Host−guest complexation-mediated codelivery of anticancer drug and photosensitizer for cancer photochemotherapy

Abstract

Although platinum-based anticancer drugs prevail in cancer treatment, their clinical applications are limited by the severe side effects as well as their ineffectiveness against drug resistant cancers. A precise combination of photodynamic therapy (PDT) and chemotherapy can synergistically improve the therapeutic outcome and thereby may overcome drug resistance through a multipronged assault. Herein, we employ the well-defined cavity of a discrete organoplatinum(II) metallacage (M) to encapsulate octaethylporphine (OEP), a photosensitizer, forming a dual-functionalized system M⊃OEP that is wrapped into the hydrophobic core of the nanoparticles (MNPs) self-assembled from an amphiphilic diblock copolymer. Using a copper-free click reaction, a targeting ligand is conjugated on the surface of the MNPs, aiming to specifically deliver a chemotherapeutic drug and a photosensitizer to cancer cells. Benefiting from the enhanced permeability and retention effect and active targeting capability, high tumor accumulation of MNPs is achieved, leading to an improved therapeutic outcome and reduced side effects. In vivo studies demonstrate that the combination of chemotherapy and PDT exhibits a superior antitumor performance against a drug-resistant tumor model attributed to their synergistic anticancer efficacy. supramolecular coordination complex | metallacage | photodynamic therapy | theranostic | drug delivery P latinum-based drugs including cisplatin, carboplatin, and oxaliplatin are used worldwide in cancer treatment; however, their dose-limiting side effects arising from the poor selectivity to cancerous tissue over normal tissues always cause serious complications in patients (1-5). Considerable attention has been given to the development of smart drug-delivery systems that can temporarily passivate platinum complexes and specifically transport the nanomedicines to tumor sites via the enhanced permeability and retention (EPR) effect (6-8). Various nanocarriers including liposomes, micelles, and dendrimers have been employed that can selectively transport platinum-based anticancer drugs to cancerous cells (9-11), while the clinical use of these nanomedicines is still limited by drug resistance, including inherent and acquired resistance, promoting researchers to combine chemotherapy with other treatment modalities to achieve synergetic anticancer efficacy through a multipronged assault (12-15).Photodynamic therapy (PDT) employs photosensitizers that upon absorbing a specific wavelength of light to release a cell-damaging version of reactive oxygen species (singlet oxygen, 1 O 2 ) that can eradicate tumors with a high specificity and negligible side effects (16)(17)(18). The sensitization effect of PDT can significantly boost the activity of chemotherapeutic agents, synergistically overcoming drug resistance through different mechanisms of actions to realize enhanced anticancer efficacy (19)(20)(21)(22). However, the full promise of PDT has not yet been achieved mainly due to the lack of ideal photosensitizers and sophisti...

Polymeric Systems Containing Supramolecular Coordination Complexes for Drug Delivery

“…Representation of the fabrication of metallacage 15 , nanocarrier 16 , and nanoparticle 17 and the application of nanoparticle 17 in cancer therapy. Reproduced with permission from [ 69 ]. Copyright 2019, National Academy of Sciences (USA).…”

Nanomaterial‐mediated platinum drug‐based combinatorial cancer therapy

“…Additionally, some nanohybrids based on Pt drugs/prodrugs and PSs were also developed by self‐assembly 42 . The well‐defined cavity of a discrete organoplatinum(II) metallacage containing a Pt‐based anticancer drug was employed to encapsulate PS of octaethylporphine (OEP), serving as dual delivery of chemotherapeutic drug and PS for combinatorial therapy 43 . The formation of host‐guest complex facilitated the co‐delivery of chemotherapeutic agent and PS with negligible aggregation of PS, which would greatly prompt PDT effect.…”

p-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies

“…It is worth mentioning that, mainly in dermatology, even UVB irradiation is considered of therapeutic use [16][17][18]. Besides the anticancer activities of photosensitizers [19][20][21], "post-antibiotic era" is experimenting with photosensitizers as alternative therapeutics for the fight against multiresistant bacteria both for medicinal [22][23][24][25] and environmental purposes [26,27].…”

“…Based on our interest in the chemistry and biology of the oxime functionality [54][55][56][57], as well as in their DNA photolytic interaction upon UV irradiation [9][10][11]43] we have decided to investigate the behaviour of carefully designed O-carbamoyl derivatives of p-pyridine amidoxime, ethanone oxime and aldoxime (VI, VII, VIII, R 1 = p-pyridyl, Figure 1) as DNA photosensitizers. Based on our previous ex-Scheme 1: Synthesis of O-carbamoyl amidoximes (8)(9)(10)(11)(12)(13), ethanone oximes (15)(16)(17)(18)(19)(20) and aldoximes (22)(23)(24)(25)(26)(27). Oxime 1 or 14 or 21, Et 3 N (1.1 equiv), R-NCO (1.1-1.8 equiv), dry chloroform or tetrahydrofuran, Ar, 0 °C → rt or reflux, 19-97%.…”