Polymer Amphiphiles for Photoregulated Anticancer Drug Delivery

Abstract

We report the synthesis of amphiphilic polymers featuring lipophilic stearyl chains and hydrophilic poly(ethylene glycol) (PEG) polymers that are connected through singlet oxygencleavable alkoxyanthracene linkers. These amphiphilic polymers assembled in water to form micelles with diameters of ~2 0 nm. Reaction of the alkoxyanthracene linkers with light and O 2 cleaved the ether C-O bonds, resulting in formation of the corresponding 9,10-anthraquinone derivatives and concomitant disruption of the micelles. These micelles were loaded with the chemotherapeutic agent doxorubicin, which was efficiently released upon photo-oxidation. The drug-loaded reactive micelles were effective at killing cancer cells in vitro upon irradiation at 365 nm, functioning through both doxorubicin release and photodynamic mechanisms.

Photoactivation Strategies for Therapeutic Release in Nanodelivery Systems

“…Photoresponsive linkers refer to those that are able to engage in linker cleavage or alteration via either photolysis, [113] oxidative fragmentation by 1 O 2 reaction, [32,[114][115][116][117] photoreduction, [118,119] or photoisomerization. [25,120] As summarized in Figure 2, these linkers comprise of several types that include ortho-nitrobenzene (ONB), [121][122][123][124][125] thioacetal ortho-nitrobenzene (TNB), [126] coumarin, [122,125,127,128] 1 O 2 -reactive cyanine, [129,130] acridine, [131] and photoreducible N-methylpyridinium.…”

“…Due to their instability, these adducts rapidly undergo a series of self-fragmentations and cellular hydrolysis, leading to its payload release. Linker cleavage via oxidative fragmentation also occurs in other linker types that include alkene, [114] bis(alkylthio)ethene, [115,159] alkylsulfide, [116] and bis(alkoxy)anthracene [32,117] ( Figure 4B). Each cleavage is triggered by 1 O 2 reaction, but it varies in its fragmentation pattern.…”

“…These include nanocontainers that engage in its production such as PS-encapsulated liposomes [292] and polymer micelles. [32,117] Wang et al demonstrated this approach using tetraphenylporphyrin PS-loaded liposomes incorporated with 7dehydrocholesterol, an ROS-reactive cholesterol precursor. [292] Irradiation at 420 nm produced 1 O 2 which contributed to vesicle fragmentation and release of cytotoxic endoperoxides derived from its reactions with 7-dehydrocholesterol.…”

“…Due to its high chemical reactivity, ROS is able to engage in various release mechanisms via either oxidative linker cleavage, nanocontainer fragmentation or disassembly. [32] However, this ROS-mediated release needs to be distinguished from photodynamic therapy (PDT), [19,[33][34][35] a therapeutic modality based on the induction of cytotoxicity via ROS-specific cellular damages. [31] Last, photoactivation is achieved by using a class of photothermal agents that display ability to produce a localized heat through surface plasmon excitation by light.…”

Spectroscopy and Reactivity of Dialkoxy Acenes

“…[10] In contrastt ot hese reversion reactions, alkoxyacenee ndoperoxides can undergo high-yielding endoperoxide decomposition pathways, in which the acetal-like linkages cleave to yield quinones and alcohols, which is useful for photooxidative cleavage of covalent bonds. [11] Given the potentialu tility of alkoxyacenes, as ystematic, quantitative understanding of how their chemical structures influence spectroscopic properties and reactivity with 1 O 2 impacts fundamental and appliedc hemistry.A vailablel iterature reports, to the best of our knowledge,a ssess these properties mainly for derivatives of three or fewer fused rings,w ith few exceptions.F or example, 9,10-dimethoxyanthracene (Scheme 1) hasacycloaddition rate constant with 1 O 2 of 1.4 10 7 m À1 s À1 -abouto ne order of magnitude larger than the commonly used reactivity standard9 ,10-diphenylanthracene. [12] Similar oxidations of naphthalene analogues are relatively slow (k % 10 4 -10 5 m À1 s À1 ), whilet he corresponding endoperoxides fragment at room temperature.…”