Jayanth Panyam, PhD
Adjunct Pharmaceutics Faculty, Department of Pharmaceutics
Adjunct Pharmaceutics Faculty, Department of Pharmaceutics
Dean, Temple University School of Pharmacy
PhD in Pharmaceutical Sciences, University of Nebraska
MS in Pharmaceutics, Banaras Hindu University
Bachelor of Pharmacy, Tamil Nadu Dr. M.G.R. Medical University
Dr. Panyam’s research is primarily focused on investigating the mechanisms of nanotechnology-based anticancer drug delivery, with emphasis on understanding how various biological factors influence the effectiveness of delivery systems. The ultimate goal is to use the knowledge derived from these studies to devise advanced delivery systems that can be effectively translated to the clinic. Drug delivery systems that are in the ~100 nm size range are of considerable interest in the field of anti-cancer drug delivery. However, the therapeutic benefit of such systems (including liposomal doxorubicin - Doxil® and albumin-bound paclitaxel – Abraxane®) have been realized in only a subset of tumor types, and even in these tumors the survival benefits have been modest. A detailed understanding of the biological fate of delivery systems and, more importantly, in the microenvironment of the target tissue is necessary to further improve treatment efficacy
Dr. Panyam’s research is primarily focused on investigating the mechanisms of nanotechnology-based anticancer drug delivery, with emphasis on understanding how various biological factors influence the effectiveness of delivery systems. The ultimate goal is to use the knowledge derived from these studies to devise advanced delivery systems that can be effectively translated to the clinic.
Drug delivery systems that are in the ~100 nm size range are of considerable interest in the field of anti-cancer drug delivery. However, the therapeutic benefit of such systems (including liposomal doxorubicin - Doxil® and albumin-bound paclitaxel – Abraxane®) have been realized in only a subset of tumor types, and even in these tumors the survival benefits have been modest. A detailed understanding of the biological fate of delivery systems and, more importantly, in the microenvironment of the target tissue is necessary to further improve treatment efficacy
- Chlamydial infection
- Drug delivery
- Polymeric systems
- Sustained release
- Tumor targeting
Nanoparticle-based approaches to overcome tumor drug resistance
Development of drug resistance and the subsequent disease recurrence contribute to poor long-term survival rates with many solid tumors. A number of new drugs including novel molecularly targeted agents are in clinical trials. There is also a significant interest in the use of nano delivery systems to improve the tumor-specific delivery of existing drugs. However, a key challenge is the limited distribution of these delivery systems within the tumor tissue. Elevated solid stress and interstitial fluid pressure (IFP) inhibit diffusive and convective movements within tumors, resulting in inefficient transport of drug carriers and heterogeneous local drug concentrations. Poor penetration of the drug carrier and the consequent lack of therapeutic drug levels in under-perfused regions of the tumor result in the ineffective elimination of cancer stem cells (CSCs), which are implicated in the development of drug resistance and disease recurrence. New clinical strategies that can effectively target and eradicate CSCs will significantly improve the currently dismal therapeutic outcomes in cancer.
Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) is a key factor contributing to the ability of CSCs to survive toxic drug concentrations. Inhibition of efflux transporters is a promising approach to overcome resistance, but currently available inhibitors suffer from disadvantages that limit their clinical use. Dr. Panyam investigated dual transporter-inhibition and drug delivery approach using targeted nanoparticles to overcome MDR. His group is evaluating both small molecules for functional inhibition and siRNA for silencing transporter expression.
Initial efforts focused on developing novel strategies to introduce various targeting ligands on the surface of nanoparticles. Until recently, incorporation of targeting ligands and other functionalities on the surface of a drug carrier posed a major technical challenge. Historically, introduction of multiple functionalities required tedious and inefficient sequential labeling/purification. To overcome this difficultly, Dr. Panyam’s group developed a novel ‘Interfacial Activity Assisted Surface Functionalization’ (IAASF) strategy, which allows the facile and simultaneous introduction of multiple ligands and functional groups onto the surface of drug-loaded polymeric nanoparticles. This methodology, along with application to tumor targeting, was published in Biomaterials (impact factor 8.38).
- Patil, Y., Toti, U., Khdair, A., Ma, L., and Panyam, J.* (2009) Facile Single-Step Multifunctionalization of Nanoparticles for Targeted Drug Delivery. Biomaterials, 30(5):859-66. (citations 154)
The IAASF technique was utilized to develop tumor-targeted nanoparticles that can simultaneously deliver an anticancer drug, such as paclitaxel, and a functional inhibitor of efflux transport. Third-generation dual P-gp and BCRP inhibitors like tariquidar have shown promising efficacy in early clinical trials. However, for maximum efficacy, it is important to limit the exposure of normal cells and tissues to the efflux inhibitor and the anticancer drug, and temporally co-localize the drug-inhibitor combination in the tumor cells. In vivo studies in a mouse model of drug-resistant tumor demonstrated significantly greater inhibition of tumor growth following treatment with targeted nanoparticles encapsulating both paclitaxel and tariquidar at a paclitaxel dose that was ineffective in the absence of tariquidar. These findings were published in the Journal of Controlled Release (impact factor 7.44).
- Patil, Y., Sadhuka, T., and Panyam, J.* (2009) Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance. J Controlled Release, 136(1):21-9. (citations 222)
Inhibition of protein expression using RNA interference is often more specific than functional inhibition using small molecules. Dr. Panyam has been investigating siRNA-mediated RNA interference as an alternate approach to overcome tumor drug resistance. In this strategy, the MDR1gene encoding for P-gp was silenced using targeted siRNA. As with tariquidar, the approach here is to achieve simultaneous gene silencing and drug delivery using tumor-targeted nanoparticles. However, unlike with tariquidar, formulation of siRNA in nanoparticles was a significant challenge; low loading efficiencies and insufficient release profiles were overcome by incorporating a cationic polymer, polyethyleneimine, in nanoparticles (International Journal of Pharmaceutics; impact factor 3.06). As in the case of tariquidar, significant tumor growth inhibition was achieved in mice with targeted nanoparticles encapsulating both paclitaxel and P-gp-targeted siRNA at a paclitaxel dose that was ineffective in the absence of gene silencing. These findings were published in Biomaterials (impact factor 8.38).
- Patil, Y., Swaminathan, S., Sadhuka, T., Ma, L., and Panyam, J.* (2010) The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance. Biomaterials, 31(2): 358-365. (citations 207)
Dr. Panyam has also been involved in developing antibodies and scFvs that could be used as ligands for specific targeting of CSCs. In collaboration with Dr. John Ohlfest and Dan Vallera (UMN), Dr. Panyam has developed a CD133 (membrane-marker for CSCs)-targeted monoclonal antibody and scFv for targeting CSCs. The results, which had several profound implications, were published in several journals including J Immunological Methods and Drug Delivery and Translational Research. In triple negative breast cancer xenografts, CD133-targeted paclitaxel nanoparticles were highly effective in inhibiting tumor growth. These findings were published in the Journal of Controlled Release (impact factor 7.44).
- Swaminathan, S., Niu, L., Roger, E., Ohlfest, J., Panyam, J.* (2013) CD133-Targeted Paclitaxel Delivery Inhibits Local Tumor Recurrence in a Mouse Model of Breast Cancer. J Controlled Release, 171(3): 280-7. (citations 63)
Another key barrier to the success of anticancer nanomedicine formulations is their poor intra-tumoral distribution and limited drug delivery to tumor cells. Recent investigations in Dr. Panyam’s laboratory have shown that human lung tumors are characterized by extensive deposition of fibrin in the extracellular matrix. The presence of fibrin is an important cause of elevated interstitial fluid pressure (IFP) in tumors. Elevated IFP, in turn, results in increased resistance to convective transport of drug carriers in the tumor matrix and decreases the amount of drug reaching tumor cells. To mimic the natural ability of tumor cells to secrete tissue digesting enzymes that enables the cells to easily traverse the tumor ECM, Dr. Panyam is investigating the co-delivery of fibrinolytic enzymes such as tissue plasminogen activator (tPA). This enzyme activates human plasminogen to plasmin and triggers lysis of the fibrin clot. In fact, it is used as a clot-dissolving agent for treatment of heart attack or pulmonary embolism victims. Studies in lung cancer models show that fibrinolytics can significantly improve the therapeutic efficacy of co-delivered anticancer drugs. These findings were published in Cancer Res (impact factor 8.56).
- Kirtane, A.R., Sadhukha, T., Kim, H., Khanna, V., Koniar, B., Panyam, J.* (2017) Fibrinolytic enzyme co-therapy to improve tumor perfusion and therapeutic efficacy of anticancer nanomedicine. Cancer Res, 77(6):1465-1475. (citations not available)
Targeted magnetic hyperthermia for lung cancer
Lung cancer (specifically, non-small cell lung cancer; NSCLC) is the leading cause of cancer-related deaths in the United States. Poor response rates and survival with current treatments clearly indicate the urgent need for developing an effective means to treat NSCLC. Magnetic hyperthermia is a non-invasive approach for tumor ablation, and is based on heat generation by magnetic materials, such as superparamagnetic iron oxide (SPIO) nanoparticles, when subjected to an alternating magnetic field. However, inadequate delivery of magnetic nanoparticles to tumor cells can result in sub-lethal temperature change and induce resistance while non-targeted delivery of these particles to the healthy tissues can result in toxicity. To overcome these problems, we are investigating aerosol-based, tumor-targeted SPIO nanoparticles to induce highly selective tumor cell kill. Tumor cell specificity is achieved by targeting SPIO nanoparticles to the epidermal growth factor receptor (EGFR), whose overexpression has been observed in as many as 70% of NSCLC patients.
In the initial studies, EGFR-targeted, inhalable SPIO nanoparticles were synthesized and characterized for targeting lung tumor cells as well as for magnetic hyperthermia-mediated antitumor efficacy in a mouse orthotopic model of NSCLC. Our results show that EGFR targeting enhances tumor retention of SPIO nanoparticles. Further, magnetic hyperthermia treatment using targeted SPIO nanoparticles resulted in significant inhibition of in vivo lung tumor growth (published in Biomaterials 2013).
- Sadhukha, T., Wiedmann, T.S., Panyam, J.* (2013) Inhalable Magnetic Nanoparticle Mediated Targeted Magnetic Hyperthermia for Lung Cancer Therapy. Biomaterials, 34(21); 5163-71. (citations 75)
Our studies also showed that magnetic hyperthermia can effectively eradicate CSCs (published in Molecular Pharmaceutics 2013). As a part of these studies, we also discovered that the extent and mechanism of hyperthermia-induced cell kill is highly dependent on the aggregation state of SPIO nanoparticles. Well-dispersed nanoparticles induced apoptosis, similar to that observed with conventional hyperthermia. Sub-micron size aggregates, on the other hand, induced temperature-dependent autophagy through generation of oxidative stress. Micron size aggregates caused rapid membrane damage, resulting in acute cell kill. Overall, this work demonstrates the potential for developing an effective anticancer treatment modality for the treatment of NSCLC based on targeted magnetic hyperthermia (published in Biomaterials 2014).
- Niu, L., Panyam, J.* (2017) Freeze Concentration-Induced Nanoparticle Aggregation: Imaging and Rational Design of Cryoprotection. J Controlled Release, 248:125-132. (Featured as the cover story and on the cover of the issue).
- Schmohl, J.U., Felices, M., Oh, F., Lenvik, A.J., Lebeau, A.M., Panyam, J., Miller, J.S., and Vallera. D.A. (2017) Engineering of anti-CD133 Tri-specific molecule capable of inducing NK expansion and driving antibody-dependent cell-mediated cytotoxicity (ADCC). Cancer Res Treat. In Press.
- Kirtane, A., Rothenberger, M.K., Frieberg, A., Nephew, K., Schultz-Darken, N., Schmidt, T., Reimann, T., Schlievert, P., Haase, A.T., Panyam, J.* (2017) Evaluation of pharmacokinetics and safety of a glycerol monolaurate vaginal cream in rhesus macaques. J Pharm Sci, 106(7):1821-1827.
- Grill, A., Shahani, K., Koniar, B., Panyam, J.* (2017) Chemopreventive efficacy of curcumin loaded PLGA microparticles in a transgenic mouse model of Her-2 positive breast cancer. Drug Del Translational Res, In Press.
- Kirtane, A.R, Panyam, J., Siegel, A.R. (2017) Assessing the benefits of drug delivery by nanocarriers: a partico/pharmacokinetic framework. IEEE Trans Biomed Engg, In Press.
- Toti U., Grill A.E. and Panyam J. (2010) Interfacial activity assisted surface functionalization: A novel approach to incorporate maleimide functional groups and cRGD peptide on polymeric nanoparticles for targeted drug delivery. Mol. Pharm. (in press).
- Shahani K., Swaminathan S., Freeman D., Blum A., Ma L. and Panyam J. (2010) Injectable sustained release microparticles of curcumin: A novel concept for chemoprevention. Cancer Res. 70(11): 4443-4452.
- Patil Y., Swaminathan S., Sadhukha T., Ma L. and Panyam J. (2010) The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance. Biomaterials 31(2): 358-365.
- Khdair A., Chen D., Dou P., Shekar M.P.V. and Panyam J. (2010) Nanoparticle-mediated combination photodynamic therapy and chemotherapy overcomes tumor drug resistance in vivo. J. Controlled Release 141(2): 137-144.
- Patil Y., Sadhukha T. and Panyam J. (2009) Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance. J. Controlled Release 136(1): 21-29.
- Patil Y., Toti U., Khdair A., Ma L. and Panyam J. (2009) Facile single-step multifunctionalization of nanoparticles for targeted drug delivery. Biomaterials 30(5): 859-866.
- Patil Y. and Panyam J. (2009) Polymeric nanoparticles for siRNA delivery and gene silencing. Int. J. Pharm. 367(102): 195-203.
- Khdair A., Handa H., Mao G. and Panyam J. (2009) Nanoparticle-mediated combination photodynamic therapy and chemotherapy overcomes tumor drug resistance in vitro. Eur. J. Pharm. Biopharm. 71(2): 214-222.