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Light-controlled drug delivery systems constitute an appealing means to direct and confine drug release spatiotemporally at the site of interest with high specificity. However, the utilization of light-activatable systems is hampered by the lack of suitable drug carriers that respond sharply to visible light stimuli at clinically relevant wavelengths. Here, a new class of self-assembling, photo- and pH-degradable polymers of the polyacetal family is reported, which is combined with photochemical internalization to control the intracellular trafficking and release of anticancer compounds.

The polymers are synthesized by simple and scalable chemistries and exhibit remarkably low photolysis rates at tunable wavelengths over a large range of the spectrum up to the visible and near infrared regime. The combinational pH and light mediated degradation facilitates increased therapeutic potency and specificity against model cancer cell lines in vitro. Increased cell death is achieved by the synergistic activity of nanoparticle-loaded anticancer compounds and reactive oxygen species accumulation in the cytosol by simultaneous activation of porphyrin molecules and particle photolysis.

Modern nanomedicines promise to revolutionize cancer diagnoses and therapies by intervening to diseased tissues at the nanoscale and biomolecular level. The major advantage that nanoscale drug delivery systems DDS exhibit is the inherent passive tumour-targeting properties primarily derived by the enhanced permeation and retention effect attributed to the presence of leaky and ill-defined vasculature network and the lack of lymphatic drain 1.

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Equally important is the possibility of active tumour targeting by the installation of recognition motifs on the surface of the nanoparticles that is, specific cancer recognition markers, antibodies, and so on. In addition, nanoparticulate DDS allow for simultaneous carriage of chemical substances such as anticancer agents and bio-imaging tags and have been proposed as an emerging platform in cancer theranostics 4. An appealing approach is the use of stimuli responsive DDS that exhibit sharp drug release changes in the presence of physiological gradients that is, endosomal pH drop or externally-controlled triggers such as temperature changes or light activation 9 , Light 11 , in particular, is a convenient means to externally activate DDS as it is generally safe, versatile — a wide range of wavelengths can be used — and can be delivered to nearly all parts of the body via catheterization or external sources Major obstacles, however, hamper the application of photocontrolled DDS in clinical use which include i the poor tissue penetration of certain wavelengths especially in the ultraviolet regime owing to extensive tissue absorbance and back scattering, ii the use of deep tissue penetrating wavelengths in the near infrared regime often requiring extensive focusing to achieve high and potentially phototoxic photon flux, which is not suitable for large tumour areas see ref.

Despite the substantial progress in light-responsive materials and biomolecular systems, and their applications in diverse areas, such as dynamic cell culture 15 , 16 , 17 , microfabrication 18 , 19 and bioimaging 20 , the necessity of introducing new photochemistries that pragmatically address the aforementioned obstacles is of paramount importance for these technologies to realize their clinical potential in the context of modern therapeutic and diagnostic modalities.

To this end, we envisioned that photochemical internalization could serve as a model light—matter interaction motif in biological systems to challenge new photochemistries. Photochemical internalization PI is a conceptually powerful tool that was introduced to actively control the intracellular trafficking of anticancer agents via an exogenously applied optical stimulus, which allows for spatiotemporally-controlled drug release and trafficking.

PI is applied by the codelivery of a bioactive agent for example, a drug molecule with a photosensitizer for example, a porphyrin molecule which upon cellular uptake is activated by a laser source 21 , In turn, the photosensitizer produces reactive oxygen species ROS , which disrupt the membrane of the endosomal compartment and allow for effective escape of the drug molecules to the cytosol.

PI has been successfully applied for the delivery of both high molecular weight such as proteins and nucleic acids 23 , 24 , 25 and low molecular weight anticancer agents such as camptothecin CPT 26 under various therapeutic scenarios. In the present study, we demonstrate for the first time, the application of PI in combinatorial photo—chemotherapy against cancer cells using a new class of dual degradable NPs coloaded with a potent chemotherapeutic anticancer compound CPT and a phototoxic drug hematoporphyrin HP.

Our system can be activated using visible, and potentially infrared wavelengths at very low doses delivered as unfocused pulse cues and exhibits simultaneous photo- and chemo-degradations, ideal for concerted light- and pH-controlled intracellular trafficking of drug cocktails, allowing for aggressive photo-induced cancer cell death.

The proposed system induces enhanced cell death rates against cancer cells in vitro , owing to the concerted photo—chemotherapeutic potency of the drug cocktail over a wide surface area by laser activation using a clinically relevant light dosage protocol. Considering the limiting factors that somewhat prevent the development of photosensitive nanomedicines vide supra we set out key design criteria to render the nanomaterials broadly addressable in the biomedical context: i simple chemistries were established so that the designed polymers are scalable and versatile for further optimization and formulation via self-assembly, ii we developed a mild photolysis strategy to allow for substantial red-shifting of the irradiation beam towards the visible and, if possible, the near infrared regime without compromising the laser working volume and iii we explored the possibility of loading drug cocktails including poprhyrin molecules to induce multimodal drug release against cancer cell lines via the photochemical internalization pathway.

Acetals have a well established hydrolysis profile under the mildly acidic conditions pH 5. In an effort to introduce red-shifted photo-lability on the backbone of the polymer in the visible, a 2-nitroresorcinol comonomer was used. The polymer was synthesized from commercially available synthons by a two-step acid catalysed polycondensation reaction of the 2-nitroresorcinol monomer with a divinyl ether derivative first step , which was subsequently end-capped with poly ethylene glycol PEG Fig.

The final product was isolated in good yield ca. The Mn of the polymer was found to be ca.

The synthetic route that was followed involved the reaction of the divinyl and bis-hydroxyl monomers in a molar ratio. The reaction kinetics of the polymerization is governed by step growth propagation 35 , 36 where the starting monomers form dimers, which further react to form tetramers and so forth.

Hence, the main product of the precursor polymer is a semitelechelic product with one vinyl and one hydroxyl end which, in theory, prevents the formation of triblock segments in the second step. Hence, further reaction with the PEG-hydroxyl should yield a di-block copolymer as the main product. In practice, the possibility of a triblock forming during the polymerization reaction cannot be neglected. However, from the GPC trace we do not see the formation of higher molecular weight products other than the final di-block copolymer and even if the triblock copolymer is present in a minute quantity it will also behave as a polymeric amphiphile and participate in the self-assembly process for the NP formation.

The photolysis process is hypothesized to be triggered by direct zwitterionic cleavage of the acetal proton followed by acid hydrolysis and formation of the starting 2-nitroresorcinol, acetaldehyde and cyclohexyl di-alcohol byproducts Fig. To further elucidate the photolysis mechanism, we synthesized a low molecular weight compound resembling the repeating unit of the polymer, in an effort to characterize the photolysis products by mass spectrometry.

The molecule Ac1 Supplementary Fig. From the 1 H NMR spectrum, it was possible to clearly trace the formation of acetaldehyde, 2-nitrophenol and the aliphatic alcohol derivative, which are the main photoproducts, along with the complete disappearance of the acetal proton as a result of the quantitative photolysis Supplementary Fig. The possible formation of carbonyl-rich photoproducts was evident in the 1.

The latter confirmed the formation of the 2-nitrophenol and the aliphatic di-alcohol, however it was not possible to trace acetaldehyde, presumably owing to its low molecular weight, below the detection limit of the instrument. It should be noted that the fact that 2-nitrophenol is unambiguously traced by both 1 H NMR and GC—MS, excludes the possibility of formation of other nitroso derivatives, which in turn confirms our proposed mechanism of acetal photolysis involving the zwitterion 37 intermediate formation as proposed in Fig.

We also used Ac1 as a model molecular probe to monitor the photolysis kinetics by following the gradual diminution of the acetal proton peak as a function of the irradiation time Supplementary Fig. To sum up, the main photoproducts comprise the formation of acetaldehyde, 2-nitrophenol and cyclohexyl di-alcohol products; carbonyl-rich photoproducts are also evident but these should exist at minute quantities and are not uncommon in photolysis studies.

Encouraged by these results, we studied the two-photon photolysis properties of the polymer in the solid and liquid phase.