Nano MOF Entrapping Hydrophobic Photosensitizer for Dual-Stimuli-Responsive Unprecedented Therapeutic Action against Drug-Resistant Bacteria

Abstract

Multidrug resistance (MDR) of bacteria is a major threat to public health globally and its unprecedented increase calls for immediate alternative medical strategies. Antimicrobial photodynamic therapy (aPDT) offers alternative modalities to combat the growing MDR typically by means of targeted cellular internalization of a photosensitizer (PS) capable of producing photoinduced reactive oxygen species (ROS). However, aPDT is severely limited by the self-aggregation behavior and hydrophobicity of PS molecules, which significantly curbs its viability for clinical application. The present study reports the use of modified nanoscale metal–organic frameworks (NMOFs) encapsulating a hydrophobic PS drug squaraine (SQ) to enhance aPDT efficacy against drug-resistant planktonic bacteria and its biofilm for the first time. Zeolitic imidazolate framework (ZIF-8) NMOF nanocrystals are attached postsynthetically with SQ (designated as ZIF8-SQ) and the resultant drug-doped NMOF is characterized by TEM, FESEM, PXRD, Raman spectroscopy, UV–vis spectroscopy, and steady-state and time-resolved fluorescence techniques. The microporous structures of ZIF-8 behave as molecular cages ceasing the self-aggregation of hydrophobic SQ. In addition, the formulated ZIF8-SQ produces cytotoxic ROS under red-light irradiation (650 nm) in a pH sensitive way primarily due to molecular level interaction and charge separation between ZIF-8 and SQ depicting a dual-stimuli-responsive nature. Most notably, ZIF8-SQ provides unparalleled aPDT action against methicillin-resistant Staphylococcus aureus (MRSA) and leads to complete loss of adherence of structurally robust bacterial biofilms. Finally, the nontoxic nature of the nanoconjugate toward human cells holds great promise for effective treatment of MRSA and other detrimental antibiotic-resistant microbes in clinical models.

Enhanced Water Stability and Photoresponsivity in Metal-Organic Framework (MOF): A Potential Tool to Combat Drug-resistant Bacteria

“…The time resolved fluorescence transients are detected using TCSPC (time-correlated single-photon counting) setup with MCP-PMT (Edinburgh instrument, U.K.), The Instrument response function (IRF) of ~80 ps using a 375 nm excitation laser source 37 . Thermal stability is recorded under a nitrogen atmosphere and all the samples are heated from 30 to 800 °C at a rate of 10 °C/min by using a PerkinElmer TGA-50H instrument 38 .…”

Metal–Organic‐Framework‐Engineered Enzyme‐Mimetic Catalysts

“…Antimicrobial PDT is also an efficient approach for combating multidrug resistance (MDR). To enhance PDT efficacy, Bagchi et al [174] entrapped a hydrophobic photosensitizer drug of squaraine into modified MOFs. Under red-light irradiation, the resulting ZIF-8-squaraine generated cytotoxic ROS, in which the polyporous ZIF-8 efficiently inhibited the selfaggregation of squaraine by the caging effect.…”

Nano-MOFs as targeted drug delivery agents to combat antibiotic-resistant bacterial infections

“…Antibiotic resistance implies significant persistence of bacteria that are capable of growing in the presence of single or more antibiotics [ 1 ]. Multidrug resistance of bacteria is a significant danger to human civilization and it progresses at a faster speed owing to inappropriate and frequent use of antibiotics [ 2 , 3 ]. Lack of effective antibiotics will make general infections like bacterial pneumonia and compound procedures such as open-heart surgery much more dangerous and life-threatening [ 4 , 5 ] in future.…”

“…These days, nanoparticles (NPs) are progressively used to target microorganisms and could fill in as an option to natural antibacterial operators [ 19 ]. The viability of antibacterial capability might be expanded by means of a NH that could be powerful enough to prevent the development of microbes in humans [ 3 ]. The NH is probably going to keep stability against degradation, improving bioavailability and intracellular transportation [ 20 , 21 ].…”

“…Past reports have exhibited the use of ZIF8 as stimuli-responsive targeted delivery framework for typical anti-cancer treatment doxorubicin [ 25 ]. Under some conditions, ZIF8 crystals can course through the circulation system pursued by moderate discharge into intracellular organelles with lower (pH 5–6), portraying its likelihood to usage as pH-sensitive drug delivery [ 3 , 26 ]. We have shown earlier that ZIF8 can effectively deliver phototherapeutic drugs into a bacterial infection site and pronouncedly killed the infection using antimicrobial photodynamic therapeutic strategies [ 3 ].…”