This is the fifth article in a review series on Nanomedicine. In Part I and Part II, we reviewed the major research and entrepreneurial development of nanomedicine and the relevant patent landscape. We then began to introduce specific fields in nanomedicine, such as Organs-on-a-chip (Part III) and Nanoparticle drug delivery (Part IV). Here, we will continue the discussion of nanoparticle drug delivery specifically for the field of cancer therapy.

Cancer Therapeutics

Cancer is one of the deadliest diseases threatening humanity worldwide, regardless of age, gender, or socio-economic status. GLOBOCAN 2012 estimated 14.1 million new cancer cases and approximately 8.2 million deaths around the world in 2012. It is also expected the number of new cases will rise to 19.3 million per year by 2025 and that deaths will be greater than13 million per year by 2030. Currently the main methods for cancer therapy are surgery, chemotherapy, radiation, and immunotherapy. However, conventional cancer therapies, and particularly the gold standard of chemotherapy, can be rather nonspecific, targeting the whole body, affecting both cancer cells and normal cells, thus require high doses. Chemotherapy often results in high toxicity and low therapeutic indices. Additionally, many cancer drugs have low water solubility, which adds further challenges for their treatment efficiency. Thus, it is crucial to develop new methods to address these challenges in cancer therapies.

Nanoparticles for Cancer Drug Delivery

Nanoparticles, due to their unique structure, often possess an enhanced permeability and retention (EPR) effect. These particles can preferentially accumulate in tumors, resulting in higher drug concentrations at targeted sites and consequently higher therapeutic efficacy with lower toxicity for surrounding normal tissue. Also nanoparticle carriers can be designed to encapsulate and deliver cancer drugs having poor water solubility. These favorable characteristics render nanoparticles as promising potential delivery systems for cancer therapies.

Today, the nanoparticle drug delivery platforms are typically liposomes, nanoparticle albumin-bound (nab) technology, polymeric nanoparticles, and metal nanoparticles. Liposomes are biocompatible and biodegradable and can encapsulate both hydrophilic and hydrophobic agents to improve the pharmacokinetics and biodistribution of drugs. The first FDA approved nanoparticle drug delivery product, Doxil (doxorubin liposomes), for the treatment of AIDS-associated Kaposi’s Sarcoma, was based on this technique (US 5,192,549). Nab technology utilizes albumin, a natural carrier of hydrophobic molecules, to mediate the transcytosis (a transcellular transport of macromolecules enclosed in membrane carriers) of albumin-bound molecules to deliver chemotherapeutic drugs. The first commercial nab product was Abraxane (nab-paclitaxel), approved for treating metastatic breast cancer in 2005 (US 6,537,579). Polymeric nanoparticles are mostly formed by self-assembling block-copolymers into a core-shell structure in an aqueous environment, with a hydrophobic core and a hydrophilic shell to stabilize the structure. Usually polymeric nanoparticles have a high loading capacity for either hydrophilic or hydrophobic small molecular drugs, as well as macromolecules, e.g., proteins and nucleic acids. Genexol-PM (paclitaxel-loaded polymeric micelles) was developed by Samyang Corporation and marketed in Europe and Korea (US 6,322,805). Metallic nanoshells, generally formed of gold or titanium, have been developed as both image contrast agents and chemotherapy drug delivery carriers. However, most of these metallic nanoparticles are still in the preclinical stage due to the latent toxicity of metal particle residues in the human body.

In the future, one of the potential improvements for nanoparticle drug delivery is molecular target nanoparticles. This technique combines molecular targeting and nanoparticle delivery by functionalizing the nanoparticle’s surfaces with targeting ligands to bind to tumor-specific surface markers and therefore enhance the uptake of the nanoparticles by the tumor. This technique results in higher intratumoral drug concentrations, reduced toxicity for normal tissues (because the normal tissues would lack the surface markers), and improved therapeutic efficacy. BIND-014, developed by Dr. Langer at MIT, and licensed to BIND Therapeutics, is a docetaxel-encapsulated nanoparticle targeting the prostate-specific membrane antigen (PSMA) (US patent 8,709,483). This past April, its Phase II trial in advanced non-small cell lung cancer (NSCLC) of squamous histology showed meaningful results with 65% of subjects exceeding the protocol defined success criteria. Another improvement is the development of nanoparticles capable of delivering a combination chemotherapeutics. CPX-351, a liposomal formulation of cytarabine and daunorubicin being developed by Celator Pharmaceuticals, combines the delivery of radiosensitizer and chemosensitizer to improve the therapeutic efficacy (US 8,022,279). Celator announced positive clinical results from the Phase 3 trial of CPX-351 in patients with high-risk acute myeloid leukemia (AML) this past March.

Click here to view table.http://www.dilworthip.com/nanomedicine-part-v-nanoparticle/

Current Pharmaceutical Development

Today, there are several clinically approved nanoparticle cancer drugs: Doxil (1995, ovarian, breast cancer); DaunoXome (1996, HIV-related Kaposi sarcoma); Ferumoxide (1997, liver imaging); Genexol-PM (breast cancer/small cell lung cancer); marketed in Europe and Korea); Depocyt (1999, lymphomatous meningitis); Myocet (2000, breast cancer, in Europe and Canada); Zevalin (2002, non-Hodgkin’s lymphoma); Abraxane (2005, metastatic breast cancer); and Oncaspar (2006, acute lymphoblastic leukemia). In addition to the clinically approved nanoparticle therapeutics, many other preclinical and clinical investigations on nanoparticle drug delivery systems are ongoing. Dr. Davis’s group at California Institute of Technology developed CRLX101, a cyclodextrin conjugated cancer drug camptothecin, to improve biocompatibility and therapeutic efficacy (US 8,110,179). They also utilized this conjugate to encapsulate siRNA, CALAA-01, for cancer therapy (US 8,557,292). Dr. Hanes developed polymeric particles with polyethylene glycol (PEG) coating to enhance the cancer drug delivery across mucous barriers (US 8,957,034). Dr. Soon-Shiong at Abraxis Bioscience continues the development of nab technique for various cancer treatment (US 9,399,071 and US 9,393,318). Alza Corporation further optimizes the liposome cisplatin nanoparticle system, SPI-077, developed by Sequus Pharmaceuticals (US 6,126,966), to target egfr receptor for better cancer drug delivery (US 8,834,920). Nippon Kayaku Co. developed PEG-poly aspartate nanoparticle to encapsulate doxorubicin, NK 911, for various cancer treatment (US 7,138,490). Supratek Pharma Inc. also developed glycoprotein micelle form of doxorubicin, SP1049C, for cancer treatment (US 8,148,338).

Recently, the success of nanoparticle drug delivery has also caught the eye of researchers and venture investors. In 2010, Abraxis BioScience, maker of Abraxane, was acquired by Celgene in cash-and-stock in a deal valued at over $3 billion. In 2015, NantPharma bought Cynviloq™ (paclitaxel nanoparticle polymeric micelle) from Sorrento Therapeutics for up to $1.3 billion. This July, BIND Therapeutics received the top bid from Pfizer for $40 million for its Section 363 auction (bankruptcy sale). This bid lets Pfizer add a cancer candidate, BIND-014, to its drug development portfolio.

Summary

Nanoparticle drug delivery is predicted to alter the future landscape of the pharmaceutical and biotechnology industries. Currently, the pipelines of pharmaceutical companies are facing challenges. A number of blockbuster drugs will come off patent in the near-term. It is crucial and urgent for many of these pharmaceutical companies to develop novel techniques and add new products to their pipelines for future market growth. Nanoparticle technology holds enormous promise for drug delivery due to its unique characteristics and has great potential to pave the road for new drug delivery systems. Let’s witness the coming revolution in this brilliant field.