added new members to the family of multifunctional theranostic nanomedicine.