Photo-unclick Chemistry and Light-activated Spatiotemporally Controlled Local Drug Release/Activation

Spatio-temporally controlled delivery (release) of biologically active compounds is the key strategy to minimize off-target effects of the compounds. For example, chemotherapeutic agents kill not only cancer cells, but also certain normal cells, causing systemic side effects. To minimize the side effects, the release of anticancer drugs into tumors should be limited locally. While various targeting strategies for site-specific delivery to tumors have been developed, effective releasing methods remain largely unexplored. Visible and near-IR light is an attractive external tool in controlling the release of drugs at the systemic level; this light can reach deep tissue and does not cause direct photodamage to normal tissue, unlike UV. However, the energy of such light is not high enough to directly cleave chemical bonds to initiate the release of drugs. My lab developed an innovative strategy, “photo-unclick chemistry”, by which drugs can be released by visible/near-IR light through singlet oxygen. We successfully demonstrated its application in prodrugs.

  1. Thapa, P., Li, M., Karki, R., Bio, M., Rajaputra, P., Nkepang, G., Woo, S., You, You.* Folate-PEG conjugates of a far-red light-activatable paclitaxel prodrug to improve selectivity towards folate receptor-positive cancer cells. ACS Omega 2017, 2, 6349-6360. [abstract]

  2. Thapa, P., Li, M., Bio, M., Rajaputra, P., Nkepang, G., Sun, Y., Woo, S., You, Y.* Far-red light-activatable prodrug of paclitaxel for the combined effects of photodynamic therapy and site-specific paclitaxel chemotherapy. J. Med. Chem. 2016, 59, 3204–3214. [abstract] Highlighted in ChemistryViews

  3. Nkepang, G., Bio, M., Rajaputra, P., Awuah, S., You, Y.* Folate receptor-mediated enhanced and specific delivery of far-red light-activatable prodrugs of Combretastatin A-4 to FR-positive tumor, Bioconjugate Chem. 2014, 25, 2175-2188. [abstract]

  4. Bio, M., Rajaputra, P., Nkepang, G., You, Y.*, A far-red light activatable, multi-functional prodrug for fluorescence optical imaging and combinational treatment, J. Med. Chem. 2014, 57, 3401-3409. [abstract]

  5. Nkepang, G., You, Y.*, Heteroatom-substituted dioxetanes and their emerging biomedical applications, Patai's Chemistry of Functional Groups, Edited by I. Marek. John Wiley & Sons, Ltd: Chichester, UK. Published online 04/28/2014. [abstract] - Invited Book Chapter

  6. Bio, M., You, Y.*, Emerging strategies for controlling drug release by using visible/near IR light, Med. Chem. 2013, 3, 192-198. - Invited Review Article

  7. Bio, M.; Rajaputra, P.; Nkepang, G.; Awuah, S. G.; Hossion, A. M. L.; You, Y.* Site-specific and far-red light-activatable prodrug of combretastain A-4 using photo-unclick chemistry, J. Med. Chem. 2013, 56, 3936-3942. [abstract] - Highlighted in SciBX: Science-Business eXchange

  8. Hossion, A. M. L.; Bio, M.; Nkepang, G.; Awuah, S. G.; You, Y.* Visible Light Controlled Release of Anti-cancer Drug through Double Activation of Prodrug, ACS Med. Chem. Lett. - 2013, 4, 124-127. [abstract] - Highlighted in the Editor's Choice.

  9. Bio, M.; Nkepang, G.; You, Y.* Click and photo-unclick chemistry of aminoacrylate for visible light-triggered drug release, Chem. Comm. 2012, 48, 6517-6519. [abstract]

  10. Nkepang, G.; Pogular, P.K.; Bio, M.; You, You.* Synthesis and singlet oxygen reactivity of 1,2-diaryloxyethenes and selected sulfur and nitrogen analogs, Photochem. Photobiol. 2012, 88, 753-759. [abstract]

  11. Murthy, R. M., Bio, M., You, Y.,* Low energy light-triggered oxidative cleavage of olefins, Tetrahedron Lett. 2009, 50, 1041-1044. [abstract]

PKPD (Pharmacokinetic and Pharmacodynamic) Modeling for Stimuli-responsive Local Delivery System

We (in collaboration with Dr. Sukyung Woo) adopted mathematical modeling approach to better (quantitative and dynamic) understand the effects of locally released functional molecules in the context of environments (e.g., cultured cells and animal model systems). We established PKPD (pharmacokinetic and pharmacodynamic) and PBPK (physiologically-based pharmacokinetic) models of locally released anticancer drugs. Singlet oxygen (SO) is cytotoxic species in photodynamic therapy (PDT). SO has unique characteristics: short life-time (~ 40 ns) and short diffusion distance (~20-200 nm) in biological systems. Thus, it cannot make direct bystander effects due to its spatio-temporal limits. Using our model NIR-activatable paclitaxel (PTX) prodrug, we demonstrated that the locally-released PTX overcame such limits and induced bystander effects to improve the antitumor effects. We established mathematical models to describe these processes, which provided in-depth understanding about the local effects. In our more recent study (publication # 1), we observed that the local treatment with light-activatable prodrug induced systemic antitumor effects.

  1. Subramaniyan, B., Rajaputra, P., Nguyen, L., Li, M., Peer, C. J., Kindrick, J., Figg, W. D., Woo, S., You, Y.* Local and systemic antitumor effects of photo-activatable paclitaxel prodrug on rat breast tumor models. Photochem. Photobiol. 2020, 96, 668-679. [abstract].

  2. Li, M., Nguyen, L., Subramaniyan, B., Bio, M., Peer, C. J., Kindrick, J., Figg, W. D., Woo, S.,* You, Y.* PBPK modeling-based optimization of site-specific chemo-photodynamic therapy with far-red light-activatable paclitaxel prodrug. J. Control. Release. 2019, 308, 86-97. [abstract]

  3. Li, M., Thapa, P., Rajaputra, P., Bio, M., Peer, C. J., Figg, W. D., You, Y.,* Woo, S.* Quantitative modeling of the dynamics and intracellular trafficking of far-red light-activatable prodrugs: implications in stimuli-responsive drug delivery system. J. Pharmacokinet. Pharmacodyn. 2017, 44, 521-536. [abstract] Journal Cover Article

  4. Rajaputra, P., Bio, M., Nkepang, G., Thapa, P., Woo, S., You, Y.* Anticancer drug released from near IR-activated prodrug overcomes spatiotemporal limits of singlet oxygen. Bioorg. Med. Chem. 2016, 24, 1540-1549. [abstract]

Single Oxygen (SO)-cleavable Produrgs for the Combination Therapy with PpIX-PDT for Non-muscle Invasive Bladder Cancers

Photo-unclick chemistry mediates visible and near IR-controlled drug release via a singlet oxygen (SO)-cleavable linker. Due to the limited diffusion distance of SO in biological systems, a photosensitizer and the SO-cleavable linker have been conjugated in one molecule or mixed in nano-drug delivery systems. In this communication, we demonstrate a new strategy to activate prodrugs with photo-unclick chemistry in an intermolecular fashion using an SO-cleavable CA4 prodrug and a mitochondria-specific photosensitizer, protoporphyrin IX, formed from prodrug hexyl-5-aminolevulinate.

  1. Rahman, K.M.M., Thapa, P., Hurst, R. Woo, S., You, Y.* Singlet oxygen activatable prodrugs of paclitaxel, SN-38, MMC, and CA4: non-mitochondria targeted prodrugs. Photochem. Photobiol. in press.

  2. Bio, M., Rajaputra, P., Lim, I., Thapa, P., Tienabeso, B., Hurst, R. E., You, Y.* Efficient activation of visible light-activatable CA4 prodrug through intermolecular photo-unclick chemistry in mitochondria. Chem. Comm. 2017, 2017, 53, 1884-1887. [abstract]

  3. Bio, M., Rajaputra, P., You, Y.* Photodynamic therapy via FRET following bioorthogonal click reaction in cancer cells. Bioorg. Med. Chem. Lett. 2016, 26, 145-148. [abstract]

Drug Discovery & Development using Machine Learning and Artifical Intelligence

Through collaborative efforts with biochemists and pharmacologists, we are also trying to discover new anticancer agents with novel mechanims. Conventional medical chemistry approaches are being used: pharomacophore determination, QSAR analysis, and structure optimization.

  1. Terzyan, S.S., Nguyen, L. T., Burgett, A.W.G., Heroux, A., Smith, C. A., You, Y., Hanigan, M. H.* Crystal structures of glutathione- and inhibitor-bound human GGT1: Critical interactions within the cysteinylglycine binding site. J. Biol. Chem. 2021, 296, 100066. [abstract]

  2. Chintharlapalli, S., Papineni, S., Liu, S., Jutooru, I., Chadalapaka, G., Cho, S., Murthy, R., You, Y., Safe, S., 2-Cyano-lup-1-en-3-oxo-20-oic acid, a cyano derivative of betulinic acid activates peroxisome proliferator-activated receptor g in colon and pancreatic cancer cells. Carcinogenesis 2007, 28, 2337-2346. [abstract]

Near IR Chromophores for Fluorescence Imaging and Photodynamic Therapy for Theranostics

Photodynamic therapy (PDT) is a unique regime destroying disease targets (cancer cells, hamful vascularture, and bacteira) by reactive oxygen species (e.g., singlet oxygen). Excited photosensitizer transfers its energy to oxygen (photonic energy à reactive chemical species). One of the key desired properties of ideal photosensitizers is effective absorption of near IR light to damage targets in deep tissue. On the other hand, optical imaging is a very effective diagnostic tool offering high sensitivity, harmless to tissue, real time monitoring, and low cost. Near IR is also required for optical imaging probe for tissue samples. We are developing new near IR chromophore as theranostic agents (fluorescence detection and PDT treatment). Because fluorescence emission and intersystem crossing (to triplet state for singlet oxygen generation) are competing process, the conventional wisdom was that one chromophore cannot be used for the dual functions. Our strategy is to maximize absorption efficiency (extinction coefficient) with balanced decay for fluorescence emission and ISC.

  1. Watley, R. L., Awuah, S. G., Bio, M., Cantu, R., Gobeze, H. H., Nesterov, V. N., D'Souza, F.,* You, Y.* Dual functioning thieno-pyrrole fused BODIPY dyes for NIR optical imaging and photodynamic therapy – singlet oxygen generation without heavy halogen atom assistance, Chem. Asian J. 2015, 10, 1335-1343. [abstract]

  2. Awuah, S. G.; Das, S.; D'Souza, F.; You, Y.* Thieno-pyrrole fused BODIPY intermediate as platform for multi-functiional NIR agents, Chemistry - An Asian Journal 2013, 8, 3123-3132. [abstract]

  3. Awuah, S. G.; You, Y.* Boron Dipyrromethene (BODIPY) Based Photosensitizers for Photodynamic Therapy. RSC Advances 2012, 2(30), 11169-11183.[abstract] - Review Article

  4. Awuah, S. G.; Polreis, J.; Biradar, V.; You, Y.,* Singlet oxygen generation by novel NIR BODIPY dyes, Org. Lett. 2011, 13, 3884-3887.[abstract]