Nano-Delivery: Nucleic Acids, Cancer Immunotherapy and Beyond

Nanoparticle-based drug delivery enables sophisticated tactics to fight disease. With their small size and their intricate engineering, nanoparticles can improve control over drug release profiles, both spatially as well as temporally, and can reduce harmful side effects. Furthermore, improved targeting and shielding capabilities allow for more favorable pharmacokinetic and pharmacodynamic profiles. Nano-delivery options are of special interest in the oncology field, as the enhanced permeability and retention (EPR) effect can improve drug retention in tumor sites. Current immunotherapy and nucleic acid delivery approaches are limited in their safety and efficacy. Due to the inherent flexibility in particle size, shape, charge, ligand functionalization, and density, nanotechnology can help open avenues to patient-specific treatments of different diseases. However, since nanoparticle drug delivery systems are so intricately designed and sophisticated, this can cause problems when translating these technologies from in vivo models to the clinic. Cambridge Healthtech Institute’s Second Annual Nano-Delivery conference is here to bring together innovators and drug discovery scientists to discuss strategies to accelerate the translation of nanoparticle drug delivery vehicles.

Final Agenda

Thursday, June 15

12:00 pm Registration


5:30 Chairperson’s Opening Remarks

Anil K. Sood, M.D., Professor, Department of Gynecologic Oncology and Department of Cancer Biology, MD Anderson Cancer Center

5:40 Nucleic Acid Delivery Systems for RNA Therapy and Gene Editing

Daniel_AndersonDaniel G. Anderson, Ph.D., Associate Professor, Department of Chemical Engineering, Institute for Medical Engineering and Science, Harvard-MIT Division of Health Sciences & Technology, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

High throughput, combinatorial approaches have revolutionized small molecule drug discovery. Here we describe our work on high throughput methods for developing and characterizing RNA delivery and gene editing systems. Libraries of degradable polymers and lipid-like materials have been synthesized, formulated and screened for their ability to deliver RNA, both in vitro and in vivo. A number of delivery formulations have been developed with in vivo efficacy, and show potential therapeutic application for the treatment of genetic disease, viral infection, and cancer.

6:10 Systemic in vivo siRNA Delivery Using Biocompatible Nanoparticles

Anil_SoodAnil K. Sood, M.D., Professor, Department of Gynecologic Oncology and Department of Cancer Biology, MD Anderson Cancer Center

Use of short interfering RNA (siRNA) as a method of gene silencing has rapidly become a powerful tool in protein function delineation, gene discovery, and drug development. To overcome existing limitations for therapeutic use of siRNA, we have developed a number of biocompatible nanoparticle strategies including DOPC, chitosan, and other nanoparticle platforms. In addition, we have also peptide and thioaptamer-based approaches for highly selective delivery. Collectively, these approaches offer new opportunities for therapeutic gene silencing.

6:40 End of Day

FRIDAY, June 16


8:30 am Chairperson’s Remarks

Frank Loganzo, Ph.D., Director, Oncology Research and Development, Pfizer

8:40 Role of Macrophages in Nanoparticle-Mediated Drug Targeting to Cancer Stem Cells

Esmaiel_JabbariEsmaiel Jabbari, Ph.D., Professor, Chemical Engineering, University of South Carolina

A major contributing factor to mortality in cancer patients is relapse after surgery and targeted therapy, and developing resistance to therapy. Breast cancer recurrence affects 30% of the patients. Cancer recurrence and resistance is related to the existence of a very small population of initiating cells or stem cells (CSCs) in the tumor tissue with high expression of ATP-binding cassette (ABC) transporter proteins associated with drug resistance. After therapy, the bulk of tumor shrinks to <1% of its initial volume and the tumor tissue becomes enriched with CSCs that are highly resistant to conventional therapies. Further, as much as 40% of the volume of solid tumors is occupied by tumor-associated macrophages (TAMs), specifically immunosuppressive M2-macrophages, which play a central role in cancer progression. One approach to overcome carrier-mediated drug resistance in CSCs is to use nanoparticles (NPs) for drug encapsulation and intracellular delivery by endocytosis. Unlike drug molecules in which their uptake is affected by up-regulation of ABC transporter proteins, NPs utilize macropinocytosis, clathrin- and caveolin-mediated endocytosis for transcellular cell uptake. Although the uptake of NPs by the mononuclear phagocyte system (MPS) and NPs’ enhanced permeation and retention in the tumor tissue is extensively investigated, little is known about the role of TAMs on uptake and toxicity of drug-loaded NPs toward CSC sub-population of cancer cells. Results on the effect of macrophages on toxicity of Paclitaxel conjugated to polyhedral oligosilsesquioxane (POSS) NPs toward breast CSCs in a novel 3D culture system will be presented.

9:10 Targeting Approaches for Cancer: ADCs and Nanoparticles

Frank_LoganzoFrank Loganzo, Ph.D., Director, Oncology Research and Development, Pfizer

Antibody-drug conjugates (ADCs) and nanoparticles are complementary approaches for the treatment of cancer. The development and application of linker-payloads for ADCs will be introduced, including opportunities for immune activation. Similarly, a polymeric nanoparticle platform with tunable features can be utilized for tumor targeting and immune modulation. There are multiple strategies to broaden the types of drugs encapsulated in nanoparticles, and various approaches to empower nanoparticles with targeting moieties to potentially enhance tumor distribution

9:40 Delivery of Tumor Necrosis Factor (TNF) to Tumors

Lawrence_TamarkinLawrence Tamarkin, Ph.D., President & CEO, CytImmune

Nanomedicines, under 100 nm, target tumors by exiting the circulation through leaky tumor blood vessels. However, other similar-sized blood components also leak into the tumor interstitial space, creating a high interstitial fluid pressure (IFP) – a physical barrier preventing systemic cancer treatments from reaching their target, the cancer cells. By design, CYT-6091 and CYT-21000 are two nanomedicines that deliver tumor necrosis factor (TNF) to tumors, causing vascular disruption and reducing IFP. CYT-21000 also delivers paclitaxel.

10:10 Coffee Break


10:40 Improving Cancer Immunotherapy with Antigen-Capturing Nanoparticles

Andrew_WangAndrew Wang, M.D., Associate Professor, Director of Clinical and Translational Research, Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill

We report an improved cancer immunotherapy approach through the use of antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NPs formulations, and we demonstrated that the set of protein antigens captured by each NP is dependent on NP surface properties. We showed that AC-NPs can deliver captured proteins to antigen-presenting cells and significantly improve the efficacy of αPD-1 treatment in the B10F10 melanoma model, generating up to 20% cure rate as compared to 0% without AC-NP.

11:10 Modulating Tumor Microenvironment via Nano-Carriers to Enhance Delivery and Function of Therapeutics and Anti-Tumor Lymphocytes

Zoreh_AmoozgarZohreh Amoozgar, Pharm.D., Ph.D., Postdoctoral Research Fellow, Radiation Oncology, MGH, Harvard Medical School

Tumor microenvironment (TME) consists of tumor cells, lymphocytes, stromal cells, tumor associated vasculature and tumor supportive matrix. TME evades host’s anti-tumor immunity and resists anti-cancer treatments. In order to find effective therapeutics, multiple elements of tumor microenvironment should be targeted to reduce resistance to therapy. Multi-compartment nano-carriers have the potential to deliver drugs to tumor cells, target stromal cells and tumor matrix with synergistic effect with host’s immune system.

11:40 Selected Poster Presentation: A New Strategy to Deliver Anti-cancer Nanodrugs and Decrease their Toxic Side Effects by Temporarily Blunting the RES Uptake using Intralipid®

Li Liu, Ph.D., Research Biologist, Department of Biological Sciences, Carnegie Mellon University

We have developed a novel strategy to temporarily blunt the reticuloendothelial system (RES) uptake of nanoparticles, a major challenge for nanoparticle delivery, by using an FDA approved lipid emulsion, Intralipid®. We have tested our new strategy by using nano- and micron-sized imaging agents, an in-development platinum-containing nanodrug, and FDA approved anti-cancer nanodrugs, e.g., Abraxane®, Marqibo®, and Onivyde®, to decrease their RES uptake and reduce their toxic side effects in liver, spleen, and kidney.

11:55 pm Enjoy Lunch on Your Own


1:40 pm Chairperson’s Remarks

R. James Christie, Scientist, Antibody Discovery and Protein Engineering, MedImmune

1:50 Delivery of Self-Amplifying Replicon-Based RNA Vaccines

Jeff_UlmerJeffrey Ulmer, Head, Preclinical R&D US, GSK Vaccines

Recent advancements have demonstrated that vaccines based on self-amplifying mRNA have the potential to combine the positive attributes of other types of vaccines without their limitations. Although the mRNA vaccine field is in its infancy, the prospects are promising. The broad utility and rapid response potential of this novel vaccine technology may enable a new generation of vaccines able to address the health challenges of the 21st century. A key enabler of success will be efficient delivery of the synthetic RNA payload.

2:20 in vivo Delivery of CRISPR/Cas9

Hao_YinHao Yin, Ph.D., Research Scientist, The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

CRISPR/Cas9 genome editing has been applied to correct disease-causing mutations in human cell lines, but delivery to adult mammalian organs to correct genetic disease genes has not been reported prior to our study. We indicate that, for the first time, CRISPR/Cas9-mediated genome editing is feasible in adult animals. In our second study, we combined lipid nanoparticle-mediated delivery of Cas9 mRNA with adeno-associated viruses encoding an sgRNA and a repair template to induce gene repair in disease animals.

2:50 Site-Specific Protein-Nanoparticle Conjugates for Cellular Targeting

Jim_ChristieR. James Christie, Scientist, Antibody Discovery and Protein Engineering, MedImmune

Targeted nanoparticles offer therapeutic potential to deliver drugs or manipulate biological targets at specific sites in the body. Here, strategies for site-specific attachment of cysteine-engineered antibody fragments (Fabs) to nanoparticles as well as characterization methods to determine the number of Fabs per nanoparticle are presented. Evaluation of cell uptake comparing targeted nanoparticles, Fabs, and mAbs demonstrated that targeted nanoparticles achieved higher cell uptake when a dimerizing receptor was targeted.

3:20 CriPec® Oligonucleotides for a Superior Therapeutic Performance

Cristianne_RijckenCristianne J.F. Rijcken, Pharm.D., Ph.D., Founder and CSO, Cristal Therapeutics

Cristal Therapeutics develops CriPec® nanomedicines with enhanced efficacy and less off-target toxicity. The lead product, CriPec® docetaxel, is in clinical development for the treatment of solid tumors. CriPec® oligonucleotides aim to overcome the traditional hurdles via prolonged circulation, less charge-related side effects, increased tumor accumulation, selective cellular uptake and potential for control of endosomal escape. CriPec® products are fully customizable and biocompatible, with a robust manufacturability at clinical scale.

3:50 Close of Symposium

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